Xueyi Dong

Tianjin Medical University, T’ien-ching-shih, Tianjin Shi, China

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Publications (21)65.48 Total impact

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    ABSTRACT: Background: Highly aggressive tumors are exposed to hypoxia and increased tumor interstitial fluid pressure (IFP) conditions which is resistant to blood supply. Physiological responses of the organism may reduce IFP through induction of orderly cell death. Specific aims: This study demonstrates that orderly cell death provided spatial structure for early angiogenesis in the hypoxic, high-IFP tumor microenvironment and the participation of linearly patterned programmed cell necrosis (LPPCN) in nascent melanoma angiogenesis. Methods: Animal model, laser capture microdissection, wound healing and transwell assays, three-dimensional cultures, zymography assays, western-blotting analysis, immunohistochemistry and RT-PCR were performed. Results: This study demonstrated a special form of cell death occurring in groups of malignant tumor cells which arrayed in lines. Both features of apoptosis and necrosis can be found in this cell death pattern and were termed as LPPCN. Its role as a stimulus of tumor angiogenesis was investigated using human melanoma samples and an animal model. Computer image analysis showed that LPPCN and tumor microvessels had identical spatial distributions. It can be induced by chronic hypoxia, high IFP and subsequent calcium influx. Higher number of tumor associated macrophages (TAM) and VEGF expression were found in the tumor with LPPCN. Based on the tumor-bearing animal model, it was found that block of caspase pathway inhibited LPPCN, microvessel density and vasculogenic mimicry (VM). Conclusions: LPPCN formation may play an important role in tumor angiogenesis due to stimulation of macrophage infiltration and HIF-1 alpha regulation, and that inhibition of LPPCN may be a novel therapeutic strategy against tumor angiogenesis and metastasis.
    No preview · Article · Jan 2016 · Journal of Cancer
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    ABSTRACT: Hypoxia plays a pivotal role in tumor progression. The functions of hypoxia and subsequent Bcl-2/Twist1 activation in epithelial-mesenchymal transition (EMT) and vasculogenic mimicry (VM) formation are currently unclear. This study aimed to investigate the role of Bcl-2/Twist1 cooperation in hypoxia-induced EMT and VM formation. In in vitro experiments, we found that hypoxia resulted in co-overexpression of Bcl-2 and Twist1, facilitated Twist1 nuclear translocation and promoted EMT and VM formation. Co-overexpression of Bcl-2 and Twist1 under normoxia could also induce EMT and promote VM formation. Furthermore, blocking Bcl-2 or Twist1 attenuated the effects of hypoxia on EMT progress and VM formation in hepatocellular carcinoma cells. In in vivo experiments, the mechanism by which hypoxia promoted Bcl-2 and Twist1 co-overexpression and induced EMT process and VM formation was demonstrated using murine xenograft models. These results above suggest that hypoxia could activate the cooperation of Bcl-2 and Twist1, Bcl-2 plays an important role in assisting Twist1 nuclear translocation which could change the expression of a wide range of genes and lead to the induction of EMT and VM formation. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Aug 2015 · Experimental and Molecular Pathology
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    ABSTRACT: Vasculogenic mimicry (VM), a newly defined pattern of tumor blood supply, describes the functional plasticity of aggressive cancer cells that form vascular networks. In our previous study, breast cancer stem cells (CSCs) were potential to participate in VM formation. In this study, breast CSCs presented the centrosome amplification (CA) phenotype and ubiquitin-specific protease 44 (USP44) upregulation. USP44 expression contributed to the establishment of bipolar spindles in breast CSCs with supernumerary centrosomes by localizing at pole-associated centrosomes. The bipolar spindle patterns of breast CSCs with CA, including planar-like and apico-basal-like, functioned differently during the VM process of CSCs. Moreover the ability of transendothelial migration in VM forming cells was increased. In vivo experiment results showed that CSCs xenografts presented linearly patterned programmed cell necrosis which provided spatial foundation for VM formation as well as angiogenesis. Breast CSCs further showed increased levels of interleukin (IL)-6 and IL-8. However, USP44 silencing induced spindle multipolarity, abated VM, reduced transendothelial migration, and consequently decreased IL-6 and IL-8 levels in breast CSCs. Finally USP44+ CSCs subclones (ALDH1+/USP44+/IL-6+/IL-8+) were identified in breast cancer specimens through consecutive sections scanning. The subclones were related not only to CA, but also to VM. Statistical analysis suggested that USP44+ CSCs subclones could be used as an independent prognostic biomarker of poor clinical outcomes in patients with breast cancer. Collectively, the identification of USP44+ CSCs subclones may contribute to the prediction of VM formation and aggressive behavior. This study provides novel insights into the therapy for advanced breast cancer. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Jul 2015 · Molecular Cancer Therapeutics
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    ABSTRACT: Aggressive tumor cells can mimic embryonic vasculogenic networks and form vasculogenic mimicry (VM). Preliminary studies demonstrated that hypoxia can promote VM formation; however, the underlying mechanism remains unclear. The present study aimed to investigate the role of the Twist1‑Bmi1 connection in hypoxia‑induced VM formation and the underlying mechanism. In the in vitro experiments, western blot analysis demonstrated that hypoxia upregulated the expression of Twist1, Bmi1, epithelial‑mesenchymal transition (EMT) markers, stem cell markers and VM‑associated markers. The 3D culture assay showed that hypoxia promoted VM formation in hepatocellular carcinoma (HCC) cell lines. Using transfection and in vitro cell experiments, the Twist1‑Bmi1 connection was confirmed to have an important role in inducing EMT, cell stemness and VM formation. In the in vivo experiments, the murine hypoxia models were established via incomplete femoral artery ligation and the mechanism by which hypoxia promoted Twist1 and Bmi1 expression and led to VM formation was demonstrated by immunohistochemistry staining and endomucin/periodic acid Schiff double‑staining. In conclusion, hypoxia upregulate the expression of Twist1 and Bmi1, and these two proteins have an important role in inducing EMT and cancer cell stemness, which contributed to VM formation.
    No preview · Article · Jul 2015 · International Journal of Molecular Medicine
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    ABSTRACT: To evaluate erythropoietin (Epo) and erythropoietin receptor (EpoR) expression, its relationship with vasculogenic mimicry (VM) and its prognostic value in human hepatocellular carcinoma (HCC), we examined Epo/EpoR expression and VM formation using immunohistochemistry and CD31/PAS (periodic acid-Schiff) double staining on 92 HCC specimens. The correlation between Epo/EpoR expression and VM formation was analyzed using two-tailed Chi-square test and Spearman correlation analysis. Survival curves were generated using Kaplan-Meier method. Multivariate analysis was performed using Cox regression model to assess the prognostic values. Results showed positive correlation between Epo/EpoR expression and VM formation (P < 0.05). Patients with Epo or EpoR expression exhibited poorer overall survival (OS) than Epo-negative or EpoR-negative patients (P < 0.05). Epo-positive/VM-positive and EpoR-positive/VM-positive patients had the worst OS (P < 0.05). In multivariate survival analysis, age, Epo and EpoR were independent prognostic factors related to OS. These results will provide evidence for further research on HCC microcirculation patterns and also will provide new possible targets for HCC diagnosis and treatment.
    No preview · Article · Jun 2015 · International journal of clinical and experimental pathology
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    ABSTRACT: Zinc finger E-box binding homeobox 2 (ZEB2), an epithelial-mesenchymal transition (EMT) regulator, has been involved in invasion and metastasis of human tumor. Although EMT may be involved in vasculogenic mimicry (VM) formation, no reports describing the relation between ZEB2 and VM are available. We hypothesize that ZEB2 may promote VM formation in hepatocellular carcinoma (HCC). Paraffin-embedded tumor tissue samples from 92 patients were immunostained with anti-ZEB2 antibody. We found that the ZEB2 nuclear expression was significantly associated with VM formation and metastasis. Patients with VM and ZEB2 nuclear expression had a shorter survival period than those without expression. In vitro, ZEB2 overexpression significantly enhanced cell motility, invasiveness, and VM formation of HepG2 cells. ZEB2 upregulation also increased VE-cadherin, Flt-1, and Flk-1 expression and activated MMPs. ZEB2 knockdown inhibited cell motility, invasiveness, and VM formation in Bel7402 cells. ZEB2 knockdown also decreased VE-cadherin, Flt-1, and Flk-1 expression and MMP activity. In addition, EMT in HepG2 cells was induced by TGF-β1 treatment, and the kinetics of expression of EMT markers and regulators were assessed by Western blot analysis. The expression of ZEB2 increased significantly, and VM formation was promoted. ZEB2 can promote VM formation through the EMT pathway. Our findings may represent a novel therapeutic target in HCC. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Mar 2015 · Experimental and Molecular Pathology
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    ABSTRACT: Vasculogenic mimicry (VM) is a functional microcirculation formed by tumor cells. Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, promote VM formation. Another specific MMP, collagenase-3 (MMP-13), has broad substrate specificity and potentially affects tumor metastasis and invasion. Here we found that MMP-13 was associated with metastasis and poor survival in 79 patients with melanoma. MMP-13 expression was inversely correlated with VM. These results were confirmed in human and mouse melanoma cell lines. We found that MMP-13 cleaves laminin-5 (Ln-5) into small fragments to accelerate tumor metastasis. Degradation of Ln-5 and VE-cadherin by MMP-13 inhibited VM formation. In conclusion, MMP-13 has a dual effect in melanoma, as it promotes invasion and metastasis but disrupts VM formation.
    Preview · Article · Feb 2015 · Oncotarget
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    ABSTRACT: Physiological vasculogenesis in embryonic tissues share some important features with pathological neoangiogenesis in tumors. Linearly Patterned Programmed Cell Necrosis (LPPCN) and Vasculogenic Mimicry (VM) have been reported in tumors. The term VM refers to the aggressive tumor cells with CD31-negative phenotype to form Periodic Αcid Schiff (PAS)-positive network, that mimics the pattern of embryonic vasculogenic networks. LPPCN had been observed in our laboratory, and served as a spatial infrastructure for VM and endothelium-dependent vessel formation. Studies have been shown that hypoxia-inducible factor-1α (HIF-1α) can induce tumor cells to form vessel-like tubes and express genes associated with VM. Therefore, an analogous investigation has been carried out to determine if these patterns existed in mouse embryonic vasculogenesis. In this essay, the results demonstrated that the number of Linearly Patterned Cell Αpoptosis (LPCA), embryo Vasculogenic Μimicry (embryo VM), endothelium-dependent vessels, and relative-protein of HIF-1α expression all showed time-dependent tendencies on E5.5-E9.5 (p < 0.05). The proteins CD133, VEGF, Twist, E-cadherin, and Vimentin showed local plexus distribution on E6.5-E7.5 (p < 0.05). LPCA and embryo VM existed in embryonic vasculogenesis. The relative protein of HIF-1α regulated the mouse embryonic vasculogenesis.
    Preview · Article · Dec 2014
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    ABSTRACT: To evaluate the prognostic value of OCT4 expression and vasculogenic mimicry (VM) in human breast cancer, we examined OCT4 expression and VM formation using immunohistochemistry and CD31/PAS (periodic acid-schiff) double staining on 90 breast cancer specimens. All patients were followed up for five-149 months following surgery. Survival curves were generated using Kaplan-Meier method. Multivariate analysis was performed using Cox regression model to assess the prognostic values. Results showed positive correlation between OCT4 expression and VM formation (p < 0.05). Both OCT4 expression and VM were also positively correlated with lymph node metastasis, higher histological grade, and Nottingham prognostic index (p < 0.05). Patients with OCT4 expression or VM formation exhibited poorer overall survival (OS) and disease-free survival (DFS) than OCT4-negative or VM-negative patients (p < 0.05). OCT4-positive/VM-positive patients also had the worst OS and DFS (p < 0.05). In multivariate survival analysis, VM, Nottingham prognostic index (NPI), and Her2 were independent prognostic factors related to OS and OCT4-positive/VM-positive patients, whereas NPI and Her2 were independent predictors of DFS. These results suggest that a combined OCT4 expression/VM could improve the prognostic judgment for breast cancer patients.
    Preview · Article · Nov 2014 · International Journal of Molecular Sciences
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    ABSTRACT: Transcription factor Slug plays an important role in the tumor invasion and metastasis of human hepatocellular carcinoma (HCC). This study aimed to explore the mechanism involved in the promotion of HCC progression by Slug. In the precent study, we demonstrated that Slug expression was significantly associated with metastasis and shorter survival time of HCC patients. Using ChIP-on-chip and microarray analysis, we identified the molecular profile of Slug downstream targets in HCC cells with Slug overexpression. The Wnt, Notch and Hedgehog pathways were identified to promote pluripotency maintaining overexpression factors sox2 and nanog. Importantly, Slug showed a close relationship with sox2 and nanog expression in HCC patients and in HCC xenografts in vivo. Notably, the DNA damaging reagent hydroxyurea had no effect on Slug, sox2 and nanog expression in HCC cells with Slug overexpression; however knockdown of Slug by the short hairpin RNA approach markedly reduced sox2 and nanog expression and inhibited HCC cell migration in vitro. The results of this study indicate that Slug promotes progression of HCC by promoting sox2 and nanog overexpression. The related molecular pathways may be used as novel therapeutic targets for HCC.
    No preview · Article · Oct 2014 · Oncology Reports
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    ABSTRACT: This study was conducted to examine the effects of doxycycline on the survival time and proliferation of hepatocellular carcinoma (HCC) in vivo and on the biological functions of HCC in vitro. This study was also designed to evaluate the effects of doxycycline on epithelial-to-mesenchymal transition (EMT)- and vasculogenic mimicry (VM)-related protein expression and on matrix metalloproteinase (MMP) and DNA methyltransferase (DNMT) activity in vitro. Human MHCC97H cells were injected into BALB/c mice, which were divided into treatment and control groups. Doxycycline treatment prolonged the mouse survival time and partly suppressed the growth of engrafted HCC tumor cells, with an inhibition rate of 43.39%. Higher amounts of VM and endothelium-dependent vessels were found in the control group than the treatment group. Immunohistochemistry indicated that epithelial (E)-cadherin expression was increased in the doxycycline-treated mice compared with the control group. In in vitro experiments, doxycycline promoted HCC cell adhesion but inhibited HCC cell viability, proliferation, migration, and invasion. Western blots, semi-quantitative RT-PCR, quantitative real-time PCR, and immunofluorescence demonstrated that doxycycline inhibited the degradation of the epithelial marker E-cadherin and downregulated the expression levels of EMT promoters, the mesenchymal marker vimentin, and the VM-associated marker vascular endothelial (VE)-cadherin. Furthermore, the activities of MMPs and DNMTs were examined in different groups via gelatin zymography and a DNMT activity assay kit. A methylation-specific polymerase chain reaction (MSP) was performed to assess the promoter methylation of CDH1 (the gene encoding E-cadherin). Doxycycline prolonged the mouse survival time by inhibiting EMT progression and VM formation.
    No preview · Article · Oct 2014 · Molecular Cancer Therapeutics
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    ABSTRACT: Hypoxia induced by antiangiogenic agents is linked to the generation of cancer stem cells (CSCs) and treatment failure through unknown mechanisms. The generation of endothelial cell-independent microcirculation in malignant tumors is defined as tumor cell vasculogenic mimicry (VM). In the present study, we analyzed the effects of an antiangiogenic agent on VM in triple-negative breast cancer (TNBC). Microcirculation patterns were detected in patients with TNBC and non-TNBC. Tientsin Albino 2 (TA2) mice engrafted with mouse TNBC cells and nude mice engrafted with human breast cancer cell lines with TNBC or non-TNBC phenotypes were administered sunitinib and analyzed to determine tumor progression, survival, microcirculation, and oxygen concentration. Further, we evaluated the effects of hypoxia induced with CoCl2 and the expression levels of the transcription factor Twist1, in the presence or absence of a Twist siRNA, on the population of CD133+ cells and VM in TNBC and non-TNBC cells. VM was detected in 35.8 and 17.8% of patients with TNBC or with non-TNBC, respectively. The growth of tumors in TNBC and non-TNBC-bearing mice was inhibited by sunitinib. The tumors in TA2 mice engrafted with mouse TNBCs and in mice engrafted a human TNBC cell line (MDA-MB-231) regrew after terminating sunitinib administration. However, this effect was not observed in mice engrafted with a non-TNBC tumor cell line. Tumor metastases in sunitinib-treated TA2 mice was accelerated, and the survival of these mice decreased when sunitinib was withdrawn. VM was the major component of the microcirculation in sunitinib-treated mice with TNBC tumors, and the population of CD133+ cells increased in hypoxic areas. Hypoxia also induced MDA-MB-231 cells to express Twist1, and CD133+ cells present in the MDA-MB-231 cell population induced VM after reoxygenation. Moreover, hypoxia did not induce MDA-MB-231 cells transfected with an sh-Twist1 siRNA cell to form VM and generate CD133+ cells. Conversely, hypoxia induced MCF-7 cells transfected with Twist to form VM and generate CD133+ cells. Sunitinib induced hypoxia in TNBCs, and Twist1 expression induced by hypoxia accelerated VM by increasing population of CD133+ cells. VM was responsible for the regrowth of TNBCs sunitinib administration was terminated.
    Preview · Article · Sep 2014 · Molecular Cancer
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    ABSTRACT: To evaluate Wnt5a expression and its role in angiogenesis of non-small-cell lung cancer (NSCLC), immunohistochemistry and CD31/PAS double staining were performed to examine the Wnt5a expression and we analyze the relationships between Wnt5a and microvessel density (MVD), vasculogenic mimicry (VM), and some related proteins. About 61.95% of cases of 205 NSCLC specimens exhibited high expression of Wnt5a. Wnt5a expression level was upregulated in the majority of NSCLC tissues, especially in squamous cell carcinoma, while its expression level in adenocarcinoma was the lowest. Wnt5a was also found more frequently expressed in male patients than in female patients. Except for histological classification and gender, little association was found between Wnt5a and clinicopathological features. Moreover, Wnt5a was significantly correlated with prognosis. Overall, Wnt5a-positive expression in patients with NSCLC indicated shorter survival time. As for vascularization in NSCLC, Wnt5a showed close association with VM and MVD. In addition, Wnt5a was positively related with β -catenin-nu, VE-cadherin, MMP2, and MMP9. The results demonstrated that overexpression of Wnt5a may play an important role in NSCLC angiogenesis and it may function via canonical Wnt signal pathway. This study will provide evidence for further research on NSCLC and also will provide new possible target for NSCLC diagnosis and therapeutic strategies.
    Preview · Article · Jun 2014 · BioMed Research International
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    ABSTRACT: Epithelial ovarian cancer is one of the most common causes of cancer-related death in women. The majority of epithelial ovarian cancer patients present with metastasis at the time of initial diagnosis. Studies have demonstrated that vasculogenic mimicry (VM) is highly correlated with metastasis and invasiveness, and epithelial-mesenchymal transition (EMT) is pivotal in VM formation. Wnt5a, a member of the Wnt protein family, can activate the non-canonical Wnt signaling pathway mediating cancer initiation and progression. Thus, the present study aimed to investigate the relationship between Wnt5a and VM and its mechanism in epithelial ovarian cancer. The present results showed that Wnt5a staining was significantly correlated with metastasis in epithelial ovarian cancer. The correlation between the expression of Wnt5a and VM or protein kinase Cα (PKCα) indicated that Wnt5a was associated with VM and may be linked to the PKC pathway. In vitro experiments revealed that Wnt5a enhanced the vasculogenic capacity, motility and invasiveness of ovarian cancer cells; however, the PKCα inhibitor blocked these effects. Western blot analysis showed that changes in Wnt5a expression coincided with changes in PKC expression and that PI3K and Snail expression increased along with Wnt5a upregulation. However, no change was observed in β-catenin levels, indicating that Wnt5a may mediate EMT and VM in ovarian cancer cells via the PKCα pathway.
    Preview · Article · Jun 2014 · Oncology Reports
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    ABSTRACT: Purpose The functions of hypoxia and subsequent hypoxia-inducible factor-1α (HIF-1α) activation in vasculogenic mimicry (VM) are currently unclear. This study aimed to investigate the effects of hypoxia on VM formation in ovarian cancer, and explore the possible mechanism involved. Experimental Design The expression levels of HIF-1α, E-cadherin, vimentin, Twist1, Slug, and VE-cadherin proteins were analyzed by immunohistochemistry in 71 specimens of epithelial ovarian cancer. The results were correlated with VM and survival analysis. We used a well-established in vitro model of a three-dimensional culture to compare VM formation under hypoxia and normoxia in ovarian cancer cell lines SKOV3 and OVCAR3. To explore the potential mechanism, we examined the effects of hypoxia on the mRNA and protein expression levels of both E-cadherin and vimentin. Results HIF-1α expression was correlated with loss of E-cadherin expression and up-regulated vimentin expression in 11 of the 18 VM-positive patients. Ovarian cancer with evidence of VM was significantly more likely to have high Twist1, Slug, and VE-cadherin expression levels. VM was observed in vitro under hypoxia. The ovarian cancer cells presented morphological epithelial–mesenchymal transition (EMT)-like changes (more fibroblastoid morphology and loss of cellular cohesiveness) under hypoxic conditions. The mRNA and protein levels demonstrated the induction of EMT after hypoxia. Clinicopathological analysis revealed that both VM and HIF-1α expression levels presented shorter survival durations. Conclusions Hypoxia contributed to VM formation by inducing EMT. These results may offer new insights for consideration in ovarian cancer treatment strategies.
    No preview · Article · Jun 2014 · Gynecologic Oncology
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    ABSTRACT: The aim of this study was to investigate the clinical significances and prognostic value of CD133 and CD44 (markers of cancer stem-like cells, CSCs), and vasculogenic mimicry (VM) in renal cell carcinoma (RCC). Immunohistochemistry was performed to detect CD133 and CD44 expression and VM in 110 RCC patients proven to exhibit de novo metastases after radical nephrectomy. In RCC, positive rates of 27.3%, 20.9%, and 21.8% were obtained for CD44, CD133, and VM, respectively. CD44 was significantly associated with tumor size, grade, stage, and histological type. CD44 expression may serve as a predictor of the number of metastases sites in RCC. CD133 expression correlated with tumor grade, stage, histological type, and tumor location. VM was positively associated with tumor grade and stage. Microvessel density (MVD) positively corresponded to tumor size, grade, and stage. CD133 expression was not associated with MVD, but significantly correlated with VM. CD44 expression correlated marginally with VM, but was found to have a significantly association with MVD. A close relationship between CSCs, MVD, and VM was established. The overall survival times of patients with CD133-high positive, CD44-high positive, VM-positive, and MVD <43 were lower than that of the patients with low positive, negative, and MVD ≥43. Tumor grade and presence of VM were independent prognostic factors of RCC. Findings show that higher CSCs and VM was correlated with more aggressive clinicopathologic. VM was an independent unfavorable prognostic factor. The authors consistently observed that CSCs may be related to angiogenesis and vasculogenic mimicry. J. Surg. Oncol. © 2013 Wiley Periodicals, Inc.
    No preview · Article · Nov 2013 · Journal of Surgical Oncology
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    ABSTRACT: Senescence, an irreversible state of cell cycle arrest, maintains metabolic activity. Although being a barrier against tumor development, senescence could also promote tumor progression by influencing the microenvironment. Necrosis is a common feature of various malignant tumors, which also has two opposing effects: pro-tumor by chronic inflammation and anti-tumor by effective cell clearance. However, the role of senescence in melanoma and whether it is associated with necrosis remain unclear. By detecting senescence-associated β-galactosidase activity and pimonidazole (hypoxia probe), we found that senescent cells (SA-β-gal positive) are mainly located around the necrotic/hypoxic areas of melanoma from C57BL/6J mice. Moreover, treatment of hypoxia induced irreversibly cellular senescence in vitro. In addition, the senescent cells may facilitate microenvironment modulation and promote the invasion of melanoma cells by secreting matrix metalloproteinase-2(MMP-2). Moreover, Kaplan-Meier analysis showed that the presence of necrosis in melanomas had an inverse correlation with patient survival and may serve as an independent prognostic marker. Therefore, hypoxic stress imposed on melanomas may lead to cellular senescence surrounding necrotic areas, and the adverse effects of necrosis in tumor may be attributed to the adjacent senescent cells with senescence-associated secretion phenotype (SASP), including secretion of MMP-2.
    No preview · Article · Jul 2013 · Pathology - Research and Practice
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    ABSTRACT: Vasculogenic mimicry (VM) refers to the unique capability of aggressive tumour cells to mimic the pattern of embryonic vasculogenic networks. Epithelial-mesenchymal transition (EMT) regulator slug have been implicated in the tumour invasion and metastasis of human hepatocellular carcinoma (HCC). However, the relationship between slug and VM formation is not clear. In the study, we demonstrated that slug expression was associated with EMT and cancer stem cell (CSCs) phenotype in HCC patients. Importantly, slug showed statistically correlation with VM formation. We consistently demonstrated that an overexpression of slug in HCC cells significantly increased CSCs subpopulation that was obvious by the increased clone forming efficiency in soft agar and by flowcytometry analysis. Meantime, the VM formation and VM mediator overexpression were also induced by slug induction. Finally, slug overexpression lead to the maintenance of CSCs phenotype and VM formation was demonstrated in vivo. Therefore, the results of this study indicate that slug induced the increase and maintenance of CSCs subpopulation and contributed to VM formation eventually. The related molecular pathways may be used as novel therapeutic targets for the inhibition of HCC angiogenesis and metastasis.
    Preview · Article · Jul 2013 · Journal of Cellular and Molecular Medicine
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    ABSTRACT: Cancer stem cells (CSCs) have been identified in various malignancies, and different properties have been examined to characterize CSCs: tumorigenicity in immunocompromised mice, stem cell surface markers, label-retaining properties, and proliferation as nonadherent spheres. This study explored the consistency and efficiency among these methods. Among the melanoma cell lines examined (A375, A875, MUM-2b, and MUM-2c), only A375 and MUM-2c grew as nonadherent spheres and continuously propagated in a defined serum-free medium in vitro. Flow cytometry and immunofluorescence analysis indicated that sphere-derived cells contained a smaller proportion of cells expressing the candidate surface markers of melanoma stem cells such as ABCB5, CD133, CD20 and CD271, and a larger proportion of cells expressing melanocytic differentiation markers such as HMB45 and S100 protein, compared with adherent cells. Surprisingly, the more highly differentiated sphere-derived melanoma cells exhibited increased tumorigenic potential in vivo, as indicated by shorter tumor incubation (A375) and smaller number of cells required to initiate tumor formation (A375 and MUM-2c) compared with those of parental cells. Despite the similarity in histopathological characteristics, the expression profile indicated that xenografts derived from sphere-derived melanoma cells exhibited a more tumorigenic phenotype with respect to the stem or the differentiation markers detected by immunohistochemical analysis. Therefore, sphere formation in nonadherent cultures may not be a preferred surrogate in-vitro method for enriching melanoma stem cells according to candidate markers but may be a favorable condition for activating potential CSCs.
    No preview · Article · Jun 2013 · Melanoma research
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    ABSTRACT: Vasculogenic mimicry (VM) refers to the condition in which tumour cells mimic endothelial cells to form extracellular matrix-rich tubular channels. VM is more extensive in more aggressive tumours. The human epidermal growth factor receptor 2 (HER2) gene is amplified in 20-30% of human breast cancers and has been implicated in mediating aggressive tumour growth and metastasis. However, thus far, there have been no data on the role of HER2 in VM formation. Immunohistochemical and histochemical double-staining methods were performed to display VM in breast cancer specimens. Transfection in MCF7 cells was performed and clones were selected by G418. The three-dimensional Matrigel culture was used to evaluate VM formation in the breast cancer cell line. According to statistical analysis, VM was related to the presence of a positive nodal status and advanced clinical stage. The positive rate of VM increased with increased HER2 expression. In addition, cases with HER2 3+ expression showed significantly greater VM channel count than those in other cases. The exogenous HER2 overexpression in MCF-7 cells induced vessel-like VM structures on the Matrigel and increased the VM mediator vascular endothelial (VE) cadherin. Our data provide evidence for a clinically relevant association between HER2 and VM in human invasive breast cancer. HER2 overexpression possibly induces VM through the up-regulation of VE cadherin. Understanding the key molecular events may provide therapeutic intervention strategies for HER2+ breast cancer.
    Preview · Article · Dec 2012 · Journal of Cellular and Molecular Medicine