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HGF/c-MET activation. (A) The HGF relative level in supernatants of HeLa, CaSki, ADSCs, and ADSCs co-cultured with either HeLa or CaSki cells. (B) HGF concentration in the supernatants of HeLa or CaSki cells co-cultured with ADSCs determined by ELISA assay. (C) The protein expression of c-MET and p-c-MET detected by Western blot. (D) The phosphorylation ratio of c-MET quantified using Image J software. (E and F) The siRNA transfection effect in the HeLa or CaSki cells detected by Western blotting. ***P<0.001.
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Background
Cervical cancer is a serious female malignancy affecting women’s health worldwide. The HGF/c-MET signaling pathway is activated in cervical cancer. Adipose-derived stem cells (ADSCs) with multipotential differentiation can carry out paracrine secretion of hepatocyte growth factor (HGF). Here, we investigated the effect and underlying mec...
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Stem cell-based therapies are considered one of the most promising disciplines in biomedicine. Bladder cancer patients could benefit from therapies directed to promote healing after invasive surgeries or to lessen urinary incontinence, a common side effect of both cancer itself and the treatment. However, the local delivery of cells producing large...
Citations
... ADSCs, abundant in adipose tissue, can differentiate into various cell types, including those comprising the TME. Moreover they also secrete cytokines regulating tumor cell proliferation and apoptosis 19,20 . These cytokines, along with chemokines, play a crucial role in modulating tumor cell behavior and immune response, contributing to the complexity of the TME 21 . ...
Adipose-derived stem cells (ADSCs) are promising in regenerative medicine. Their proliferation, survival and activation are influenced by specific signals within their microenvironment, also known as niche. The stem cell niche is regulated by complex interactions between multiple cell types. When transplanted in a specific area, ADSCs can secrete several immunomodulatory factors. At the same time, a tumor microenvironment can influence stem cell behavior, modulating proliferation and their ability to differentiate into a specific phenotype. Whitin this context, we exposed ADSCs to plasma samples derived from human patients diagnosed with prostate cancer (PC), or precancerous lesions (PL), or benign prostatic hyperplasia (BPH) for 4, 7 or 10 days. We then analyzed the expression of main stemness-related markers and cell-cycle regulators. We also measured cytokine production and polyamine secretion in culture medium and evaluated cell morphology and collagen production by confocal microscopy. The results obtained from this study show significant changes in the morphology of ADSCs exposed to plasma samples, especially in the presence of prostate cancer plasma, suggesting important implications in the use of ADSCs for the development of new treatments and application in regenerative medicine.
... Interestingly, MET has been recognised as an oncogene associated with Ras, PI3K and Wnt signalling pathways [32]. In addition, MET expression is higher in cervical cancer versus normal cervical tissues, and targeting MET reduces migration, invasion and proliferation in cervical cell lines [33,34]. This upregulation of MET seems to be dependent on E5 and E6 oncoproteins ( [35,36], which suggests that HPV can modulate MET functions through different mechanisms. ...
Multiple cellular pathways are affected by HPV E6 and E7 oncoproteins, including endocytic and cellular trafficking. HPV-16 E7 can target the adaptor protein (AP) complex, which contains proteins important during endocytosis transport. To further investigate the role of HPV E7 during this process, we analysed the expression of cell surface proteins in NIKS cells expressing HPV-16 E7. We show that different cell surface proteins are regulated by HPV-16 E7 via interaction with AP2. We observed that the expression of MET and CD109 membrane protein seems to be upregulated in cells expressing E7. Moreover, the interaction of MET and CD109 with AP2 proteins is disrupted by HPV-16 E7. In addition, in the absence of HPV-16 E7, there is a downregulation of the cell membrane expression of MET and CD109 in HPV-positive cell lines. These results expand our knowledge of the functions of E7 and open new potential cellular pathways affected by this oncoprotein.
... Enhancing the expression and activation of c-MET promotes uncontrolled cellular proliferation, survival, angiogenesis, invasion, metastasis, and chemoresistance (11)(12)(13). Recently, activation and overexpression of the HGF/c-MET pathway can promote cervical cancer proliferation and invasion of cervical cancer (14,15). More importantly, c-MET activates different downstream intracellular signaling pathways, such as Ras/MAPK/ERK and Ras/PI3K/AKT, pathways are intimate associations with resistance to various anti-tumor drugs (16). ...
Background:
The drug resistance of chemotherapeutic agents leads to unsatisfactory survival rates for cervical cancer (CC) patients. We aimed to explore the effect of FOXP2 on the sensitivity of CC cells to cisplatin (DDP) and its mechanism in Changde, China in 2018.
Methods:
A Total of 6 cervical cancer tissue samples including 3 patients with cisplatin sensitivity and 3 patients with cisplatin resistance, who received DDP-based treatment, were obtained from Changde First People's Hospital, Changde City during 2021, and FOXP2 level was detected by Western blot. The expression levels of FOXP2 and c-MET (hepatocyte growth factor receptor, c-MET) in cells were determined by q-PCR and Western blot analysis. The cell survival, apoptosis, and clone formation were analyzed by flow cytometry, MTT assay, or clone formation assay. Dual-luciferase reporter assays and Chromatin immunoprecipitation were applied to verify the regulation between FOXP2 and c-MET.
Results:
FOXP2 was downregulated in cisplatin-resistant cervical cancer tissues and cells compared with control. FOXP2 overexpression in SiHa/DDP cells inhibited cell proliferation and promoted cell apoptosis, whereas down-regulation of FOXP2 in SiHa cells had the opposite result. FOXP2 enhanced chemosensitive to DDP in CC cells. FOXP2 is negatively correlated with c-MET expression level in SiHa and SiHa/DDP cells. Mechanistically, FOXP2 binds to the promoter region of c-MET to regulate its expression in CC cells negatively. Overexpression of c-MET can attenuate the enhancement of DDP-induced apoptosis caused by FOXP2 overexpression.
Conclusion:
This is a novel study on the role of FOXP2 in promoting the DDP sensitivity of CC cells by inhibiting c-MET. The FOXP2/c-MET signaling axis uncovered in the present study may be a novel therapeutic target for the DDP therapy resistance of CC.
... Informed consent was obtained from all the participators. hADSCs were isolated by the collagenase digestion method (Luo et al. 2018;Zhai et al. 2020). Under sterile conditions, the adipose tissue (50-100 g) was washed three times with phosphate buffer solution (PBS) to remove anesthetic drugs and blood cells. ...
Adipose derived stem cells (ADSCs) have been increasingly explored for use in cell-based therapy against ischemic diseases. However, unsatisfactory angiogenesis limits the therapeutic efficacy. Netrin-1, a known axon guidance molecule, improves neovascularization in the ischemic region. Thus, our study was performed to evaluate the potential effect of Netrin-1 on the angiogenic behaviors of human ADSCs (hADSCs). hADSCs acquired from human abdominal adipose tissue were modified by liposome transfection of Netrin-1 plasmid, and the proliferation of hADSCs was determined by Cell Counting Kit-8 (CCK-8) assay. The transcript levels of pro-invasive proteins such as matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP-9), were measured to test migratory and invasive capabilities, and the levels of vascular endothelial growth factors were assayed to monitor angiogenic activity. Our results showed that Netrin-1 overexpression enhanced the proliferation of hADSCs, and promoted the migration and invasion of hADSCs, as indicated by increased levels of MMP-2 and MMP-9. Furthermore, Netrin-1 overexpression increased the expression of vascular endothelial growth factor and placental growth factor in hADSCs. Our results highlighted the possibility that genetic modification of hADSCs by Netrin-1 overexpression might be beneficial for cell transplantation therapy against ischemic diseases.
... A study investigated the impact of ASCs on the proliferation and migration of cervical cancer cell lines [255]. The data suggest that both co-culture with ASCs and using an ASC-conditioned medium promoted the proliferation and invasion of cervical cancer cells in vitro. ...
The significant increase in the incidence of obesity represents the next global health crisis. As a result, scientific research has focused on gaining deeper insights into obesity and adipose tissue biology. As a result of the excessive accumulation of adipose tissue, obesity results from hyperplasia and hypertrophy within the adipose tissue. The functional alterations in the adipose tissue are a confounding contributing factor to many diseases, including cancer. The increased incidence and aggressiveness of several cancers, including colorectal, postmenopausal breast, endometrial, prostate, esophageal, hematological, malignant melanoma, and renal carcinomas, result from obesity as a contributing factor. The increased morbidity and mortality of obesity-associated cancers are attributable to increased hormones, adipokines, and cytokines produced by the adipose tissue. The increased adipose tissue levels observed in obese patients result in more adipose stromal/stem cells (ASCs) distributed throughout the body. ASCs have been shown to impact cancer progression in vitro and in preclinical animal models. ASCs influence tumor biology via multiple mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma. Emerging evidence indicates that obesity induces alterations in the biological properties of ASCs, subsequently leading to enhanced tumorigenesis and metastasis of cancer cells. As the focus of this review is the interaction and impact of ASCs on cancer, the presentation is limited to preclinical data generated on cancers in which there is a demonstrated role for ASCs, such as postmenopausal breast, colorectal, prostate, ovarian, multiple myeloma, osteosarcoma, cervical, bladder, and gastrointestinal cancers. Our group has investigated the interactions between obesity and breast cancer and the mechanisms that regulate ASCs and adipocytes in these different contexts through interactions between cancer cells, immune cells, and other cell types present in the tumor microenvironment (TME) are discussed. The reciprocal and circular feedback loop between obesity and ASCs and the mechanisms by which ASCs from obese patients alter the biology of cancer cells and enhance tumorigenesis will be discussed. At present, the evidence for ASCs directly influencing human tumor growth is somewhat limited, though recent clinical studies suggest there may be some link.
... They have self-renewal ability and can secrete a variety of cytokines. Therefore, ADSCs are thought to serve specific roles in the onset and progression of some diseases, such as the occurrence and development of breast cancer, cervical cancer and other types of tumors (12,13), as well as of a variety of autoimmune diseases. At present, the transplantation of ADSCs for the treatment of autoimmune diseases is an important topic in academic circles. ...
The aim of the present study was to explore the effect and mechanism of action of adipose-derived stem cells (ADSCs) on Sjögren syndrome (SS) to develop novel and more effective methods for SS treatment. ADSCs, dexamethasone or normal saline was injected into the submandibular gland (SMG) of three 12-week-old non-obese diabetic (NOD) mice. The degree of lymphocyte infiltration was considered as a criterion for judging disease progression, hematoxylin and eosin staining was performed to observe the pathological state, and the expression levels of TAZ, E-cadherin and α-catenin were assessed by western blotting. ADSC transplantation triggered an inhibitory effect on the progression of SS, which was slightly stronger compared with that of dexamethasone treatment. This was found to be related to the Hippo signaling pathway. In addition, TAZ protein expression levels decreased gradually with the progression of the disease; immunofluorescence staining showed that the expression of E-cadherin and TAZ followed similar trends. Notably, the expression of TAZ, p-TAZ, E-cadherin and α-catenin in NOD mice were lower compared with that in Control mice. Similarly, the ratio of p-TAZ/TAZ also decreased, which means that the activation level of Hippo signal pathway decreased. The results suggest that ADSCs may exert a therapeutic effect against SS and may postpone its progression by upregulating the Hippo signaling pathway.
... Recent experiments have revealed the tumor-promoting role of HGF in cancer. Overexpression of HGF enhances the growth and invasion of cervical cancer cells via affecting c-Met [435]. By inducing the c-Met/PI3K/Akt axis, HGF induces EMT and mediates drug resistance in pancreatic cancer [436]. ...
Cancer is one of the leading causes of death worldwide, and the factors responsible for its progression need to be elucidated. Exosomes are structures with an average size of 100 nm that can transport proteins, lipids, and nucleic acids. This review focuses on the role of exosomes in cancer progression and therapy. We discuss how exosomes are able to modulate components of the tumor microenvironment and influence proliferation and migration rates of cancer cells. We also highlight that, depending on their cargo, exosomes can suppress or promote tumor cell progression and can enhance or reduce cancer cell response to radio- and chemo-therapies. In addition, we describe how exosomes can trigger chronic inflammation and lead to immune evasion and tumor progression by focusing on their ability to transfer non-coding RNAs between cells and modulate other molecular signaling pathways such as PTEN and PI3K/Akt in cancer. Subsequently, we discuss the use of exosomes as carriers of anti-tumor agents and genetic tools to control cancer progression. We then discuss the role of tumor-derived exosomes in carcinogenesis. Finally, we devote a section to the study of exosomes as diagnostic and prognostic tools in clinical courses that is important for the treatment of cancer patients. This review provides a comprehensive understanding of the role of exosomes in cancer therapy, focusing on their therapeutic value in cancer progression and remodeling of the tumor microenvironment.
Graphical Abstract
... Regarding proliferation and aggressiveness, Zhai et al demonstrated that ASCs elicit growth and invasion in cervical cancer by modulation of the HGF/c-Met pathway. 135 In ovarian cancer, ASCs have a stimulating effect on cancer growth and invasion, which is mediated by elevated MMP-2 and MMP-9 expression, thymosin beta 4X-linked expression, and stabilization of the TAZ protein by PAX8 expression. 49,136,137 In conclusion, ASCs seem to promote the progression of ovarian and cervical cancer whereas in prostate cancer the current data are less clear. ...
Adipose-derived stem or stromal cells (ASCs) possess promising potential in the fields of tissue engineering and regenerative medicine due to their secretory activity, their multilineage differentiation potential, their easy harvest, and their rich yield compared to other stem cell sources. After the first identification of ASCs in humans in 2001, the knowledge of their cell biology and cell characteristics have advanced, and respective therapeutic options were determined. Nowadays, ASC-based therapies are on the verge of translation into clinical practice. However, conflicting evidence emerged in recent years about the safety profile of ASC applications as they may induce tumor progression and invasion. Numerous in-vitro and in-vivo studies demonstrate a potential pro-oncogenic effect of ASCs on various cancer entities. This raises questions about the safety profile of ASCs and their broad handling and administration. However, these findings spark controversy as in clinical studies ASC application did not elevate tumor incidence rates, and other experimental studies reported an inhibitory effect of ASCs on different cancer cell types. This comprehensive review aims at providing up-to-date information about ASCs and cancer cell interactions, and their potential carcinogenesis and tumor tropism. The extracellular signaling activity of ASCs, the interaction of ASCs with the tumor microenvironment, and 3 major organ systems (the breast, the skin, and genitourinary system) will be presented with regard to cancer formation and progression.
... hADSCs have been reported to efficiently promote the invasion of human endothelial cells 41 and of breast cancer and cervical cancer cells. [42][43][44] And finally, human bone marrow-derived skeletal stem cells (hBM-SSCs) were demonstrated to control the motility of human prostate cancer cells in an in vivo mouse metastasis model. 45 In our opinion, the fact that apart from MSCs the totally different entity of hematopoietic progenitor cells (HPCs) also harbor a motility-inducing potential, strongly suggests this feature to be common to multipotent stem cells. ...
... 15,61 hADSCs induce invasive behavior by paracrine targeting of the hepatocyte growth factor (HGF)/ mesenchymal-epithelial transition factor (c-Met) pathway. 44 hUC-MSCs and hUC-MSC-derived extracellular vesicles drive breast cancer motility via activation of the extracellular signal-regulated kinases (ERK) pathway, which can be blocked by the clinically used ERK inhibitor UO126. 52,53 The pro-migratory effects of hPMSCs mediated by HGF-induced adenosine 3ʹ,5ʹ-cyclic monophosphate (cAMP) production and Ras-related protein 1 (Rap1) activation was shown to be affected by the well-known protein kinase A (PKA) inhibitor H89, and by treatment with Rap1 siRNA or a c-Met blocking antibody. ...
It is the hope of clinicians and patients alike that stem cell-based therapeutic products will increasingly become applicable remedies for many diseases and injuries. Whereas some multipotent stem cells are already routinely used in regenerative medicine, the efficacious and safe clinical translation of pluripotent stem cells is still hampered by their inherent immunogenicity and tumorigenicity. In addition, stem cells harbor the paracrine potential to affect the behavior of cells in their microenvironment. On the one hand, this property can mediate advantageous supportive effects on the overall therapeutic concept. However, in the last years, it became evident that both, multipotent and pluripotent stem cells, are capable of inducing adjacent cells to become motile. Not only in the context of tumor development but generally, deregulated mobilization and uncontrolled navigation of patient's cells can have deleterious consequences for the therapeutic outcome. A more comprehensive understanding of this ubiquitous stem cell feature could allow its proper clinical handling and could thereby constitute an important building block for the further development of safe therapies.
... More important, the first follow-up studies of patients after in situ injections of allogenic ADSCs are encouraging in terms of an absence of allogenic immunization [119]. Among all these clinical trials, no evidence of a potential pro-oncogenic role of ADSCs has been shown despite pre-clinical studies that raised some evidence that adipose stem cells might have a role in the tumor microenvironment as well as in tumor promotion [132][133][134]. A recent report demonstrated that human lipoaspirate material had no pro-oncogenic properties in vitro [135]. ...
... In addition, there is some unresolved questions especially on the viability and potential cell death and loss of activity with local administration. To our knowledge only one experimental study conducted in rats and using a bioluminescent marker, demonstrated that the presence of cells decreased rapidly after two days post-injection within a fistula [132]. This poses the problem of repeated injections of ADSCs but the rhythm remains to be fixed. ...
Between 20 to 25% of Crohn’s disease (CD) patients suffer from perianal fistulas, a marker of disease severity. Seton drainage combined with anti-TNFα can result in closure of the fistula in 70 to 75% of patients. For the remaining 25% of patients there is room for in situ injection of autologous or allogenic mesenchymal stem cells such as adipose-derived stem/stromal cells (ADSCs). ADSCs exert their effects on tissues and effector cells through paracrine phenomena, including the secretome and extracellular vesicles. They display anti-inflammatory, anti-apoptotic, pro-angiogenic, proliferative, and immunomodulatory properties, and a homing within the damaged tissue. They also have immuno-evasive properties allowing a clinical allogeneic approach. Numerous clinical trials have been conducted that demonstrate a complete cure rate of anoperineal fistulas in CD ranging from 46 to 90% of cases after in situ injection of autologous or allogenic ADSCs. A pivotal phase III-controlled trial using allogenic ADSCs (Alofisel®) demonstrated that prolonged clinical and radiological remission can be obtained in nearly 60% of cases with a good safety profile. Future studies should be conducted for a better knowledge of the local effect of ADSCs as well as for a standardization in terms of the number of injections and associated procedures.
