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CXCR4SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis and adhesion. The role of PAX3-FKHR in expression of CXCR4
... These prochemotactic compounds belong to families of chemokines, growth factors, bioactive lipids, and some small molecules known as alarmines78917] . Chemokines and some proangiopoietic growth factors are released from the damaged tissues in response to damage-related hypoxia involving hypoxia-inducible factor 1 alpha (HIF-1α) [47] activation of transcription of genes encoding chemokines (e.g., SDF- 1; interleukin 8, IL-8)48495051 and selected growth factors (e.g., vascular endothelial growth factor, VEGF) that are primarily involved in promoting vascularization of damaged organs. Also released from damaged cells during tissue/organ injury are so-called alarmines or damage-associated molecular pattern molecules (DAMPs, also known as danger-associated molecular pattern molecules), which can initiate and perpetuate immune responses and subsequent repair processes [52,53] . ...
... This mechanism plays an important role, primarily in metastasis of malignant cells to the tissues susceptible to the toxic effects of chemotherapy or radiotherapy, such as bones, lungs, liver and abdominal and pelvic cavities. Nevertheless, in several well-controlled animal experimental models, it has been demonstrated that blockade of CXCR4 [50], CXCR7 [95], or c-Met [81] receptors by employing small molecular inhibitors; downregulation of these receptors by shRNA strategies [95] ; in vivo administration of blocking antibodies against SDF-1 [50,61,96] or MCP-1 [80]; or application of S1P-binding aptamers [17] significantly diminished the process of chemotherapy-or radiotherapy-related dissemination of tumor cells to various organs. However, the future of potent anti-metastatic drugs will depend on molecules that interfere with migration and adhesion processes of CSCs and DTCs downstream of surface receptors. ...
... This mechanism plays an important role, primarily in metastasis of malignant cells to the tissues susceptible to the toxic effects of chemotherapy or radiotherapy, such as bones, lungs, liver and abdominal and pelvic cavities. Nevertheless, in several well-controlled animal experimental models, it has been demonstrated that blockade of CXCR4 [50], CXCR7 [95], or c-Met [81] receptors by employing small molecular inhibitors; downregulation of these receptors by shRNA strategies [95] ; in vivo administration of blocking antibodies against SDF-1 [50,61,96] or MCP-1 [80]; or application of S1P-binding aptamers [17] significantly diminished the process of chemotherapy-or radiotherapy-related dissemination of tumor cells to various organs. However, the future of potent anti-metastatic drugs will depend on molecules that interfere with migration and adhesion processes of CSCs and DTCs downstream of surface receptors. ...
There are well-known side effects of chemotherapy and radiotherapy that are mainly related to the toxicity and impaired function of vital organs; however, the induction by these therapies of expression of several pro-metastatic factors in various tissues and organs that in toto create a pro-metastatic microenvironment is still, surprisingly, not widely acknowledged. In this review, we support the novel concept that toxic damage in various organs leads to upregulation in "bystander" tissues of several factors such as chemokines, growth factors, alarmines, and bioactive phosphosphingolipids, which attract circulating normal stem cells for regeneration but unfortunately also provide chemotactic signals to cancer cells that survived the initial treatment. We propose that this mechanism plays an important role in the metastasis of cancer cells to organs such as bones, lungs, and liver, which are highly susceptible to chemotherapeutic agents as well as ionizing irradiation. This problem indicates the need to develop efficient anti-metastatic drugs that will work in combination with, or follow, standard therapies in order to prevent the possibility of therapy-induced spread of tumor cells.
... Moreover, we have succeeded in suppressing post-chemotherapeutic leukemic regrowth in the hepatic niche by inhibiting the SDF-1/CXCR4 axis, thus resulting in an improvement in the overall survival. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells [18,19] or leukemic niches such as bone marrow [20], we demonstrated that this axis works even in the extramedullary niche of leukemic cells. These results provide a better understanding of the mechanisms of the extramedullary dissemination and aid in the development of ALL therapies that target the extramedullary niche. ...
... The SDF-1/CXCR4 axis is a key factor in the migration and proliferation of various cells, including neoplastic cells in vivo [18,19,28]. Thus, we sought to directly examine the influence of the SDF-1/CXCR4 axis on leukemic cell migration and proliferation. ...
... We also demonstrated that the SDF-1/CXCR4 axis plays a crucial role in causing liver pathology. Recent studies revealed SDF- 1/CXCR4 axis involvement in the development and metastasis of solid tumor [18,19]. This axis has also been known to play an indispensable role in the homing, proliferation, and survival of both normal hematopoietic and leukemic cells in the BM niche [18,29,30,31,32,33,34,35] . ...
In acute lymphoblastic leukemia (ALL) patients, the bone marrow niche is widely known to be an important element of treatment response and relapse. Furthermore, a characteristic liver pathology observed in ALL patients implies that the hepatic microenvironment provides an extramedullary niche for leukemic cells. However, it remains unclear whether the liver actually provides a specific niche. The mechanism underlying this pathology is also poorly understood. Here, to answer these questions, we reconstituted the histopathology of leukemic liver by using patients-derived primary ALL cells into NOD/SCID/Yc (null) mice. The liver pathology in this model was similar to that observed in the patients. By using this model, we clearly demonstrated that bile duct epithelial cells form a hepatic niche that supports infiltration and proliferation of ALL cells in the liver. Furthermore, we showed that functions of the niche are maintained by the SDF-1/CXCR4 axis, proposing a novel therapeutic approach targeting the extramedullary niche by inhibition of the SDF-1/CXCR4 axis. In conclusion, we demonstrated that the liver dissemination of leukemia is not due to nonselective infiltration, but rather systematic invasion and proliferation of leukemic cells in hepatic niche. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells or leukemic niches such as bone marrow, we demonstrated that this axis works even in the extramedullary niche of leukemic cells. Our findings form the basis for therapeutic approaches that target the extramedullary niche by inhibiting the SDF-1/CXCR4 axis.
... Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in children [21]. CXCR4 is highly expressed on the surface of RMS cells, with higher expression in the more clinically aggressive alveolar subtype of RMS compared to the embryonal subtype [21, 22]. High CXCR4 expression also correlates with unfavorable primary sites, advanced stage, marrow involvement, decreased overall survival, and eventfree survival in RMS [23]. ...
... High CXCR4 expression also correlates with unfavorable primary sites, advanced stage, marrow involvement, decreased overall survival, and eventfree survival in RMS [23]. CXCL12 has no effect on the proliferation or survival of RMS cells, but does stimulate processes related to cell invasion and metastasis [22]. CXCL12 increases adhesion of RMS cells to endothelium. ...
... CXCL12 increases adhesion of RMS cells to endothelium. RMS cells also follow a directional chemotaxis towards bone marrow stroma, a CXCL12-rich environment, which may indicate a role of CXCR4 in tendency of RMS to preferentially metastasize to bone marrow [21, 22]. However, CXCL12 did not increase the survival of RMS cells exposed to radiation or chemotherapy, indicating that CXCR4 may not play a role in the development of treatment resistance [24]. ...
The molecular basis of sarcoma remains poorly understood. However, recent studies have begun to uncover some of the molecular pathways involved in sarcomagenesis. The chemokine receptor CXCR4 has been implicated in sarcoma development and has been found to be a prognostic marker for poor clinical outcome. There is growing evidence that overexpression of CXCR4 plays a significant role in development of metastatic disease, especially in directing tumor cells towards the preferential sites of metastases in sarcoma, lung and bone. Although further investigation is necessary to validate these pathways, there is potential for clinical application, particularly in the use of pharmacologic inhibitors of CXCR4 as means of preventing sarcoma metastasis.
... Moreover, in some instances, CXCR4 may not be responsible for invasion but rather is critical for the outgrowth of micrometastases [109]. CXCR4 and CXCR7 were both identified in RMS cells, which play overlapping and distinct roles in regulating metastatic behavior [110, 111]. CXCR4 was more highly expressed on the more metastatic alveolar RMS cell lines than on the less metastatic lines derived from embryonal RMS (ERMS) [111]; yet, the expression of CXCR7 is inverse [110] . ...
... CXCR4 and CXCR7 were both identified in RMS cells, which play overlapping and distinct roles in regulating metastatic behavior [110, 111]. CXCR4 was more highly expressed on the more metastatic alveolar RMS cell lines than on the less metastatic lines derived from embryonal RMS (ERMS) [111]; yet, the expression of CXCR7 is inverse [110] . Although CXCL12 did not affect proliferation or survival of these cell lines through CXCR4 or CXCR7, migration, chemotaxis, and adhesion were often observed [111]. ...
... CXCR4 was more highly expressed on the more metastatic alveolar RMS cell lines than on the less metastatic lines derived from embryonal RMS (ERMS) [111]; yet, the expression of CXCR7 is inverse [110] . Although CXCL12 did not affect proliferation or survival of these cell lines through CXCR4 or CXCR7, migration, chemotaxis, and adhesion were often observed [111]. In other findings, it was observed that hypoxia enhances both CXCR4 and CXCR7 promoter activity and receptor expression in ERMS cells [112]. ...
Chemokines, small pro-inflammatory chemoattractant cytokines that bind to specific G-protein-coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The chemokine CXCL12 (also called stromal-derived factor-1) is an important α-chemokine that binds primarily to its cognate receptor CXCR4 and thus regulates the trafficking of normal and malignant cells. For many years, it was believed that CXCR4 was the only receptor for CXCL12. Yet, recent work has demonstrated that CXCL12 also binds to another seven-transmembrane span receptor called CXCR7. Our group and others have established critical roles for CXCR4 and CXCR7 on mediating tumor metastasis in several types of cancers, in addition to their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Here, we review the current concepts regarding the role of CXCL12 / CXCR4 / CXCR7 axis activation, which regulates the pattern of tumor growth and metastatic spread to organs expressing high levels of CXCL12 to develop secondary tumors. We also summarize recent therapeutic approaches to target these receptors and/or their ligands.
... It is believed that the organs that express high SDF-1 (e.g., lymph nodes, lungs, liver, or bones) may direct the metastasis of CXCR4-expressing tumor cells. Supporting this hypothesis, it has been reported that several cancers expressing CXCR4 (e.g., breast, ovarian, and prostate cancers, rhabdomyosarcoma, and neuroblastoma) metastasize to the bones through the bloodstream in an SDF-1-dependent manner [11, 25,272829303132. The role of the SDF-1–CXCR4 axis in regulating the trafficking/homing of tumor cell metastasis seems to share some of the molecular mechanisms involved in normal stem cell processes. ...
... Further, it has been shown that oncoproteins also induce CXCR4 expression . These are known as PAX3–FKHR [31, 43] and RET/PTC [44]. The PAX3–FKHR fusion leads to enhanced migration and adhesion of rhabdomyosarcoma cells [31] , while RET/PTC-induced expression enhanced the transforming ability of breast cancer cells [44]. ...
... These are known as PAX3–FKHR [31, 43] and RET/PTC [44]. The PAX3–FKHR fusion leads to enhanced migration and adhesion of rhabdomyosarcoma cells [31] , while RET/PTC-induced expression enhanced the transforming ability of breast cancer cells [44]. Tumor progression, especially in tumor metastasis, is also affected by CXCR4–SDF-1 signaling through the induction of tumor-associated integrin activation and signaling [45]. ...
The chemokine receptor CXCR4 belongs to the large superfamily of G protein-coupled receptors and has been identified to play a crucial role in a number of biological processes, including the trafficking and homeostasis of immune cells such as T lymphocytes. CXCR4 has also been found to be a prognostic marker in various types of cancer, including leukemia and breast cancer, and recent evidence has highlighted the role of CXCR4 in prostate cancer. Furthermore, CXCR4 expression is upregulated in cancer metastasis, leading to enhanced signaling. These observations suggest that CXCR4 is important for the progression of cancer. The CXCR4-CXCL12 (stromal cell-derived factor 1 (SDF-1)) axis has additionally been identified to have a role in normal stem cell homing. Interestingly, cancer stem cells also express CXCR4, indicating that the CXCR4-SDF-1 axis may direct the trafficking and metastasis of these cells to organs that express high levels of SDF-1, such as the lymph nodes, lungs, liver, and bone. This review focuses on the current knowledge of CXCR4 regulation and how deregulation of this protein may contribute to the progression of cancer.
... Activation of CXCR4 produces specific cellular changes that are consistent with a migratory and invasive cell phenotype. Exposure of cells to CXCL12 produces upregulation of matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9 [25, 26, 29,3536373839. In addition, CXCL12 enhances adhesion to components of the extracellular matrix such as fibronectin, laminin, and collagen types I/III [37, 40], or to other cell types (e.g., endothelial or bone marrow stromal cells) [29, 41, 42]. ...
... Exposure of cells to CXCL12 produces upregulation of matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9 [25, 26, 29,3536373839. In addition, CXCL12 enhances adhesion to components of the extracellular matrix such as fibronectin, laminin, and collagen types I/III [37, 40], or to other cell types (e.g., endothelial or bone marrow stromal cells) [29, 41, 42]. These changes are mediated in large part by integrin signaling [29, 43, 44]. ...
... High CXCR4 expression is associated with poor tumor-specific survival, independent of tumour stage and differentiation grade [96, 97] Rhabdomyo sarcoma Several rhabdomyosarcoma cell lines express cell-surface CXCR4 protein. CXCL12 increases cell motility, induces chemotaxis, increases adhesion to extracellular matrix, and stimulates secretion of MMP-2 [37] Small cell lung cancer CXCR4 mRNA and cell-surface protein are detected in cell lines. CXCL12 induces proliferation, increases adherence and motility, and induces morphological changes such as filopodia formation [98] Thyroid cancer Human thyroid carcinoma cell lines express CXCR4 protein, and CXCR4 is upregulated in primary papillary thyroid carcinomas compared to normal thyroid tissue. ...
Chemokines are peptide mediators involved in normal development, hematopoietic and immune regulation, wound healing, and inflammation. Among the chemokines is CXCL12, which binds principally to its receptor CXCR4 and regulates leukocyte precursor homing to bone marrow and other sites. This role of CXCL12/CXCR4 is "commandeered" by cancer cells to facilitate the spread of CXCR4-bearing tumor cells to tissues with high CXCL12 concentrations. High CXCR4 expression by cancer cells predisposes to aggressive spread and metastasis and ultimately to poor patient outcomes. As well as being useful as a marker for disease progression, CXCR4 is a potential target for anticancer therapies. It is possible to interfere directly with the CXCL12:CXCR4 axis using peptide or small-molecular-weight antagonists. A further opportunity is offered by promoting strategies that downregulate CXCR4 pathways: CXCR4 expression in the tumor microenvironment is modulated by factors such as hypoxia, nucleosides, and eicosanoids. Another promising approach is through targeting PPAR to suppress CXCR4 expression. Endogenous PPARgamma such as 15-deoxy-Delta(12,14)-PGJ(2) and synthetic agonists such as the thiazolidinediones both cause downregulation of CXCR4 mRNA and receptor. Adjuvant therapy using PPARgamma agonists may, by stimulating PPARgamma-dependent downregulation of CXCR4 on cancer cells, slow the rate of metastasis and impact beneficially on disease progression.
... Since metastasis and tumor spread is a major factor limiting survival of cancer patients, the clinical need to prevent or target metastasis is a therapeutic priority in clinical oncology. It is well known that tumors respond to several prometastatic chemotactic factors, and therefore it would be difficult to inhibit their metastatic potential by inhibiting just one or even a few receptor axes [4,6,7,33]. For example, in a model of metastatic rhabdomyosarcoma, we previously demonstrated that exposure to irradiation [4,6,7] or chemotherapy678 of several organs upregulates the levels of chemokines and growth factors, such as SDF-1, HGF/SF, VEGF, and MCP-1, in addition to bioactive lipids such as S1P, C1P, LPA, and LPC, which are endowed with strong chemotactic activities with respect to normal as well as malignant cells [3,6,7]. ...
... As in chemotherapeutics, exposure to irradiation leads also to the release of several alarmines (e.g., ATP and UTP) from the damaged cells (manuscript in preparation). Moreover, in several well-controlled animal experimental models, it has been demonstrated that blockade of CXCR4 [4,33,34], CXCR7 [35], or c-Met [4,36] receptors by employing small-molecule inhibitors; downregulation of these receptors by shRNA strategies [27,37]; in vivo administration of blocking antibodies against SDF-1 [38] or MCP-1 [39,40]; or application of S1P-binding aptamers [6] significantly diminishes chemotherapy-or radiotherapy-related dissemination of tumor cells to various organs. Since it is impossible to target all these pro-metastatic factors at the same time, it is obvious that future anti-metastatic drugs must depend on potent molecules that interfere with migration and adhesion processes of cancer cells downstream of the surface receptors for these pro-metastatic factors. ...
One of side effects of chemotherapy and radiotherapy is the induction of several factors in various tissues and organs that create a pro-metastatic microenvironment for cancer cells that survive initial treatment.
In the present study, we employed human ovarian cancer cell line A2780 and immunodeficient mice xenogrfat model to test effect of both ibuprofen and dexamethasone to ameliorate the therapy-induced pro-metastatic microenvironment in bone marrow, liver, and lung.
In our studies, we found that total body irradiation or administration of cisplatin increases the metastatic spread of human ovarian cancer cells transplanted into immunodeficient mice compared with animals unexposed to irradiation or cisplatin. Moreover, conditioned media harvested from irradiated murine bone marrow, lung, and liver chemoattracted human ovarian cancer cells, and this chemotactic activity was inactivated by heat, suggesting a major involvement of peptide or peptide-bound chemoattractants. We also observed that human ovarian cancer cells proliferate better if exposed to cell debris harvested from irradiated murine bone marrow. Finally, the pro-metastatic microenvironment in mice induced by radio- or chemotherapy was significantly ameliorated if animals were treated at the time of radiochemotherapy administration with non-steroid (ibuprofen) or steroid (prednisone) anti-inflammatory drugs.
In summary, we propose that a radiochemotherapy-induced, pro-metastatic microenvironment plays an important role in the metastasis of cancer cells that are resistant to treatment. Such cells have characteristics of cancer stem cells and are highly migratory, and simple, intensive, anti-inflammatory treatment by non-steroid agents to suppress induction of pro-metastatic factors after radiochemotherapy would be an interesting anti-metastatic treatment alternative.
... The CXCL12-CXCR4 biological axis consisting of the chemotactic factor CXCL12 and its specific receptor CXCR4 plays an important role in cancer metastasis567. This axis facilitates tumor metastasis in breast cancer, non-small cell lung cancer, rhabdomyosarcoma , and other human malignant tumors, and the blocking of CXCL12-CXCR4 biological axis inhibits metastasis891011. KDEL signal sequence is located in the carboxyl end of structural and functional proteins in the endoplasmic reticulum (ER). ...
The CXCL12-CXCR4 biological axis consisting of the chemotactic factor CXCL12 and its specific receptor CXCR4 plays an important role in oral cancer metastasis. High expression of CXCR4 may help oral squamous cancer cells invade local tissues and metastasize to lymph nodes. No obvious association was observed between CXCL12 expression and lymph node metastasis, suggesting that CXCL12 chemotaxis may only be related to CXCR4 expression on the tumor cell membrane. KDEL can be retained by receptors on the surface of the intracellular endoplasmic reticulum (ER) and also be called an ER retention signal sequence. So we adopted the KDEL sequence in this study to generate a CXCL12-KDEL fusion protein in combination with a traceable E-tag label. As such, CXCL12 was retained in the ER. Specific receptor CXCR4 binds to the CXCL12-KDEL, was also retained in the ER, and was thus prevented from reaching the oral squamous cancer cell surface. We reduced the cell surface level of CXCR4 and called the technique "intracellular sequestration." By this way, we have finished blocking of CXCL12-CXCR4 biological axis and inhibiting lymph node metastasis of oral carcinoma.
... The SDF-1a-CXCR4 interaction promotes tumour progression by several possible mechanisms. CXCR4/SDF-1 interactions trigger the activation of many downstream pathways, including Ca 2+ influx, activation of the MAPK/ERK-1/2 pathway, activation of phosphatidylinositol 3-kinase and Akt, as well as increased NF-jB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity891011. Because of its involvement in both metastasis and primary tumour growth, CXCR4 is an ideal target to investigate novel therapeutic interventions. Some studies have successfully shown that blockade of CXCR4 or CXCR4/SDF- 1 interactions by siRNA and chemical inhibitors suppressed cancer cell proliferation, invasion and metastasis. ...
The increased migration and invasion of breast carcinoma cells are key events in the development of metastasis to the lymph nodes and distant organs. CXCR4, the receptor for stromal-derived factor-1, is reportedly involved in breast carcinogenesis and invasion. In this study, we investigated a novel biphenyl urea derivate, TPD7 for its ability to affect CXCR4 expression as well as function in breast cancer cells. We demonstrated that TPD7 inhibited the breast cancer proliferation and down-regulated the CXCR4 expression on breast cancer cells both over-expressing and low-expressing HER2, an oncogene known to induce the chemokine receptor. Treatments with pharmacological proteasome inhibitors partial suppressed TPD7-induced decrease in CXCR4 expression. Real-time PCR analysis revealed that down-regulation of CXCR4 by TPD7 also occurred at the translational level. Inhibition of CXCR4 expression by TPD7 further correlated with the suppression of SDF-1α-induced migration and invasion in breast tumour cells, knockdown of CXCR4 attenuated TPD7-inhibitory effects. In addition, TPD7 treatment significantly suppressed matrix metalloproteinase (MMP)-2 and MMP-9 expression, the downstream targets of CXCR4, perhaps via inactivation of the ERK signaling pathway. Overall, our results showed that TPD7 exerted its anti-invasive effect through the down-regulation of CXCR4 expression and thus had the potential for the treatment of breast cancer.
© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
... MMP9 is a protease is involved in the breakdown of extracellular matrix and that has been associated with CSC in solid tumors [30]. CXCR4 is a chemokine receptor for the stromal-derived factor 1 that plays an important role in the induction of chemotactic and invasive responses in several solid tumors [27], including osteosarcoma [31] and RMS [32], [33]. Rhabdospheres showed higher MMP9 expression and activity, higher migration ability, and increased CXCR4-positive cell fraction in comparison to native cells. ...
Rhabdomyosarcoma is the most frequent soft tissue sarcoma in children and adolescents, with a high rate of relapse that dramatically affects the clinical outcome. Multiagent chemotherapy, in combination with surgery and/or radiation therapy, is the treatment of choice. However, the relapse rate is disappointingly high and identification of new therapeutic tools is urgently needed. Under this respect, the selective block of key features of cancer stem cells (CSC) appears particularly promising. In this study, we isolated rhabdomyosarcoma CSC with stem-like features (high expression of NANOG and OCT3/4, self-renewal ability, multipotency). Rhabdomyosarcoma CSC showed higher invasive ability and a reduced cytotoxicity to doxorubicin in comparison to native cells, through a mechanism unrelated to the classical multidrug resistance process. This was dependent on a high level of lysosome acidity mediated by a high expression of vacuolar ATPase (V-ATPase). Since it was not associated with other paediatric cancers, like Ewing's sarcoma and neuroblastoma, V-ATPase higher expression in CSC was rhabdomyosarcoma specific. Inhibition of lysosomal acidification by the V-ATPase inhibitor omeprazole, or by specific siRNA silencing, significantly enhanced doxorubicin cytoxicity. Unexpectedly, lysosomal targeting also blocked cell growth and reduced the invasive potential of rhabdomyosarcoma CSC, even at very low doses of omeprazole (10 and 50 µM, respectively). Based on these observations, we propose lysosome acidity as a valuable target to enhance chemosensitivity of rhabdomyosarcoma CSC, and suggest the use of anti-V-ATPase agents in combination with standard regimens as a promising tool for the eradication of minimal residual disease or the prevention of metastatic disease.
... Also, SDF-1 is responsible for deregulated adhesion and integrin-dependent bone marrow retention of Philadelphia (Ph+) CD34+ cells in chronic myeloid leukemia. Elevated levels of SDF-1 are associated with increased osteoclast activity and osteolytic bone disease in patients with multiple myeloma [8,9]. Even if the concept of CSCs was anticipated by the genius of Rudolph Virchow, the father of modern pathology, more than 150 years ago, who along with Julium Connheim proposed the idea of " lost " embryonic remnants during developmental organogenesis that lie dormant and may give rise to malignancies [10], it is only in the last few years that scientists have begun to develop strategies aimed at inhibiting CSCs at a molecular level, the only way cancer can truly be attacked, by crossing the border between histology and molecular biology. ...
According to recent epidemiological studies, malignant diseases represent the second cause of mortality worldwide and metastasis is the main cause of morbidity and mortality in most cancers. Even if the concept of "cancer stem cells" (CSCs) was anticipated by the genius of Rudolph Virchow, the father of modern pathology, more than 150 years ago, it is only in last few years that that scientists have begun to develop strategies aimed at inhibiting CSCs at a molecular level, the only way cancer can truly be attacked, by crossing the border between histology and molecular biology. The current concise review aims at emphasizing the main characteristics of tumor initiating cells, bridging the basic science to clinical hematology and oncology.
... Also, SDF-1 is responsible for deregulated adhesion and integrin-dependent bone marrow retention of Philadelphia (Ph+) CD34+ cells in chronic myeloid leukemia. Elevated levels of SDF-1 are associated with increased osteoclast activity and osteolytic bone disease in patients with multiple myeloma [8,9]. Even if the concept of CSCs was anticipated by the genius of Rudolph Virchow, the father of modern pathology, more than 150 years ago, who along with Julium Connheim proposed the idea of " lost " embryonic remnants during developmental organogenesis that lie dormant and may give rise to malignancies [10], it is only in the last few years that scientists have begun to develop strategies aimed at inhibiting CSCs at a molecular level, the only way cancer can truly be attacked, by crossing the border between histology and molecular biology. ...
According to recent epidemiological studies, malignant diseases represent the second cause of mortality world-wide and metastasis is the main cause of morbidity and mortality in most cancers. Even if the concept of "cancer stem cells" (CSCs) was anticipated by the genius of Ru-dolph Virchow, the father of modern pathology, more than 150 years ago, it is only in last few years that that scien-tists have begun to develop strategies aimed at inhibiting CSCs at a molecular level, the only way cancer can tru-ly be attacked, by crossing the border between histology and molecular biology. The current concise review aims at emphasizing the main characteristics of tumor initiating cells, bridging the basic science to clinical hematology and oncology.
... In this study, we have also found MET amplification in RMS. Some results showed that MET possibly has a function not only in ARMS, which carries a dominant genetic lesion in an upstream transcription factor, but also in ERMS, in which the molecular mechanisms responsible for PAX3/PAX7 upregulation are more elusive [38,39,40]. The data of Riccardo indicated that MET may be necessary for RMS maintenance, and MET-directed therapies may be effective in the treatment of RMS [41]. ...
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. The genetic etiology of RMS remains largely unclear underlying its development and progression. To reveal novel genes more precisely and new therapeutic targets associated with RMS, we used high-resolution array comparative genomic hybridization (aCGH) to explore tumor-associated copy number variations (CNVs) and genes in RMS. We confirmed several important genes by quantitative real-time polymerase chain reaction (QRT-PCR). We then performed bioinformatics-based functional enrichment analysis for genes located in the genomic regions with CNVs. In addition, we identified miRNAs located in the corresponding amplification and deletion regions and performed miRNA functional enrichment analysis. aCGH analyses revealed that all RMS showed specific gains and losses. The amplification regions were 12q13.12, 12q13.3, and 12q13.3-q14.1. The deletion regions were 1p21.1, 2q14.1, 5q13.2, 9p12, and 9q12. The recurrent regions with gains were 12q13.3, 12q13.3-q14.1, 12q14.1, and 17q25.1. The recurrent regions with losses were 9p12-p11.2, 10q11.21-q11.22, 14q32.33, 16p11.2, and 22q11.1. The mean mRNA level of GLI1 in RMS was 6.61-fold higher than that in controls (p = 0.0477) by QRT-PCR. Meanwhile, the mean mRNA level of GEFT in RMS samples was 3.92-fold higher than that in controls (p = 0.0354). Bioinformatic analysis showed that genes were enriched in functions such as immunoglobulin domain, induction of apoptosis, and defensin. Proto-oncogene functions were involved in alveolar RMS. miRNAs that located in the amplified regions in RMS tend to be enriched in oncogenic activity (miR-24 and miR-27a). In conclusion, this study identified a number of CNVs in RMS and functional analyses showed enrichment for genes and miRNAs located in these CNVs regions. These findings may potentially help the identification of novel biomarkers and/or drug targets implicated in diagnosis of and targeted therapy for RMS.
... Another possible pathway is the binding of stromalderived factor-1 (SDF-1) to both CXC chemokine receptor-4 (CXCR4) and CXCR7. In studies of rhabdomyosarcoma cell lines, activation of these receptors resulted in increased locomotion , adhesion to fibronectin, and increased release of matrix metalloproteinases (MMPs) [36,37]. Another common site of peritoneal invasion is the omentum. ...
Peritoneal sarcomatosis (PSC) is defined as peritoneal involvement of multiple sarcomatous tumors. Desmoplastic small round cell tumors (DSRCT) and rhabdomyosarcomas are the most common pediatric PSC cases. PSC has been treated with chemotherapy and mainly palliative surgery, but long-term outcome has been poor. New imaging technologies have improved the evaluation of disease extent and patterns of peritoneal dissemination, and cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is being evaluated as a treatment option to prolong remission in pediatric patients. We will review the clinical characteristics, potential biologic mechanisms, radiographic characteristics, and potential therapies for pediatric PSC patients. Pediatr Blood Cancer 2013; 60: 12–17. © 2012 Wiley Periodicals, Inc.
... We discovered that mGluR5 antagonists significantly inhibited SDF-1/CXCR4-dependent migration and metastasis. Although the SDF-1/CXCR4 system mainly functions as a chemotactic factor in cancer cells, it is also involved in the several metastatic processes, such as neovascularization, cell adhesion, invasion, outgrowth and epithelial to mesenchymal transition383940414243. In the present study, mGluR5 regulated the cell migration associated with the SDF-1/CXCR4 system; however, it is unlikely that mGluR5 antagonists suppress SDF-1/CXCR4-dependent metastasis only via inhibited cell migration. ...
We have demonstrated that blocking CXCR4 may be a potent anti-metastatic therapy for CXCR4-related oral cancer. However, as CXCR4 antagonists are currently in clinical use to induce the mobilization of hematopoietic stem cells, continuous administration as an inhibitor for the metastasis may lead to persistent leukocytosis. In this study, we investigated the novel therapeutic downstream target(s) of the SDF-1/CXCR4 system, using B88-SDF-1 cells, which have an autocrine SDF-1/CXCR4 system and exhibit distant metastatic potential in vivo. Microarray analysis revealed that 418 genes were upregulated in B88-SDF-1 cells. We identified a gene that is highly upregulated in B88-SDF-1 cells, metabotropic glutamate receptor 5 (mGluR5), which was downregulated following treatment with 1,1' -[1,4-Phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD3100), a CXCR4 antagonist. The upregulation of mGluR5 mRNA in the SDF-1/CXCR4 system was predominately regulated by the Ras-extracellular signal-regulated kinase (ERK)1/2 pathway. Additionally, the growth of B88-SDF-1 cells was not affected by the mGluR5 agonist (S)-3,5-DHPG (DHPG) or the mGluR5 antagonists 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP). However, we observed that DHPG promoted B88-SDF-1 cell migration, whereas both MPEP and MTEP inhibited B88-SDF-1 cell migration. To assess drug toxicity, the antagonists were intraperitoneally injected into immunocompetent mice for 4 weeks. Mice injected with MPEP (5 mg/kg) and MTEP (5 mg/kg) did not exhibit any side effects, such as hematotoxicity, allergic reactions or weight loss. The administration of antagonists significantly inhibited the metastasis of B88-SDF-1 cells to the lungs of nude mice. These results suggest that blocking mGluR5 with antagonists such as MPEP and MTEP could prevent metastasis in CXCR4-related oral cancer without causing side effects.
... Of the factors secreted by hBMSCs during BMP exposure, a surprising outcome was found with the use of BMP-5, which was not particularly osteogenic (Figures 1, 2), in the secretion of SDF-1. SDF-1 is a chemokine that binds CXCR4 which influences chemotaxis of lymphocytic cells to areas of inflammation and homing of stem/progenitor cells during development and tissue regeneration (Libura et al., 2002). The current findings suggest that through SDF-1 up-regulation, BMP-5 could help modulate proper trafficking of immune cells and progenitor cells to an injured area. ...
Bone morphogenetic proteins (BMPs) other than the clinically available BMP-2 and BMP-7 may be useful for improving fracture healing through both increasing osteogenesis and creating a favorable healing environment by altering cytokine release by endogenous cells. Given the spectrum of potential applications for BMPs, the objective of this study was to evaluate various BMPs under a variety of conditions to provide further insight into their therapeutic capabilities. The alkaline phosphatase (ALP) activity of both C2C12 and human adipose-derived stem cells (hASCs) was measured after exposure of increasing doses of recombinant human BMP-2, -4, -5, -6, -7, or -9 for 3 and 7 days. BMPs-2, -4, -5, -6, -7, and -9 were compared in terms of their ability to affect the release of stromal derived factor-1 (SDF-1), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (b-FGF) from human bone marrow stromal cells (hBMSCs). Gene expression of ALP, osteocalcin, SDF-1, VEGF, and b-FGF following shRNA-mediated knockdown of BMP-2 and BMP-6 in hBMSCs or human osteoblasts under osteogenic differentiation conditions was also evaluated. Collectively, BMPs-6 and -9 produced the greatest osteogenic differentiation of C2C12 and hASCs as determined by ALP. The hBMSC secretion of SDF-1 was most affected by BMP-5, VEGF by BMP-4, and b-FGF by BMP-2. The knockdown of BMP-2 in BMSCs had no effect on any of the genes measured whereas BMP-6 knockdown in hBMSCs caused a significant increase in VEGF gene expression. BMP-2 and BMP-6 knockdown in human osteoblasts caused significant increases in VEGF gene expression and trends toward decreases in osteocalcin expression. These findings support efforts to study other BMPs as potential bone graft supplements, and to consider combined BMP delivery for promotion of multiple aspects of fracture healing.
... Chondroitin sulfate proteoglycan 4 (CSPG4) is a unique glycoproteinproteoglycan complex that has been implicated in numerous aspects of melanoma cell biology and carcinoma (including HNSCC) with usefulness as a CSC in glioblastoma183184185186187188189. CXCR4 is a chemokine receptor that has been suggested to contribute to the metastasis of several cancers and has been found to be overexpressed in metastatic HNSCC190191192193194195196197. CD166, present in all three embryological layers, is usually found in cells involved in growth and migration and has been implicated in cancers throughout the body indicating that research into its ability to identify CSCs at different stages of HNSCC may prove very useful [198]. ...
Head and neck squamous cell carcinoma (HNSCC) is one of the world's top ten most common cancers. Current survival rates are poor with only 50% of patients expected to survive five years after diagnosis. The poor survival rate of HNSCC is partly attributable to the tendency for diagnosis at the late stage of the disease. One of the reasons for treatment failure is thought to be related to the presence of a subpopulation of cells within the tumour called cancer stem cells (CSCs). CSCs display stem cell-like characteristics that impart resistance to conventional treatment modalities and promote tumour initiation, progression, and metastasis. Specific markers for this population have been investigated in the hope of developing a deeper understanding of their role in the pathogenesis of HNSCC and elucidating novel therapeutic strategies.
... The SDF-1a-CXCR4 interaction promotes tumor progression by several possible mechanisms [3,20,21]. For example, SDF-1a that is secreted by stromal cells acts as a chemoattractant allowing the metastatic spread of tumor cells to various cellular niches, such as bone marrow, and ultimately fosters the growth and survival of these cells [15,22,23]. Several novel CXCR4 antagonists have shown promising in vitro anti-cancer activity in several tumor cell types, including those derived from breast. ...
CXCR4, the receptor for stromal-derived factor-1, is reportedly involved in breast carcinogenesis. However, the mechanisms through which CXCR4 contributes to breast cancer cell growth and metastases are poorly understood. In this study, we examined the putative in vitro and in vivo anti-cancer effects of the specific CXCR4 inhibitor AMD3465. Here, we report that AMD3465 triggers a reduction in breast cancer cell invasiveness in vitro, and promotes marked changes in oncogenic signaling proteins including a reduction in STAT3, JAK2, AKT, and CXCR4 phosphorylation and the reduced expression of GSK3 and cMYC. Using three breast cancer cell lines as murine syngeneic immunocompetent breast cancer models, we found that AMD3465 inhibited breast tumor formation and reduced tumor cell metastases to the lung and liver. Furthermore, treatment with AMD3465 significantly reduced the infiltration of myeloid CD11b positive cells at the aforementioned metastatic sites as well as the spleen implying this agent could regulate the formation of the tumor microenvironment and conceivably the premetastatic niche. In conclusion, our studies suggest that AMD3465 inhibits breast cancer growth and metastases by acting on tumor cells as well as immune cells that constitute the tumor microenvironment. This process appears to be regulated, at least in part, through the modulation of oncogenic signaling that includes the STAT3 pathway. Thus, CXCR4 could be a novel target for breast cancer therapy.
... Although it is still unclear, that what leads to the overexpression of CXCR4 in different tumor cells, previous reports implicate the involvement of various genetic and epigenetic factors [23]. PAX3-and PAX7-FKHR gene fusion [24], mutations in the von Hippel Lindau gene [25], hypoxic conditions in the tumor microenvironment [26], NF-kB [21], vascular endothelial growth factor [27], and tumor necrosis factor alpha [28] have all been found to regulate CXCR4 overexpression in different tumor cells. Recently, the epidermal growth factor receptor, c-erbB2, and its encoding gene, HER2/neu, have also been implicated in the positive regulation of CXCR4 expression at the post-transcriptional level [29,30]. ...
Accumulating evidence(s) indicate that CXCL12-CXCR4 signaling cascade plays an important role in the process of invasion and metastasis that accounts for more than 80% of deaths in hepatocellular carcinoma (HCC) patients. Thus, identification of novel agents that can downregulate CXCR4 expression and its associated functions have a great potential in the treatment of metastatic HCC. In the present report, we investigated an anthraquinone derivative, emodin for its ability to affect CXCR4 expression as well as function in HCC cells. We observed that emodin downregulated the expression of CXCR4 in a dose-and time-dependent manner in HCC cells. Treatment with pharmacological proteasome and lysosomal inhibitors did not have substantial effect on emodin-induced decrease in CXCR4 expression. When investigated for the molecular mechanism(s), it was observed that the suppression of CXCR4 expression was due to downregulation of mRNA expression, inhibition of NF-κB activation, and abrogation of chromatin immunoprecipitation activity. Inhibition of CXCR4 expression by emodin further correlated with the suppression of CXCL12-induced migration and invasion in HCC cell lines. In addition, emodin treatment significantly suppressed metastasis to the lungs in an orthotopic HCC mice model and CXCR4 expression in tumor tissues. Overall, our results show that emodin exerts its anti-metastatic effect through the downregulation of CXCR4 expression and thus has the potential for the treatment of HCC.
... Signals from cytokines and chemokine receptors are directly involved in the release of BM progenitors into circulation. The SDF-1a/CXCR4 pathway has been shown to directly control the expression of molecules involved in extracellular matrix assembly and degradation, including MMP2 and MMP9, in smooth muscle cells, cancer cells metastatic to BM, and human CD34 þ progenitors [112][113][114][115][116]. In BM CD34 þ progenitors, expression of MMP2 is upregulated by granulocyte-colony stimulating factor (G-CSF) and SCF, factors that facilitate their mobilization into circulation [109]. ...
The ontogeny of hematopoietic stem cells (HSCs) is complex, with multiple sites of embryonic origin as well as several locations of expansion and maturation in the embryo and the adult. Hematopoietic progenitors (HPs) with diverse developmental potential are first found in the yolk sac, aorta-gonad-mesonephros (AGM) region and placenta. These progenitors then colonize the fetal liver where they undergo expansion and maturation. HSC from the fetal liver colonize the fetal bone marrow, governed by a complex orchestration of transcription programs including migratory molecules with chemotactic activity, adhesion molecules and molecules that modulate the extracellular matrix. Understanding the mechanisms that regulate the patterns of HSC migration between fetal liver to the fetal bone marrow could improve the engraftment potential of embryonic stem cell-derived hematopoietic progenitors (ES-HPs), since these cells might display a migratory behavior more similar to early HPs than to adult HSCs. Understanding the changes in migratory behavior in the context of fetal liver to fetal bone marrow HSC migration could lead to new approaches in the treatment of blood malignancies. Here, we will review the current knowledge in the field of fetal liver to the fetal bone marrow HSCs migration during development, focusing on changes in expression of molecules important for this process and exploring its clinical applications.
... Activated CXCR4 increases intracellular calcium mobilization and induces phosphorylation of focal adhesion components such as FAK and Pyk2444546 . The PI3K/AKT and MAPK signal transduction pathways contribute to chemotaxis, cell migration [42, 47], and secretion of various matrix metalloproteinases (MMP's) including MMP-2 and MMP-9 [46, 48]. MMP-2 and MMP-9 are involved in the migration of cells through the basement membrane [49]. ...
In the Western world, peripheral vascular disease (PVD) has a high prevalence with high morbidity and mortality. In a large percentage of these patients, lower limb amputation is still required. Studies of ischaemic skeletal muscle disclosed evidence of endogenous angiogenesis and adaptive skeletal muscle metabolic changes in response to hypoxia. Chemokines are potent chemoattractant cytokines that regulate leukocyte trafficking in homeostatic and inflammatory processes. More than 50 different chemokines and 20 different chemokine receptors have been cloned. The chemokine stromal-cell-derived factor-1 (SDF-1 aka CXCL12) is a constitutively expressed and inducible chemokine that regulates multiple physiological processes, including embryonic development and organ homeostasis. The biologic effects of SDF-1 are mediated by chemokine receptor CXCR4, a 352 amino acid rhodopsin-like transmembrane-specific G protein-coupled receptor (GPCR). There is evidence that the administration of SDF-1 increases blood flow and perfusion via recruitment of endothelial progenitor cells (EPCs). This review will focus on the role of the SDF-1/CXCR4 system in the pathophysiology of PVD and discuss their potential as therapeutic targets for PVD.
... We showed that AT-MSCs overexpressing CXCR4 stimulated with SDF-1 migrated markedly faster and relocated at a larger distance than control GFP-expressing cells. Similar significant increase in parameters of relocating cells after SDF-1 addition was shown by Libura et al. for CXCR4-expressing rhabdomyosarcoma cell line [30]. Our data indicate that overexpression of CXCR4 on AT-MSCs leads to increased migratory abilities similar to BM-MSCs with lentivirally induced CXCR4 expression, which was presented by Kyriakou et al. [31] . ...
This study evaluates usefulness of CXCR4 overexpression via retroviral transduction in adipose tissue-derived mesenchymal stem cells (AT-MSCs) as a strategy to increase their migration and engraftment ability.
AT-MSCs were isolated from lipoaspirates from human healthy donors with liberase 3. Cells were transduced with retroviral vector carrying either CXCR4 or green fluorescent protein (GFP) complementary DNA, and neo-resistant colonies were selected and used in experiments. Chemotaxis, invasion through Matrigel, motor activity, gene expression, osteodifferentiation potential, and engraftment into bone marrow of nonobese diabetic/severe combined immunodeficient mice were analyzed for CXCR4-overexpressing cells and GFP-control cells.
Approximately 90% of retrovirus-transduced AT-MSCs expressed CXCR4 or GFP and maintained their ability to differentiate into osteocytes. CXCR4-transduced AT-MSCs displayed enhanced migration and higher invasiveness toward SDF-1 gradient. The upregulation of CXCR4 led to phosphorylation of mitogen-activated protein and AKT kinases and an increase in metalloproteinase expression after SDF-1 stimulation. The transplantation of CXCR4-transduced AT-MSCs into nonobese diabetic/severe combined immunodeficient mice led to increased engraftment into bone marrow in comparison to GFP-transduced AT-MSCs.
Adipose tissue is one of the alternative sources of MSCs to bone marrow. We showed that AT-MSCs overexpressing CXCR4 preserve their ability for osteodifferentiation. Enhanced migration and engraftment of the transduced AT-MSCs into bone marrow indicate the usefulness of this strategy in overcoming low engraftment of MSCs in clinical approaches of cellular therapies for bone disorders and can represent a powerful tool in regenerative medicine and gene therapies. Thus, these cells may be used as an alternative to bone marrow-derived MSCs.
... Although it is still unclear what leads to the overexpression of CXCR4 in cancer cells, studies point to genetic and microenvironmental factors [44] . PAX3-and PAX7- FKHR gene fusion [45], mutations in the von Hippel Lindau tumor suppressor gene [46], hypoxia in the tumor microenvironment [47], NF-kB [30] , and inflammatory cytokines such as vascular endothelial growth factor [48] and tumor necrosis factor alpha [44], have all been implicated in CXCR4 overexpression. Recently, the epidermal growth factor receptor, c-erbB2, and its encoding gene, HER2/neu, have also been implicated in the positive regulation of CXCR4 expression at the post-transcriptional level [49,50]. ...
The CXC chemokine receptor-4 (CXCR4), a Gi protein-coupled receptor for the ligand CXCL12/stromal cell-derived factor-1α (SDF-1α), is known to be expressed in various tumors. This receptor mediates homing of tumor cells to specific organs that express the ligand CXCL12 for this receptor and plays an important role in tumor growth, invasion, metastasis, and angiogenesis. Thus, a priori, agents that can downregulate CXCR4/CXCL12 signaling cascade have potential against cancer metastasis. In this study, we report the identification of butein (3, 4, 2', 4'-tetrahydroxychalcone) as a novel regulator of CXCR4 expression and function. We found that butein downregulated the expression of CXCR4 in HER2-overexpressing breast cancer cells in a dose- and time-dependent manner. The decrease in CXCR4 expression induced by butein was not cell type-specific as the inhibition also occurred in pancreatic, prostate, multiple myeloma, head and neck, and hepatocellular cancer cell lines. When investigated for the molecular mechanism(s), it was found that the downregulation of CXCR4 was not due to proteolytic degradation but rather to transcriptional regulation as indicated by downregulation of mRNA expression, inhibition of NF-κB activation evident by both DNA binding, and reporter assays, and suppression of chromatin immunoprecipitation activity. Suppression of CXCR4 expression by butein correlated with the inhibition of CXCL12-induced migration and invasion of both breast and pancreatic cancer cells. Overall, our results demonstrate for the first time that butein is a novel inhibitor of CXCR4 expression and thus has a potential in suppressing metastasis of cancer.
... Prior studies have identified altered risks of HIV infection and AIDS progression associated with genetic variation in CXCL12, focused largely on a common G->A single nucleotide polymorphism (SNP) (rs1801157) in the 3' untranslated region (UTR) (Hendel, Henon et al. 1998; Modi, Scott et al. 2005; Petersen, Glashoff et al. 2005; Vidal, Peraire et al. 2005; Vissoci Reiche, Ehara Watanabe et al. 2006). The CXCL12-CXCR4 axis also regulates metastatic behavior in tumor cell lines (Libura, Drukala et al. 2002; Kucia, Jankowski et al. 2004). Prior studies have found a positive association between the minor allele at rs1801157 and risk of carcinoma of the breast (Zafiropoulos, Crikas et al. 2004; Razmkhah, Talei et al. 2005), lung (Razmkhah, Doroudchi et al. 2005), prostate (Hirata, Hinoda et al. 2007), and colon (Hidalgo-Pascual, Galan et al. 2007). ...
CXCL12 provides a chemotactic signal-directing leucocyte migration and regulates metastatic behaviour of tumour cells. We conducted a population-based case-control study to test the hypothesis that common genetic variation in CXCL12 individual single nucleotide polymorphism (SNP) alleles and haplotypes] is associated with the risk of cervical carcinoma. Cases (n = 917) were residents of western Washington State diagnosed with invasive squamous cell cervical carcinoma (SCC), invasive adenocarcinoma or adenosquamous carcinoma, or adenocarcinoma in situ of the cervix. Control participants (n = 849) were identified from the source population by random digit telephone dialling and frequency matched to cases on county and age. Nine CXCL12 tagSNPs chosen from the SeattleSNPs database were genotyped. The minor allele of intronic SNP rs266085 was inversely associated with cervical cancer under a recessive genetic effects model (OR = 0.74, 95% CI: 0.56-0.98). Among the ten common haplotypes inferred from the nine tagSNPs, one haplotype defined by minor alleles at 5'-flanking SNP rs17885289 and rs266085, and common alleles at the other seven SNPs occurred among 7.8% of cases and 10.6% of controls (dominant model OR = 0.72, 95% CI: 0.56-0.93; recessive model OR = 0.35, 95% CI: 0.12-0.97; and log-additive model OR = 0.72, 95% CI: 0.57-0.90). A stepwise procedure identified rs17885289, rs266085 and 3'-untranslated region (UTR) SNP rs266093 as the most parsimonious subset of SNPs necessary to define the haplotype inversely associated with cervical cancer risk in our study. A 3'-UTR SNP, rs1801157, previously found to be related to HIV pathogenesis, was not associated with cervical cancer risk. Further population-based studies are warranted to confirm these associations between genetic variation in CXCL12 and cervical cancer risk.
... Breast cancer Muller, et al. [76]; Tamamura, et al. [147]; Chen, et al. [198]; Liang, et al. [148]; Li, et al. [199]; Lee, et al. [200]; Liang, et al. [77]; Schmid, et al. [201]; Cabioglu, et al. [202]; Shim, et al. [203]; Liang, et al. [78]; Hao, et al. [92] Esophageal cancer Gockel, et al. [204]; Kaifi, et al. [205]; Koishi, et al. [206]; Sasaki, et al. [207] Gastrointestinal Cancer Ottaiano, et al. [97]; Tachibana, et al. [46]; Zeelenberg, et al. [95]; Kim, et al. [208] Gynecological cancer Kodama, et al. [209]; Jiang, et al. [210]; Pils, et al. [211]; Porcile, et al. [212] Head and neck cancer Samara, et al. [213]; Yoon, et al. [90] Hepatocellular carcinoma Begum, et al. [214]; Schimanski, et al. [215]; Shibuta, et al. [216] Leukemia & Lymphoma Barretina, et al. [217]; Burger, et al. [218]; Dao-Ung, et al. [219]; Fierro, et al. [220]; Ghobrial, et al. [221]; Voermans, et al. [62]; Ishibe, et al. [94]; Jin, et al. [222]; Juarez, et al. [223]; Konoplev, et al. [224]; Mohle, et al. [225]; Monaco, et al. [226]; Scupoli, et al. [227]; Spoo, et al. [228]; Tavor, et al. [229]; Wu, et al. [230]; Bertolini, et al. [231]; Chan, et al. [232]; Piovan, et al. [233] Lung cancer Kijima, et al. [133]; Spano, et al. [234]; Hartmann, et al. [135]; Burger, et al. [134]; Phillips, et al. [235] Melanoma Robledo, et al. [125]; Scala, et al. [126]; Murakami, et al. [127]; Takenaga, et al. [128]; Scala, et al. [129] ; Longo- Imedio, et al. [130] Multiple myeloma Alsayed, et al. [236]; Moller, et al. [237] Pancreatic cancer Koshiba, et al. [151]; Mori, et al. [152]; Marchesi, et al. [238]; Hermann, et al. [104] Prostate cancer Taichman, et al. [239]; Darash-Yahana, et al. [240]; Sun, et al. [241]; Akashi, et al. [242]; Chinni, et al. [243]; Hart, et al. [244]; Mochizuki, et al. [245]; Wang, et al. [251246] Renal carcinoma Jones, et al. [247]; Pan, et al. [248]; Reckamp, et al. [249]; Staller, et al. [250]; Struckmann, et al. [251] Sarcoma Libura, et al. [252]; Laverdiere, et al. [253]; Oda, et al. [254] Thyroid cancer Hwang, et al. [255]; De Falco, et al. [256] Semin Cancer Biol. Author manuscript; available in PMC 2011 May 10. ...
Chemokines (chemotactic cytokines) are a family of proteins associated with the trafficking and activation of leukocytes and other cell types in immune surveillance and inflammatory response. Besides their roles in the immune system, they play pleiotropic roles in tumor initiation, promotion, and progression. Chemokines can be classified into four subfamilies of chemokines, CXC, CC, C, or CX3C, based on their number and spacing of conserved cysteine residues near the N-terminus. This CXC subfamily can be further subclassified into two groups, depending on the presence or absence of a tripeptide motif glutamic acid-leucine-arginine (ELR) in the N-terminal domain. ELR(-)CXCL12, which binds to CXCR4 has been frequently implicated in various cancers. Over the past several years, studies have increasingly shown that the CXCR4/CXCL12 axis plays critical roles in tumor progression, such as invasion, angiogenesis, survival, homing to metastatic sites. This review focuses on involvement of CXCR4/CXCL12 interaction in neuroectodermal cancers and their therapeutic potentials. As an attractive therapeutic target of CXCR4/CXCL12 axis for cancer chemotherapy, development history and application of CXCR4 antagonists are described.
... In the present study, we have shown that CXCR4 is expressed by tumor cells in stage I NSCLC, CXCR4 is located in the nucleus and/or in the cytoplasm of tumor cells, and strong nuclear staining was correlated with better survival. CXCR4 has been found to be expressed in breast cancer [8], thyroid cancer [9], rhabdomyosarcoma [14], pancreatic cancer [15], hepatocellular carcinoma [16] and leukemia [17]. The present study is the first to report CXCR4 expression in NSCLC, like that found in small-cell lung cancer [11]. ...
The expression of CXCR4 has been implicated in metastatic dissemination in different models of breast cancer and melanoma. In the present study, we evaluated CXCR4 expression in non-small-cell lung cancer (NSCLC) and the relationship between CXCR4 expression and the prognosis of stage I disease.
Using immunohistochemical analysis, we retrospectively analyzed CXCR4 expression in specimens from 61 patients with completely resected pathologically confirmed stage I NSCLC for whom clinical follow-up data were available.
In the present study, we have shown that: CXCR4 is expressed by tumor cells in stage I NSCLC; CXCR4 is located in the nucleus and/or in the cytoplasm of tumor cells; strong nuclear staining was observed in 17 cases (29.8%); patients whose tumors had CXCR4-positive nuclear staining had a significantly longer duration of survival than patients whose tumors had no nuclear expression (P = 0.039, log-rank test). Interestingly, the 5-year metastasis rates were 23.5% and 34.1% in patients with CXCR4-positive and CXCR4-negative nuclear expression, respectively (P = 0.2).
Strong CXCR4-positive nuclear staining was associated with a significantly better outcome in early-stage NSCLC. The mechanisms underlying this clinically and biologically important finding need to be further explored.
Rhabdomyosarcoma (RMS) represents the most common sarcoma of soft tissue among children. Two main RMS subtypes are alveolar (ARMS) and embryonal (ERMS). The major goal of this study was to find differentially expressed genes between RMS subtypes that could explain higher metastatic potential in ARMS and would be useful for the differential diagnosis. Using RQ-PCR analysis we compared expression of Snail1 and Snail-related genes among 7 ARMS and 8 ERMS patients' samples obtained from the primary tumors and among 2 alveolar and 2 embryonal cell lines. Our results show that Snail1 is highly expressed both in ARMS patients' samples and the alveolar cell lines. We also found that the expression of E-Cadherin was downregulated and the expression of Matrix Metalloproteinases 2 and 9 (MMP-2 and MMP-9) was upregulated in ARMS. We assume that, as in many tumors, also in RMS Snail1 acts as a regulator for pathways known for their role in cells' metastasis and that Snail1 activity results in increased MMPs and decreased E-Cadherin expression. Our findings may explain higher ARMS aggressiveness. Moreover, we suggest that further studies should be performed to verify if Snail1 can be considered as a potential target for ARMS therapy.
Cancer tissues have biological characteristics similar to those observed in embryos during development. Many types of cancer cells acquire pro-invasive ability through epithelial-mesenchymal transition (EMT). Similar processes (gastrulation and migration of cranial neural crest cells (CNCCs)) are observed in the early stages of embryonic development in Xenopus during which cells that originate from epithelial sheets through EMT migrate to their final destinations. This study examined Xenopus embryonic tissues to identify anti-cancer compounds that prevent cancer invasion. From the initial test of known anti-cancer drugs, AMD3100 (an inhibitor of CXCR4) and Paclitaxel (a cytoskeletal drug targeting microtubules) effectively prevented migration during gastrulation or CNCCs development. Blind-screening of 100 synthesized chemical compounds was performed, and nine candidates that inhibited migration of these embryonic tissues without embryonic lethality were selected. Of these, C-157 (an analog of podophyllotoxin) and D-572 (which is an indole alkaroid) prevented cancer cell invasion through disruption of interphase microtubules. In addition, these compounds affected progression of mitotic phase and induced apoptosis of SAS oral cancer cells. SAS tumors were reduced in size after intratumoral injection of C-157, and peritoneal dissemination of melanoma cells and intracranial invasion of glioma cells were inhibited by C-157 and D-572. When the other analogues of these chemicals were compared, those with subtle effect on embryos were not tumor suppressive. These results suggest that a novel chemical-screening approach based on Xenopus embryos is an effective method for isolating anti-cancer drugs especially targeting cancer cell invasion and proliferation. This article is protected by copyright. All rights reserved.
To determine the clinical significance of C-X-C chemokine receptor type 4 (CXCR4) and β-catenin in osteosarcoma, their protein expression levels were assessed in 96 osteosarcoma and 20 osteochondroma cases using immunohistochemistry. Additionally, CXCR4 and β-catenin mRNA expression levels were measured in 16 fresh osteosarcoma and 16 adjacent healthy tissue samples using fluorescent reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In the osteosarcoma samples, the positive CXCR4 protein expression rate was significantly higher than the rate in the osteochondroma samples (68.75 vs. 20.00%; P<0.01). Furthermore, β-catenin protein expression was detected in 61.46% of osteosarcoma cases and 25.00% of osteochondroma cases. Similarly, the RT-qPCR data identified increased CXCR4 and β-catenin mRNA expression levels in the osteosarcoma compared with adjacent control tissues. It was determined that CXCR4 (P<0.01) and β-catenin (P<0.05) expression were significantly associated with the clinical Enneking stage, metastasis and survival of osteosarcoma. Furthermore, multivariate analysis identified CXCR4 and β-catenin protein expression levels, as well as clinical stage and metastasis, as significant risk factors for survival in patients with osteosarcoma (P<0.05). In conclusion, the present study determined that CXCR4 and β-catenin are abnormally expressed in osteosarcoma tissues, and, therefore, may be important during osteosarcoma progression.
The chemokine receptor CXCR4 has been reported to be aberrantly expressed in human cancer and has been shown to participate in cancer metastasis. We compared the expression of CXCR4 in conventional high-grade and low-grade central osteosarcomas, and determined if an association between CXCR4 expression and prognosis could be made.
The aim of our study was to elucidate the effect of tacrolimus (FK506) and of C-X-C chemokine receptor type 4 (CXCR4), which is a receptor specific to the stromal cell-derived factor-1α (SDF‑1α), on growth and metastasis of hepatocellular carcinoma (HCC). Following treatment with different concentrations of FK506, AMD3100 or normal saline (NS), the proliferation of Morris rat hepatoma 3924A (MH3924A) cells was measured by the MTT assay, the expression of CXCR4 was analyzed with immunohistochemistry, and the morphological changes and the invasiveness of cells were studied with a transwell assay and under a scanning electron microscope, respectively. In addition, August Copenhagen Irish rat models implanted with tumor were used to examine the pathological changes and invasiveness of tumor in vivo, the expression of CXCR4 in tumor tissues and the expression of SDF‑1α in the adjacent tissues to the HCC ones, using immunohistochemistry. In vitro, FK506 (100‑1,000 µg/l) significantly promoted the proliferation of MH3924A cells (P<0.01), and increased the expression of CXCR4 in MH3924A cells, albeit with no significance (P>0.05). By contrast, AMD3100 had no effect on the proliferation of MH3924A cells, but significantly reduced the expression of CXCR4 (P<0.05). The invasiveness of MH3924A cells was significantly (P<0.01) enhanced following treatment with FK506, SDF‑1α, FK506 + AMD3100, FK506 + SDF‑1α or FK506 + AMD3100 + SDF‑1α. In vivo, tumor weight (P=0.041), lymph node metastasis (P=0.002), the number of pulmonary nodules (P=0.012), the expression of CXCR4 in tumor tissues (P=0.048) and that of SDF‑1α in adjacent tissues (P=0.026) were significantly different between the FK506-treated and the NS group. Our results suggest that FK506 promotes the proliferation of MH3924A cells and the expression of CXCR4 and SDF‑1α in vivo. Therefore, inhibiting the formation of the CXCR4/SDF‑1α complex may partly reduce the promoting effect of FK506 on HCC.
Unlabelled:
Ewing sarcoma is the second most common bone cancer in pediatric patients. Although the primary cause of death in Ewing sarcoma is metastasis, the mechanism underlying tumor spread needs to be elucidated. To this end, the role of the CXCR4/SDF-1a chemokine axis as a mediator of Ewing sarcoma metastasis was investigated. CXCR4 expression status was measured in primary tumor specimens by immunohistochemical staining and in multiple cell lines by quantitative reverse transcriptase PCR and flow cytometry. Migration and invasion of CXCR4-positive Ewing sarcoma cells toward CXCL12/SDF-1a were also determined. Interestingly, while CXCR4 status was disparate among Ewing sarcoma cells, ranging from absent to high-level expression, its expression was found to be highly dynamic and responsive to changes in the microenvironment. In particular, upregulation of CXCR4 occurred in cells that were subjected to growth factor deprivation, hypoxia, and space constraints. This upregulation of CXCR4 was rapidly reversed upon removal of the offending cellular stress conditions. Functionally, CXCR4-positive cells migrated and invaded toward an SDF-1a gradient and these aggressive properties were impeded by both the CXCR4 small-molecule inhibitor AMD3100, and by knockdown of CXCR4. In addition, CXCR4-dependent migration and invasion were inhibited by small-molecule inhibitors of Cdc42 and Rac1, mechanistically implicating these Rho-GTPases as downstream mediators of the CXCR4-dependent phenotype.
Implications:
This study reveals the highly plastic and dynamic nature of CXCR4 expression in Ewing sarcoma and supports a model in which stress-induced upregulation of CXCR4 contributes to tumor metastasis to lung and bone marrow, which express high levels of SDF-1a.
We observed that sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) strongly enhance in vitro motility and adhesion of human rhabdomyosarcoma (RMS) cells. This effect was observed at physiological concentrations of both bioactive lipids, which are present in biological fluids, and is much stronger than the effects observed in response to known RMS pro-metastatic factors such as stromal derived factors-1 (SDF-1) or hepatocyte growth factor/scatter factor (HGF/SF). We also present novel evidence that the levels of S1P and C1P increase in several organs after y-irradiation or chemotherapy, which indicates induction of an unwanted pro-metastatic environment related to treatment. Most importantly, we found that the metastasis of RMS cells in response to S1P can be effectively inhibited in vivo with the S1P-specific binder NOX-S93 that is based on a high affinity Spiegelmer. We propose that bioactive lipids play a previously underappreciated role in dissemination of RMS and the unwanted side effects of radio/chemotherapy by creating a pro-metastatic microenvironment. Therefore, an anti-metastatic treatment with specific S1P-binding scavenger such as NOX-S93 could become a part of standard radio/chemotherapy.
Rhabdomyosarcoma (RMS) is the most common type of pediatric soft tissue sarcoma. The MET receptor has an important role in the biology of RMS, and its overexpression and hyperactivation correlate with the metastatic ability of RMS. Consequently, interfering with MET expression or functionality may constitute a sound strategy for reducing the progression and metastatic potential of RMS. Our study reveals that downregulation of the MET receptor leads to changes in the morphology of ARMS cell in vivo. Tumors acquire a spindle shape that is characteristic of muscle fibers. Inhibition of MET expression or function leads to (i) a decreased expression of the early myogenic marker MyoD, (ii) a decreased ability of ARMS cells to metastasize to bone marrow cavities, (iii) downregulation of CXCR4 receptor expression and (iv) a decreased migration of MET-depleted cells towards gradients of HGF and SDF-1. Finally, we demonstrate that in vitro differentiation of alveolar RMS cells decreases their metastatic behavior by reducing both the expression of the MET and CXCR4 receptors and their migratory response to HGF and SDF-1. These findings suggest that blockers of MET receptor function and inducers of RMS cells differentiation may be clinically useful for reducing the aggressiveness and metastatic potential of RMS and may have significant implications for its treatment.
Rhabdomyosarcoma (RMS) represents the most common sarcoma of soft tissue among children. Two main RMS subtypes are alveolar (ARMS) and embryonal (ERMS). The major goal of this study was to find differentially expressed genes between RMS subtypes that could explain higher metastatic potential in ARMS and would be useful for the differential diagnosis. Using RQ-PCR analysis we compared expression of Snail1 and Snail-related genes among 7 ARMS and 8 ERMS patients' samples obtained from the primary tumors and among 2 alveolar and 2 embryonal cell lines. Our results show that Snail1 is highly expressed both in ARMS patients' samples and the alveolar cell lines. We also found that the expression of E-Cadherin was downregulated and the expression of Matrix Metalloproteinases 2 and 9 (MMP-2 and MMP-9) was upregulated in ARMS. We assume that, as in many tumors, also in RMS Snail1 acts as a regulator for pathways known for their role in cells' metastasis and that Snail1 activity results in increased MMPs and decreased E-Cadherin expression. Our findings may explain higher ARMS aggressiveness. Moreover, we suggest that further studies should be performed to verify if Snail1 can be considered as a potential target for ARMS therapy.
CXCR7 was identified as another stromal-derived factor-1 (SDF-1)-binding receptor that also binds the interferon-inducible T-cell chemoattractant (I-TAC), and we became interested in its potential role in migration/adhesion of normal hematopoietic stem/progenitor cells (HSPCs) as well as selected leukemia cell lines. To address this normal human bone marrow-, umbilical cord blood-, and mobilized peripheral blood-derived cells as well as 16 selected human leukemic cell lines were phenotyped for CXCR7 expression. The expression of CXCR7 in hematopoietic cell lines was analyzed at transcriptional level. The biologic significance of CXCR7 expression was subsequently tested in signal transduction studies as well as in in vitro proliferation and chemotactic assays. We noted that CXCR7 is expressed at very low levels (approximately 3-6%) in normal human CD34(+) cells isolated from bone marrow, umbilical cord blood, and mobilized peripheral blood. More importantly, when we employed I-TAC, which activates CXCR7, but not CXCR4, we did not observe any chemotactic responsiveness in human clonogenic progenitors. As expected, I-TAC also did not affect clonogenic growth of human CD34(+) cells. In contrast, functional CXCR7, whose expression is regulated in an NF-κΒ-dependent manner, as we report here, is highly expressed in several human myeloid malignant cell lines. I-TAC-induced activation of CXCR7 in human hematopoietic cell lines leads to phosphorylation of MAPKp42/44 and AKT, and enhanced cell adhesion and slightly cell migration. In conclusion, CXCR7 is expressed at very low level on normal human HSPCs and does not play a direct role in their proliferation or slightly cell migration; however, in contrast, it is involved in trafficking/adhesion of human leukemic cells.
The overexpression of macrophage migration inhibitory factor (MIF) has been observed in many tumors and is implicated in oncogenic transformation and tumor progression. MIF activates CXCR2 and CD74 receptors and, as recently reported, may also bind to the stromal-derived factor-1 (SDF-1)-binding receptor CXCR4. Here, we report that human rhabdomyosarcoma (RMS) cell lines secrete MIF and that this chemokine (a) induces phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 and AKT, (b) stimulates RMS cell adhesion, (c) enhances tumor vascularization, but surprisingly (d) decreases recruitment of cancer-associated fibroblasts (CAF). Because RMS cells used in our studies do not express CXCR2 and CD74 receptors, the biological effects of MIF on RMS cells depend on its interaction with CXCR4, and as we report here for the first time, MIF may also engage another SDF-1-binding receptor (CXCR7) as well. Interestingly, downregulation of MIF in RMS cells inoculated into immunodeficient mice led to formation of larger tumors that displayed higher stromal cell support. Based on these observations, we postulate that MIF is an important autocrine/paracrine factor that stimulates both CXCR4 and CXCR7 receptors to enhance the adhesiveness of RMS cells. We also envision that when locally secreted by a growing tumor, MIF prevents responsiveness of RMS to chemoattractants secreted outside the growing tumor (e.g., SDF-1) and thereby prevents release of cells into the circulation. On the other hand, despite its obvious proangiopoietic effects, MIF inhibits in CXCR2/CD74-dependent manner recruitment of CAFs to the growing tumor. Our data indicate that therapeutic inhibition of MIF in RMS may accelerate metastasis and tumor growth.
We observed that human rhabdomyosarcoma (RMS) cells highly express a tissue factor that promotes thrombin formation, which indirectly and directly affects RMS progression. First, we found that thrombin activates platelets to generate microvesicles (PMV), which transfer to RMS cells' alpha2beta3 integrin and increase their adhesiveness to endothelial cells. Accordingly, RMS cells covered with PMVs showed higher metastatic potential after i.v. injection into immunodeficient mice. Furthermore, PMVs activate mitogen-activated protein kinase (MAPK)p42/44 and AKT to chemoattract RMS cells. We also found that RMS cells express functional protease-activated receptor-1 (PAR1) and PAR3 and respond to thrombin stimulation by MAPKp42/44 and MAPKp38 phosphorylation. To our surprise, thrombin did not affect RMS proliferation or survival; it inhibited the chemotactic and adhesive properties of RMS cells. However, when PAR1-specific agonist thrombin receptor-activating peptide 6 was used, which does not activate PAR3, selective PAR1 stimulation enhanced RMS proliferation. To learn more on the role of PAR1 and PAR3 antagonism in RMS proliferation and metastasis, we knocked down both receptors by using a short hairpin RNA strategy. We found that although thrombin does not affect growth of PAR1(-/-) cells, it stimulated the proliferation of PAR3(-/-) cells. More importantly, PAR3(-/-) cells, in contrast to PAR1(-/-) ones, formed larger tumors in immunodeficient mice. We conclude that thrombin is a novel underappreciated modulator of RMS metastasis and that we have identified a novel role for PAR3 in thrombin signaling.
We have demonstrated that the α-chemokine stromal-derived factor (SDF)-1-CXCR4 axis plays an important role in rhabdomyosarcoma (RMS) metastasis. With the recent description of CXCR7, a new receptor for SDF-1 that also binds the interferon-inducible T-cell α chemoattractant (ITAC) chemokine, we became interested in the role of the CXCR7-SDF-1/ITAC axis in RMS progression. To address this issue, we evaluated 6 highly metastatic alveolar (A)RMS and 3 less metastatic embryonal (E)RMS cell lines and found that all these cell lines express CXCR7. Although CXCR4 was expressed at a much higher level by highly metastatic ARMS lines, CXCR7 was present at a high level on ERMS lines. We also noticed that CXCR7 expression on RMS cells was downregulated in hypoxic conditions. More importantly, the CXCR7 receptor on RMS cell lines was functional after stimulation with ITAC and SDF-1 as evidenced by mitogen-activated protein kinase (MAPK)p42/44 and AKT phosphorylation as well as CXCR7 internalization, chemotaxis, cell motility and adhesion assays. Similarly to CXCR4, signaling from activated CXCR7 was not associated with increased RMS proliferation or cell survival. Moreover, CXCR7(+) RMS cells responded to SDF-1 and I-TAC in the presence of CXCR4 antagonists (T140, AMD3100). Furthermore, while intravenous injection of RMS cells with overexpressed CXCR7 resulted in increased seeding efficiency of tumor cells to bone marrow, CXCR7 downregulation showed the opposite effect. In conclusion, the CXCR7-SDF-1/ITAC axis is involved in the progression of RMS; targeting of the CXCR4-SDF-1 axis alone without simultaneous blockage of CXCR7 will be an inefficient strategy for inhibiting SDF-1-mediated prometastatic responses of RMS cells.
Lung cancer is the leading cause of cancer deaths worldwide. Small cell lung cancer (SCLC), which comprises 15% of all lung cancers, is almost exclusively due to smoking and is highly aggressive due to early widespread metastasis. While combination chemotherapy has lead to modest improvements in outcome, the five-year overall survival for SCLC remains at 5%. Identifying distinct biochemical pathways of metastasis and chemotherapy resistance in SCLC may lead to novel therapeutic approaches and improve survival in SCLC patients. The chemokine receptor CXCR4 is emerging as an important target in cancer growth, metastasis, relapse and resistance to therapy. In this article, we review the structure and function of CXCR4 and its ligand, CXCL12, as well as mechanisms of CXCR4/CXCL12 signal transduction in lung cancer. We review the current preclinical and translational research involving this pathway in lung cancer and the clinical development of several novel agents targeting the CXCR4/CXCL12 pathway. Further understanding of the CXCR4/CXCL12 pathway in SCLC and NSCLC may provide a rationale for innovative research on the CXCR4 receptor as a potential novel therapeutic target in lung cancer.
The role of bone marrow (BM)-derived cells in pancreatic beta-cell regeneration remains unresolved. We examined whether BM-derived cells are recruited to the site of moderate pancreatic injury and contribute to beta-cell regeneration.
Low-dose streptozotocin (STZ) treatment was used to induce moderate pancreatic damage and hyperglycemia. Enhanced green fluorescent protein-positive (EGFP) BM chimeras were evaluated for beta-cell regeneration after STZ treatment.
To test the hypothesis that pancreatic tissue injury induces a stromal cell-derived factor (SDF)-1 gradient to chemoattract the stem cells, we evaluated the expression of mRNA for SDF-1 in damaged pancreatic tissue. SDF-1 was significantly increased in the pancreas after damage, peaking at day 10. The majority of BM cells expressing mRNA for pancreatic development markers were detected in the subpopulation of CD45/Sca-1/Lin very small embryonic-like (VSEL) cells. VSEL cells mobilized from BM to peripheral blood in response to pancreatic damage, peaking in peripheral blood at day 5, and were enriched in the pancreas 10 to 15 days after STZ treatment. To confirm a role for BM-derived cells in pancreatic beta-cell regeneration, we prepared EGFP-->B6 chimeras. In the EGFP chimeras, EGFP cells were detected around duct and islets and were positive for insulin after STZ treatment. However, STZ-induced hyperglycemia was reduced only transiently (49-77 days) after pancreatic injury.
These data suggest that VSEL cells are mobilized into injured pancreatic tissue and contribute to beta-cell regeneration. Transplantation of BM-derived cells improves the function of injured pancreas, although the response is not sufficient to restore sustained normoglycemia.
Rhabdomyosarcomas (RMS) express CXCR4 and CXCR7 receptors that bind prometastatic alpha-chemokine stromal-derived factor-1 (SDF-1). In this report, we analyzed the activity of both promoters in a model of less metastatic human embryonal-RMS cell line (RD) and more metastatic alveolar-like RMS (RD cells transduced with paired box gene 3/forkhead homologue; PAX3-FKHR fusion gene). First, CXCR4 is barely detectable in RD and becomes upregulated in RD/PAX3-FKHR cells. In contrast, CXCR7 highly expressed in RD becomes downregulated in RD/PAX3-FKHR cells. Next, promoter deletion and mutation studies revealed that whereas (a) expression of CXCR4 in RD and RD/PAX3-FKHR cells required nuclear respiratory factor-1 (NRF-1) binding site and (b) was additionally upregulated by direct interaction of NRF-1 with PAX3-FKHR, CXCR7 promoter activity required a proximal nuclear factor-kappaB-binding motif. The requirement of these factors for CXCR4 and CXCR7 promoter activities was additionally supported after blocking NRF-1 and nuclear factor-kappaB. Furthermore, CXCR4 expression in PAX3-FKHR(+) RMS cells seems to be enhanced because of the interaction of PAX3-FKHR and NRF-1 proteins in the proximal part of the promoter that prevents access of the negative regulator of transcription YY1 to its binding site. Finally, although hypoxia enhances CXCR4 and CXCR7 promoter activity and receptor expression in RD cells, it inhibits CXCR7 expression in RD/PAX3-FKHR cells. In conclusion, SDF-1 binding receptors CXCR4 and CXCR7 are differently regulated in RMS cells. The upregulation of CXCR4 and downregulation of CXCR7 expression by PAX3-FKHR or hypoxia may give SDF-1 an advantage to better engage the CXCR4 receptor, thus increasing RMS motility.
Hepatocyte growth factor (HGF) and its receptor play an important role in the formation and progression of glioma and can promote tumor proliferation. In this study, we investigated the ability of HGF to promote the proliferation and invasion of U251n cells; we also tested the effects of HGF on stromal cell-derived factor 1 (SDF1) and CXCR4 mRNA expression.
We measured the effect of HGF on the proliferation of U251n cells using enzyme-linked immunosorbent assays (ELISAs) to detect incorporated bromodeoxyuridine (BrdU) as a marker of DNA synthesis. The effects of HGF and SDF-1 on U251n cell invasion and proliferation were measured using the inhibitors K252a to c-Met and AMD3100 to CXCR4. SDF-1 and CXCR4 mRNA and protein expression were measured using quantitative polymerase chain reaction (PCR) and fluorescence-activated cell sorter (FACS) analysis. Small interfering (si)RNAs were also used to down-regulate HGF and c-Met expression in U251n cells.
HGF significantly increased U251n cell proliferation and invasion in a dose-dependent manner; K252a blocked this. AMD3100 blocked invasion but not proliferation. CXCR4 and SDF-1 mRNAs were up-regulated when cells were treated with HGF. CXCR4 and SDF-1 mRNA levels and HGF and c-Met protein levels were down-regulated after cells were transfected with siRNAs.
HGF has a direct effect on glioma cell proliferation and invasion. HGF up-regulates SDF-1 and CXCR4 mRNA expression and contributes to cell invasion.
The interaction of multiple myeloma (MM) cells with the bone marrow (BM) milieu plays a crucial role in MM pathogenesis. Stromal cell-derived factor-1 (SDF1) regulates homing of MM cells to the BM. In this study, we examined the role of RhoA and Rac1 GTPases in SDF1-induced adhesion and chemotaxis of MM. We found that both RhoA and Rac1 play key roles in SDF1-induced adhesion of MM cells to BM stromal cells, whereas RhoA was involved in chemotaxis and motility. Furthermore, both ROCK and Rac1 inhibitors reduced SDF1-induced polymerization of actin and activation of LIMK, SRC, FAK, and cofilin. Moreover, RhoA and Rac1 reduced homing of MM cells to BM niches. In conclusion, we characterized the role of RhoA and Rac1 GTPases in SDF1-induced adhesion, chemotaxis, and homing of MM cells to the BM, providing the framework for targeting RhoA and Rac1 GTPases as novel MM therapy.
Hematopoietic and epithelial cancer cells express CXCR4, a seven-transmembrane G-protein-coupled chemokine receptor. Stromal cells within the bone marrow microenvironment constitutively secrete stromal cell-derived factor-1 (SDF-1/CXCL12), the ligand for CXCR4. Activation of CXCR4 induces leukemia cell trafficking and homing to the marrow microenvironment, where CXCL12 retains leukemia cells in close contact with marrow stromal cells that provide growth and drug resistance signals. CXCR4 antagonists, such as Plerixafor (AMD3100) and T140 analogs, can disrupt adhesive tumor-stroma interactions and mobilize leukemia cells from their protective stromal microenvironment, making them more accessible to conventional drugs. Therefore, targeting the CXCR4-CXCL12 axis is a novel, attractive therapeutic approach that is explored in ongoing clinical trials in leukemia patients. Initially, CXCR4 antagonists were developed for the treatment of HIV, where CXCR4 functions as a co-receptor for virus entry into T cells. Subsequently, CXCR4 antagonists were noticed to induce leukocytosis, and are currently used clinically for mobilization of hematopoietic stem cells. However, because CXCR4 plays a key role in cross-talk between leukemia cells (and a variety of other tumor cells) and their microenvironment, cancer treatment may become the ultimate application of CXCR4 antagonists. Here, we summarize the development of CXCR4 antagonists and their preclinical and clinical activities, focusing on leukemia and other cancers.
Chemokines are involved in human hepatocellular carcinoma (HCC) carcinogenesis. However, the exact mechanism of chemokines in HCC carcinogenesis remains unknown. Here we investigated the roles of chemokine receptor 4 (CXCR4) and chemokine ligand 12 (CXCL12) in the metastasis of HCC. We found that the expression levels of CXCR4 mRNA in HCC tissues, MHCC97 cells, and HUVEC cells were 2.52 +/- 1.13, 2.34 +/- 1.16 and 1.63 +/- 1.26, respectively and that the CXCR4 protein levels were 1.38 +/- 0.13, 1.96 +/- 0.32 and 1.86 +/- 0.21, respectively. In contrast, CXCR4 was not detected in normal hepatic tissues. In 78 HCC patients, we also found that the concentration of CXCL12 in cancerous ascitic fluid was 783-8,364 pg/ml and that CXCL12 mRNA level in HCC metastasis portal lymph nodes was 1.21 +/- 0.87 but undetectable in normal hepatic tissues. Finally we discovered that recombinant human CXCL12 could induce MHCC97 cells and HUVEC cells to migrate with chemotactic indexes (CI) of 3.9 +/- 1.1 and 4.1 +/- 1.6, respectively. Cancerous ascitic fluid could also induce the migration of MHCC97 cells with a CI of 1.9 +/- 0.8. Thus, our data suggest that CXCR4 and CXCL12 may play an important role in the metastasis of HCC by promoting the migration of tumor cells.
Complement has recently been implicated in developmental pathways and noninflammatory processes. The expression of various complement components and receptors has been shown in a wide range of circulating myeloid and lymphoid cells, but their role in normal hematopoiesis and stem cell homing has not yet been investigated. We report that normal human CD34(+) cells and lineage-differentiated hematopoietic progenitors express the complement anaphylatoxin C3a receptor (C3aR) and respond to C3a. Moreover, C3a, but not the biologically inactive desArg-C3a, induces calcium flux in these cells. Furthermore, we found that C3 is secreted by bone marrow stroma and that, although C3a does not influence directly the proliferation/survival of hematopoietic progenitors, it (1) potentiates the stromal cell-derived factor 1 (SDF-1)-dependent chemotaxis of human CD34(+) cells and lineage-committed myeloid, erythroid, and megakaryocytic progenitors; (2) primes SDF-1-dependent trans-Matrigel migration; and (3) stimulates matrix metalloproteinase-9 secretion and very late antigen 4 (VLA-4)-mediated adhesion to vascular cell adhesion molecule 1 (VCAM-1). Furthermore, we found that murine Sca-1(+) cells primed by C3a engrafted faster in lethally irradiated animals. These results indicate that normal human hematopoietic stem and progenitor cells express functional C3aR and that the C3aR-C3a axis sensitizes the responses of these cells to SDF-1 and thus may be involved in promoting their homing into the bone marrow via cross talk with the SDF-CXC chemokine receptor-4 (CXCR4) signaling axis. C3a is the first positive regulator of this axis to be identified.
It has been suggested that bone marrow (BM)-derived hematopoietic stem cells transdifferentiate into tissue-specific stem cells (the so-called phenomenon of stem cell plasticity), but the possibility of committed tissue-specific stem cells pre-existing in BM has not been given sufficient consideration. We hypothesized that (i) tissue-committed stem cells circulate at a low level in the peripheral blood (PB) under normal steady-state conditions, maintaining a pool of stem cells in peripheral tissues, and their levels increase in PB during stress/tissue injury, and (ii) they could be chemoattracted to the BM where they find a supportive environment and that the SDF-1-CXCR4 axis plays a prominent role in the homing/retention of these cells to BM niches. We performed all experiments using freshly isolated cells to exclude the potential for 'transdifferentiation' of hematopoietic stem or mesenchymal cells associated with in vitro culture systems. We detected mRNA for various early markers for muscle (Myf-5, Myo-D), neural (GFAP, nestin) and liver (CK19, fetoprotein) cells in circulating (adherent cell-depleted) PB mononuclear cells (MNC) and increased levels of expression of these markers in PB after mobilization by G-CSF (as measured using real-time RT-PCR). Furthermore, SDF-1 chemotaxis combined with real-time RT-PCR analysis revealed that (i) these early tissue-specific cells reside in normal murine BM, (ii) express CXCR4 on their surface and (iii) can be enriched (up to 60 x) after chemotaxis to an SDF-1 gradient. These cells were also highly enriched within purified populations of murine Sca-1(+) BM MNC as well as of human CD34(+)-, AC133(+)- and CXCR4-positive cells. We also found that the expression of mRNA for SDF-1 is upregulated in damaged heart, kidney and liver. Hence our data provide a new perspective on BM not only as a home for hematopoietic stem cells but also a 'hideout' for already differentiated CXCR4-positive tissue-committed stem/progenitor cells that follow an SDF-1 gradient, could be mobilized into PB, and subsequently take part in organ/tissue regeneration.
Adhesion molecules and stromal cell-derived factor-1 (SDF-1)/CXCR4 signaling play key roles in homing and mobilization of hematopoietic stem cells (HSC). Active signaling through SDF-1/CXCR4 and upregulation of adhesion molecules are required for homing, whereas downregulation of adhesion molecules and disruption of SDF-1/CXCR4 signaling are required for mobilization of HSC. We studied the surface expression of CXCR4 very late activation antigen (VLA)-4 and VLA-5 on myeloma cells mobilized with cyclophosphamide and GM-CSF in 12 multiple myeloma patients undergoing HSC mobilization for autologous transplantation. We also studied the plasma levels of SDF-1 in apheresis collection of these patients. We observed a statistically significant decrease in the levels of SDF-1 and surface expression of CXCR4 on myeloma cells in four consecutive apheresis collections compared with premobilization bone marrow specimens. We also observed a statistically significant decrease in surface expression of VLA-4 in myeloma cells in the apheresis collections compared with premobilization bone marrow samples. Furthermore, myeloma cells derived from apheresis collections had decreased adhesion and trans-stromal migration in response to SDF-1, which could be reversed by short incubation with interleukin-6. Hence, mobilization of myeloma cells involves SDF-1/CXCR4 signaling and downregulation of VLA-4.
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