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BM-EPCs were mobilzed into ciculation in orthotropic HCC mice. (A) A schematic and flow chart shows how GFP + -BM orthotropic HCC mice were established to assess the contribution of BM-EPCs to HCC induced neovascularization. (B) GFP + BM orthotopic HCC mice with classic pathological characteristics . 1, The gross change of liver in GFP + BM-orthotopic HCC mice, 2, Intratumor hemorrhage. 3, Intratumor neovasculariztion, bar, 10 µm (paraffin, H&E, 2 µm). (C) FCM analysis of GFP positive rate of BMCs in GFP transgenic mice, normal mice, and GFP + BM HCC mice, respectively. (D and E) Dynamic change of circulating BM-EPCs and serum VEGF, PDGF in HCC mice vs sham-operation group. The number of circulating GFP + CD133 + , GFP + CD34 + , GFP + VEGFR2 + cells, and the levels of serum VEGF, PDGF in HCC group increased significantly compared with those in sham-operation group. * P<0.05; ** P<0.01; normal, normal mice; n=8. ◼, HCC mice group; ◻, sham-operation group.
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Obvious neovascularization is a key feature of hepatocellular carcinoma (HCC) and the status of neovascularization in HCC is closely correlated with the tumor growth and patient prognosis. The actual effect of current antivascular treatment including embolization to HCC is not satisfactory. Compensatory angiogenesis is one of the primary causes res...
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... HCC model. In order to trace BM cells (BMCs), GFP + BM-C57BL/6 mice were established by transplanting whole BMCs of GFP-transgenic mice (22) (Fig. 1A). Four weeks later, FCM analysis was used to confirm full BM recovery. Orthotropic HCC mice were induced by an intrahe- patic injection of 1~2x10 5 H22 hepatoma cells (23) (gift from Dr Rutian Li, Institute of Oncology, Nanjing University, China). The control group received the same volume of PBS. To further confirm the role of EPCs on ...
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... success of establishing the GFP-labeled BM-orthotropic HCC model. The pathological examinations demonstrated that GFP + BM-orthotropic HCC mice retained classic clinicopatho- logical characteristics (Fig. 1B). The high GFP + rate of circulating nucleated cells in the HCC model (>95%) (Fig. 1C) suggested that nearly all BMCs express GFP stably, guaranteeing success in distinguishing BM-EPCs derived VECs from pre-existed VECs (Fig. ...
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... success of establishing the GFP-labeled BM-orthotropic HCC model. The pathological examinations demonstrated that GFP + BM-orthotropic HCC mice retained classic clinicopatho- logical characteristics (Fig. 1B). The high GFP + rate of circulating nucleated cells in the HCC model (>95%) (Fig. 1C) suggested that nearly all BMCs express GFP stably, guaranteeing success in distinguishing BM-EPCs derived VECs from pre-existed VECs (Fig. ...
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... examinations demonstrated that GFP + BM-orthotropic HCC mice retained classic clinicopatho- logical characteristics (Fig. 1B). The high GFP + rate of circulating nucleated cells in the HCC model (>95%) (Fig. 1C) suggested that nearly all BMCs express GFP stably, guaranteeing success in distinguishing BM-EPCs derived VECs from pre-existed VECs (Fig. ...
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... HCC mice were 1.26±0.70, 1.77±1.35 and 1.08±0.59%, respectively, which increased dramatically compared with those in control mice (0.12±0.15, 0.31±0.24, and 0.46±0.34%). By day 21, mean percentages of circulating GFP + CD133 + , GFP + VEGFR2 + cells (1.88±0.98 and 1.8±0.88%) were also elevated relative to control mice (0.20±0.23 and 0.55±0.19%) (Fig. 1D). The ELISA results indicated that compared with a transient increase in the control, serum VEGF and PDGF maintained at a higher level were obviously induced by HCC (Fig. ...
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... day 21, mean percentages of circulating GFP + CD133 + , GFP + VEGFR2 + cells (1.88±0.98 and 1.8±0.88%) were also elevated relative to control mice (0.20±0.23 and 0.55±0.19%) (Fig. 1D). The ELISA results indicated that compared with a transient increase in the control, serum VEGF and PDGF maintained at a higher level were obviously induced by HCC (Fig. ...
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... into the endothelium because the stem cells would be undetectable after the loss of their surface markers during differentiation. Based on the broad sensing of BM-EPCs (7,21), the GFP combined with the EC-specific antigen CD31 (18) makes it easy to identify whether the BM-EPCs incorporate into the vascular endothelium in the GFP + BM HCC mice (Fig. 1A). In this study, we found that the CD31 + GFP + cells existed not only in the peripheral vessels but also in the intratumoral vessels and in vessel walls of different sizes, such as sinusoids, central veins and hepatic veins (Fig. 2D-F). These CD31 + GFP + cells offer direct evidence that the BM-EPCs contribute to the HCC-induced ...
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... BM-EPCs, were mainly concen- trated in HCC tissues ( Fig. 2A), as measured by quantitative PCR (Fig. 2B). Moreover, also injected BM-EPCs homed to TT with high specificity (Fig. 3D). To understand the homing mecha- nism, the expression of cell adhesion molecules ICAM1, VCM1 and VEGF in TT and TF was examined. We found increased serum VEGF, PDGF (Fig. 1E) and that VEGF, ICAM1 and VCAM1 were predominately expressed in TT (Fig. 4). ICAM-1 is considered the main cellular adhesive molecule and VEGF is the most essential mobilization factor (29,30). We reason- ably inferred that with HCC proliferation, the BM-EPCs were mobilized into circulation by BM mobilization factors released from HCC ...
Citations
... Bone marrow endothelial progenitor cells (BM-EPCs), a type of stem cell derived from adult bone marrow, have the ability to self-renew and differentiate into mature endothelial cells, and have been shown to promote angiogenesis during tumor growth and metastasis [15] . Recent studies have shown that CSCs promoted BM-EPC differentiation and induce tumor angiogenesis [16] . ...
Prostate cancer (PCa) is one of the most common malignant tumors in men worldwide. The tumor microenvironment (TME) plays an important role in the development of tumors, and regulation of the acidic TME caused by insufficient tissue perfusion and tumor progression is an important strategy in cancer treatment. However, the effects of an acidic TME on PCa are unknown. In this study, we first examined the effects of an acidic TME on PCa through bioinformatics analysis of the TCGA database, and proposed a prognostic risk assessment model based on the acidic TME that could effectively predict the progression, metastasis and prognosis of PCa. Then, using cell proliferation, matrix adhesion, and Transwell migration and invasion assays, we showed that the acidic TME promoted PCa development and progression. Finally, we demonstrated that Asiaticoside, a traditional Chinese herb, may act as a potential drug to target and inhibit cancer stem cells (CSCs), thereby reducing tumor angiogenesis in PCa. Taken together, this study provided new perspective for the pathogenesis of PCa and highlighted a novel therapeutic strategy that targets PCa CSCs.
... LSECs drive HCC neoangiogenesis by upregulation of VEGFR and recruitment of bone-marrow-derived endothelial progenitor cells (BM-EPC).44,45 By secretion of chemokines (CXCL10, CCL2, CCL3) and upregulation of adhesion molecules such as VCAM-1 and CD151, LSECS in the TME facilitate recruitment of leucocytes, such as regulatory T cells, thereby contributing to an immunosuppressive tumour milieu.46,47 ...
Hepatocellular carcinoma (HCC) is a major public health burden with increasing incidence and mortality worldwide. Arising almost exclusively on the background of chronic liver disease, the tumour microenvironment plays a tremendous role in the occurrence and progression of HCC. With the emergence of checkpoint inhibitor‐based combination therapies as first‐line therapy in advanced HCC, the tumour microenvironment has drawn increasing attention as a target for novel therapeutic approaches. In fact, checkpoint‐inhibitor‐based immunotherapies currently dominate clinical studies on HCC therapy. Importantly, whilst checkpoint‐inhibitor‐based immune‐oncology primarily targets T‐cells, the tumour microenvironment consists of a wide variety of different cell populations that show complex interactions with each other and the malignant tumour cells. Stromal cells and representatives of the innate immune system, such as macrophages, neutrophils and natural killer cells hereby orchestrate the initial immune response and thus appear as attractive targets for broad therapeutic effects, less susceptible to immune escape. In this review, we aim to discuss the current knowledge on the role of innate immune cells and stromal cell populations in HCC initiation and progression as well as related novel therapeutic concepts. The tumour microenvironment consists of a wide variety of different cell populations that show complex interactions with each other and the malignant tumour cells. In this review, we aim to discuss the current knowledge on the role of innate immune cells and stromal cell populations in HCC initiation and progression as well as related novel therapeutic concepts.
... According to two reports, more than 90% of hepatocellular cancers stain positive for PSMA in the tumor vasculature [19,20]. Zhu et al. suggested that the process of endothelial cell recruitment to HCC occurs early and throughout the process of hepatic tumorigenesis, making an endothelial cell tracer an ideal marker for early disease detection [21]. In another study assessing 103 HCC tissue samples using immunohistochemical staining, Jiao and collaborators reported PSMA expression in more than 74% of tumor vasculature [22]. ...
Background
While prostate specific membrane antigen (PSMA) is overexpressed in high-grade prostate cancers, it is also expressed in tumor neovasculature and other malignancies, including hepatocellular carcinoma (HCC). Importantly, no functional imaging for HCC is clinically available, making diagnosis and surveillance following local therapies particularly challenging. ¹⁸ F-DCFPyL binds with high affinity to PSMA yet clears rapidly from the blood pool. PET imaging with ¹⁸ F-DCFPyL may represent a new tool for staging, surveillance and assessment of treatment response in HCC. The purpose of this Functional Imaging Liver Cancer (FLIC) trial is to assess the ability of ¹⁸ F-DCFPyL-PET/CT to detect sites of HCC.
Methods
This is a phase II multi-site prospective imaging trial with a plan to enroll 50 subjects with suspected HCC on standard of care CT or MRI and eligible for standard local treatment. Participants will undergo a baseline ¹⁸ F-DCFPyL-PET/CT, prior to therapy. Subjects will also be scanned with ¹⁸ F-FDG-PET/CT within 2 weeks of ¹⁸ F-DCFPyL-PET/CT. Participants will undergo histopathologic assessment and standard of care local treatment for HCC within a multidisciplinary team context. Participants with histopathologic confirmation of HCC and a positive baseline ¹⁸ F-DCFPyL-PET/CT will undergo a post-treatment ¹⁸ F-DCFPyL-PET/CT during the first routine follow-up, typically within 4–8 weeks. Subjects with negative baseline ¹⁸ F-DCFPyL-PET/CT will not be re-scanned after treatment but will remain in follow-up. Participants will be followed for 5-years to assess for progression-free-survival. The primary endpoint is the positive predictive value of ¹⁸ F-DCFPyL-PET for HCC as confirmed by histopathology. Secondary endpoints include comparison of ¹⁸ F-DCFPyL-PET/CT with CT, MRI, and ¹⁸ F-FDG-PET/CT, and evaluation of the value of ¹⁸ F-DCFPyL-PET/CT in assessing treatment response following local treatment. Exploratory endpoints include next generation sequencing of tumors, and analysis of extracellular vesicles to identify biomarkers associated with response to therapy.
Discussion
This is a prospective imaging trial designed to evaluate whether PSMA-PET/CT imaging with ¹⁸ F-DCFPyL can detect tumor sites, assess local treatment response in HCC patients, and to eventually determine whether PSMA-PET/CT could improve outcomes of patients with HCC receiving standard of care local therapy. Importantly, this trial may help determine whether PSMA-selective radiopharmaceutical therapies may be beneficial for patients with HCC.
Clinical trial registration
NIH IND#133631. Submission date: 04-07-2021. Safe-to-proceed letter issued by FDA: 05.07.2021. NIH IRB #00080. ClinicalTrials.gov Identifier NCT05009979 . Date of Registry: 08-18-2021. Protocol version date: 01-07-2022.
... 21,23 HCC are highly vascular neoplasms and the recruitment of bone marrow-derived endothelial progenitor cells that are essential for neoangiogenesis occurs in the early phases of HCC development. 43 As a result, an endothelial cell marker such as PSMA can be valuable as a tracer for early detection of HCC and occult metastatic disease. Gallium-68-PSMA has a sufficiently long half-life and minimal physiological uptake by the native liver which makes it suitable for liver imaging. ...
Accurate classification of well-differentiated hepatocellular neoplasms can be challenging especially in core biopsies. Prostate specific membrane antigen (PSMA) has been shown to highlight tumor-associated neovasculature in many nonprostatic solid tumors including hepatocellular carcinoma (HCC). Archived 164 hepatectomies and explants with 68 HCCs, 31 hepatocellular adenoma (HA), 24 dysplastic nodules (DN), and 42 metastases were retrieved, and pathologic parameters were evaluated. Sensitivity, specificity, accuracy, positive, and negative predictive values for correct diagnosis of HCC were calculated for PSMA and CD34 immunostains in tissue sections and HCC tissue microarrays. PSMA positivity was defined as capillarized sinusoidal/tumor-associated vessel staining involving ≥5% of the tumor area. In all, 55/68 (80.9%)HCC and 37/42 (88.1%) of liver metastasis were PSMA positive. PSMA was negative in HA, DN, and background liver (100% specificity). CD34 had a 98.5% sensitivity but a 65.5% specificity in identifying HCC.
PSMA sensitivity remained high in the HCC tissue microarray (89.7%). PSMA was more accurate than CD34 (95.5% vs. 69.7%) in distinguishing grade 1 HCC from HA and high-grade DN while retaining high sensitivity (80%). The degree of PSMA positivity in
HCC was greater in older,male, and human immunodeficiency virus patients (P<0.05). No associations were found between PSMA staining and other tumor parameters (P>0.05). PSMA is a marker of neoangiogenesis with increased expression in both primary and
metastatic hepatic malignancies. Neovascular PSMA expression is more specific and accurate than CD34 for differentiating HCC from benign and precursor hepatic lesions. Diagnostic and therapeutic utility of PSMA radioligands in malignant liver neoplasms warrant further clinical investigations.
... The highly angiogenic nature of HCC is associated with increased classical growth factors such as VEGF and PDGF, whilst classical adhesion molecules such as ICAM-1 and VCAM-1 are preferentially expressed on tumour tissue. It has been shown that bone marrow-derived erythroid progenitor cells (BM-EPCs) play a prominent role in HCC angiogenesis (Zhu et al., 2012). LSEC expression of distinct adhesion molecules and growth factors could drive BM-EPCs recruitment, especially since BM-EPC homing to tumour tissue is thought to be via cellular adhesion molecules ICAM-1, VCAM-1, and VEGF. ...
Liver sinusoidal endothelial cells (LSEC) form a unique barrier between the liver sinusoids and the underlying parenchyma, and thus play a crucial role in maintaining metabolic and immune homeostasis, as well as actively contributing to disease pathophysiology. Whilst their endocytic and scavenging function is integral for nutrient exchange and clearance of waste products, their capillarisation and dysfunction precedes fibrogenesis. Furthermore, their ability to promote immune tolerance and recruit distinct immunosuppressive leukocyte subsets can allow persistence of chronic viral infections and facilitate tumour development. In this review, we present the immunological and barrier functions of LSEC, along with their role in orchestrating fibrotic processes which precede tumourigenesis. We also summarise the role of LSEC in modulating the tumour microenvironment, and promoting development of a pre-metastatic niche, which can drive formation of secondary liver tumours. Finally, we summarise closely inter-linked disease pathways which collectively perpetuate pathogenesis, highlighting LSEC as novel targets for therapeutic intervention.
... Some studies have reported that the levels of circulating hematopoietic stem cells (HSCs) and EPCs in the peripheral blood rise with advancing tumor stage [20][21][22]. They also correlate with tumor staging, distant metastasis and recurrence after surgical treatment [23,24]. ...
Background and aim: Circulating hematopoietic stem cells (HSCs), circulating endothelial progenitor cells (EPCs) and cancer stem cells (CSCs) contribute to tumor development and progression and can predict patient outcome. The aim of this study was to investigate the frequency of circulating HSCs, EPCs and CSCs in the peripheral blood of patients with hepatocellular carcinoma (HCC) and to explore their potential prognostic significance for HCC patients.
Methods: The study included 30 HCC patients and 20 healthy controls. The HSCs and EPCs were enumerated with CD45, CD34, CD133, CD144 markers, while CSCs were enumerated with CD45, CD44, CD133 markers using flow cytometry.
Results: The mean percentages of circulating HSCs were significantly lower in HCC patients than the controls (p = .001), whereas the mean percentages of EPCs within the HSCs subpopulation were significantly higher in the HCC patients than the controls (p = .002). The absolute count of CSCs within 100,000 peripheral blood mononuclear cells was 23.5 ± 3.4 in the HCC patients. Also, the mean percentages of circulating HSCs, EPCs and the number of CSCs were significantly increased in patients with multiple hepatic focal lesions than in patients with a single hepatic focal lesion. Both circulating HSCs and EPCs showed significant positive correlation with the level of AFP and with the numbers of CSCs. In the meantime, the numbers of CSCs revealed significant direct correlation with ALT, AST and AFP levels. The one-year overall survival (OS) of the patients was 77.5%. High levels of CSCs, HSCs and EPCs at diagnosis were all associated with worse outcome for the HCC patients.
Conclusions: Significant changes in the levels of the circulating HSCs, EPCs and CSCs occur in HCC. These changes help the diagnosis and the prediction of HCC outcome, as higher levels of these cells are associated with worse OS.
... Data on circulating KDR + (CD34 − CD133 − ) cells are largely lacking in the literature. Increased levels of circulating KDR + bonemarrow-derived EPCs were reported in a cancer mouse model [38], which is compatible with our findings in glioma patients. Increased HPC levels were observed previously in untreated GBM patients [39], while levels seem to normalize Figure 5: Correlation between plasma factors and EPC subtypes. ...
Although extensive angiogenesis takes place in glial tumors, antiangiogenic therapies have remained without the expected success. In the peripheral circulation of glioma patients, increased numbers of endothelial precursor cells (EPCs) are present, potentially offering targets for antiangiogenic therapy. However, for an antiangiogenic therapy to be successful, the therapy should specifically target glioma-related EPC subsets and secreted factors only. Here, we compared the EPC subsets and plasma factors in the peripheral circulation of patients with gliomas to acute myocardial infarctions. We investigated the five most important EPC subsets and 21 angiogenesis-related plasma factors in peripheral blood samples of 29 patients with glioma, 14 patients with myocardial infarction, and 20 healthy people as controls, by FACS and Luminex assay. In GBM patients, all EPC subsets were elevated as compared to healthy subjects. In addition, HPC and KDR ⁺ cell fractions were higher than in MI, while CD133 ⁺ and KDR ⁺ CD133 ⁺ cell fractions were lower. There were differences in relative EPC fractions between the groups: KDR ⁺ cells were the largest fraction in GBM, while CD133 ⁺ cells were the largest fraction in MI. An increase in glioma malignancy grade coincided with an increase in the KDR ⁺ fraction, while the CD133 ⁺ cell fraction decreased relatively. Most plasma angiogenic factors were higher in GBM than in MI patients. In both MI and GBM, the ratio of CD133 ⁺ HPCs correlated significantly with elevated levels of MMP9. In the GBM patients, MMP9 correlated strongly with levels of all HPCs. In conclusion, the data demonstrate that EPC traffic in patients with glioma, representing neoplasia, is different from that in myocardial infarction, representing tissue regeneration. Glioma patients may benefit from therapies aimed at lowering KDR ⁺ cells and HPCs.
... The standardization is based on the use of state-of-the-art bright fluorochrome conjugates and the combination of the CD34, CD45, CD133, and CD309 markers. [14][15][16][17][18][19][20][21][22][23] Quantitative changes in the circulating Endothelial Progenitor Cells (EPCs) population, therefore, might be considered as a significant indicator of angiogenesis activity. [24][25][26] The heterogeneous nature of colorectal carcinoma and the changes in their genomic integrity also play a considerable role in the generation of drug resistance and in mechanisms promoting development of metastases to the liver. ...
... [24][25][26]45,46] Circulating endothelial cell progenitors mobilized by VEGF have been found to promote angiogenesis. [14,15,18,20] High level of EPCs was correlated with advances of the disease and return to normal following antiangiogenic treatment. [18,26] Matsusaka et al and Ronzoni et al have also reported that the high number of EPCs is correlated with poor outcome for patients with metastatic colorectal cancer. ...
... The experience of many research centers indicates that the level of endothelial progenitor cells (EPCs) is essential for tumor growth. [14][15][16][17][18][19][20][21][22][23] Recently, Zhu et al [14] revealed that EPCs are mobilized and incorporated into tumor vessels throughout the whole process of hepatocellular carcinoma (HCC) growth and Sun et al demonstrated the role of EPCs in HCC neovascularization. [23] EPCs constitute a relatively small, reaching less than 3%, subpopulation of hematopoietic CD45+ stem cells and a larger, amounting to 35%, subpopulation of vascular endothelium CD45-cells. ...
Angiogenesis represents one of the critical mechanisms that facilitates carcinoma development. The study objective was to evaluate whether the microsatellite instability of colorectal carcinoma has impact on the angiogenesis activity in liver metastases.
In a cohort of 80 randomly selected patients with stage IV colorectal carcinoma, 30% were recognized as microsatellite unstable (Microsatellite instability high-frequency (MSI-H)). The endothelial progenitor cell fraction (CD309+) was counted within the subpopulation of CD34+CD45+ cell and CD34+CD45- cells by flow cytometer. vascular endothelial growth factor (VEGF) factor levels were quantified in serum samples by enzyme-linked immunosorbent assay (ELISA). A control group consisted of 36 healthy volunteers. The relationship of genomic instability to angiogenesis activity was evaluated by multivariate analysis in comparison to the controls, adopting a P < .05 value as statistically significant.
The expression of endothelial progenitor cells (EPCs) and VEGF was significantly higher in MSI-H compared to both microsatellite stability (MSS) patients and healthy controls (P < .008). Multi-parametric analysis showed microsatellite instability (OR=9.12, P < .01), metastases in both lobes (OR = 32.83, P < .001) and simultaneous metastases outside liver (OR = 8.32, P < .01), as independent factors associated with increased angiogenesis as assessed by measures of EPC and VEGF. A higher percentage of EPCs within the white blood cell fraction (total % EPCs / white blood cells (WBC)) and higher serum concentrations of VEGF were present in patients with MSI-H colorectal cancer, and not with MSS cancers (P < .001).
MSI-H patients with colorectal cancer metastases are associated with the overexpression of circulating EPCs and VEGF, potentially driving angiogenesis. This should be considered in therapeutic decision-making.
... The participation of the BM-EPC subpopulation in HCC angiogenesis is considered uncertain by one of the authors [5,64] but otherwise, is mostly accepted [28,29,62,65,66]. Different types of BM-derived cells exhibit effects on HCC tumour growth in a coordinated manner by promoting angiogenesis. ...
... It was proven on a murine HCC model that during the development of HCC, a large number of bone marrow EPCs were mobilized into the circulation. Incorporation of these cells into ECs of different types of vessels (sinuses, capillary and great vessels) was observed [66]. Higher concentrations of circulating EPCs in patients with advanced unresectable HCC, as compared to patients with resectable HCC or those with liver cirrhosis, were observed [65]. ...
The liver is perfused by both arterial and venous blood, with a resulting abnormal microenvironment selecting for more-aggressive malignancies. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality worldwide. HCC is characterized by its hypervascularization. Improving the efficiency of anti-angiogenic treatment and mitigation of anti-angiogenic drug resistance are the top priorities in the development of non-surgical HCC therapies. Endoglin (CD105), a transmembrane glycoprotein, is one of the transforming growth factor β (TGF-β) co-receptors. Involvement of that protein in angiogenesis of solid tumours is well documented. Endoglin is a marker of activated endothelial cells (ECs), and is preferentially expressed in the angiogenic endothelium of solid tumours, including HCC. HCC is associated with changes in CD105-positive ECs within and around the tumour. The large spectrum of endoglin effects in the liver is cell-type- and HCC- stage-specific. High expression of endoglin in non-tumour tissue suggests that this microenvironment might play an especially important role in the progression of HCC. Evaluation of tissue expression, as well as serum concentrations of this glycoprotein in HCC, tends to confirm its role as an important biomarker in HCC diagnosis and prognosis. The role of endoglin in liver fibrosis and HCC progression also makes it an attractive therapeutic target. Despite these facts, the exact molecular mechanisms of endoglin functioning in hepatocarcinogenesis are still poorly understood. This review summarizes the current data concerning the role and signalling pathways of endoglin in hepatocellular carcinoma development and progression, and provides an overview of the strategies available for a specific targeting of CD105 in anti-angiogenic therapy in HCC.
... Concerning these results, literature shows that there is still a controversy to which account EPC migrate to the hypoxic tumor site and displays a plethora of variety in results [24], additionally stimulated by the already discussed inhomogeneous characterization and identification methods. Recently, a growing body of evidence suggests that migration depends mainly on histological tumor type together with tumor stage [29,35,39,40]. Thus, endothelial progenitor cells could play a critical role especially in initiating neo-vessel formation in early stage of tumor growth via the regulation of the angiogenic switch [41] as recently described for renal cell carcinoma [42]. ...
Objectives
Angiogenesis and neovascularisation plays a crucial role for tumorigenesis and tumor progression in head and neck squamous cell carcinoma (HNSCC). The aim of our study was to investigate the neovascularization capacity by endothelial progenitor cells (EPC) in tumor patient as a possible predictor for tumor progression and tumor stage.
Materials and methods
Therefore, we investigated the cell number and biologic activity by cell migration and colony-forming ability of EPC. Cells were isolated from the peripheral venous blood of 79 patients who suffer HNSCC in different stages of disease. Thirty-three healthy individuals served as the control group.
Results
Significantly increased biological activities were reflected by expression of the migration rate (1027 ± 1510) in comparison to the control group (632 ± 269) and the clonal potency measured by colony-forming unit (CFU) (tumor patients (19.7 ± 12.3) vs. control group (10.84 ± 4.8)). To determine whether or not EPC number can be used as a valid prognostic marker for clinical outcome of tumor patients, we furthermore compared a “high EPC-number-subgroup” (HI) with a “low EPC-number-subgroup” (LO) in a Kaplan-Meier survival curve. The HI-subgroup shows herein clearly a worse outcome.
Conclusions
Our findings indicate a possible pathway for EPC to play a critical role in the vasculogenesis and consequently in the progression of HNSCC.
Clinical Relevance.
Our findings could serve as possible predictors for the neovascularisation potential in HNSCC tumor patients.
