Presence Of Vasculogenic Mimicry Research Articles

BMET-10VASCULOGENIC MIMICRY IN LUNG CANCER BRAIN METASTASIS

OBJECTIVE: Vasculogenic mimicry (VM) is involved in the process of tumor (including gliomas) initiation and progression. However, the existence and prognostic significance of VM in brain metastases have not been elucidated. In this study, we were trying to detect the presence of VM in brain metastases original from lung cancer, and correlate to patient prognosis. METHODS: The clinical data were retrospectively reviewed in 60 patients received surgical removal for lung cancer brain metastases at our department from 2000 to 2014. The VM was determined by utility of CD34-PAS dual staining. RESULTS: In 60 brain metastatic tumor samples, the VM (PAS positive but CD34 negative channel) were found in 22 cases, and the VM-positive rate in brain metastases was 36.6%. The univariate analysis showed that patient KPS scoring, age and treatment strategy, but not VM, were related with patient survival time. The multivariate analysis indicated that KPS scoring and treatment strategy after brain metastasis surgery were closely related to patient prognosis. CONCLUSION: VM exits in lung cancer brain metastases, but does not associate with patient prognosis. Longer survival of patient was related with KPS scoring (over 70) and treatment strategy after surgery.

Epithelial Mesenchymal Transition and Vascular Mimicry in Breast Cancer Stem Cells.

Vasculogenic mimicry (VM), a newly defined pattern of tumor microvascularization differs from angiogenesis and vasculogenesis in its noninvolvement of endothelial cells, by which highly aggressive tumor cells can form vessel-like structures themselves, because of their high plasticity. The presence of VM has been shown to be strongly associated with a poor prognosis in several types of cancer, but biological features of tumor cells that form VM remains unknown. Human breast cancer, characterized by a group of highly heterogeneous lesions, is the most common cancer in women and one of the leading causes of cancer-related deaths worldwide. The epithelialmesenchymal transition (EMT) state in breast cancer has been associated with cancer stem cell (CSC) properties, self-renewal capabilities, resistance to conventional therapies, and a tendency for posttreatment recurrence. With increasing knowledge about cancer stem cell phenotypes and functions, they are implicated in VM formation. Studies also indicate that EMT is relevant to the acquisition and maintenance of stem cell-like characteristics and is involved in VM. This review discusses the correlation between CSCs, EMT, and VM formation with a focus on breast cancer. Also, the signalling molecules and pathways involved in VM and some recently defined direct VM targeting strategies in breast cancer are reviewed here.

Vasculogenic mimicry: a new prognostic sign of human osteosarcoma.

Vasculogenic mimicry (VM), a formation of nonendothelial microvascular channels, has been generally recognized as a new pattern of neovascularization in aggressive malignancies. However, whether VM is present and clinically significant in osteosarcoma remains unknown. We identified VM by CD34/periodic acid-Schiff double staining of osteosarcoma specimens before chemotherapy and investigated its prognostic implications. Tumors were also immunohistochemically stained for focal adhesion kinase (FAK) and migration inducing gene 7 (Mig-7) to determine whether these markers are associated with the occurrence of VM. VM was found in 15 of 66 osteoblastic-type osteosarcoma samples (22.7%), and the incidence of VM did not differ with respect to patient sex, age, tumor size, tumor site, surgical type, or histologic response to preoperative chemotherapy. However, Kaplan-Meier survival analysis determined that the presence of VM and the tumor necrosis rate after preoperative chemotherapy are associated with both the overall survival (P = .011 and P = .040, respectively) and metastasis-free survival (P = .002 and P = .045, respectively). Furthermore, Cox proportional hazards analysis showed that the presence of VM and the histologic response to preoperative chemotherapy were independent indicators for both poor overall survival (P = .007 and P = .024, respectively) and poor metastasis-free survival (P = .002 and P = .027, respectively). The expression level of FAK and Mig-7 were higher in the VM group than the non-VM group (P = .017 and P = .021, respectively). These results demonstrate the presence of VM in osteoblastic osteosarcoma and suggest that VM is an unfavorable prognostic factor with FAK and Mig-7 expressions as a potential mechanism of VM formation in osteosarcoma.

Clinical significances and prognostic value of cancer stem-like cells markers and vasculogenic mimicry in renal cell carcinoma

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.

Vasculogenic mimicry is a prognostic factor for postoperative survival in patients with glioblastoma

A previous report has confirmed the existence and clinical significance of vasculogenic mimicry (VM) in glioma. However, its conclusions about the negative clinical significance of VM in glioblastoma are based on a small group of patients and, thus, might be unconvincing. The aim of the present study was to reevaluate the clinical significance of VM in glioblastoma. Patients were classified as VM-positive or VM-negative according to CD34 and periodic acid-Schiff staining. The association between VM and the clinical characteristics of the patients was analyzed. Univariate and multivariate analyses were carried out to identify the independent prognostic factors for overall survival using the Cox regression hazard model. Survival times were estimated using the Kaplan-Meier method and compared using the log-rank test. Of all 86 glioblastomas, 23 were found to have VM. The presence of VM in glioblastoma was not associated with gender, age, Karnofsky performance status, hydrocephalus, tumor burden, microvessel density, tumor relapse, or the extent of tumor resection. The univariate and multivariate analyses revealed that VM is an independent prognostic factor for overall survival. The median survival time for patients with VM was 11.17 months compared with 16.10 months for those without VM (P = 0.017). In addition to VM, an age of 65 years or older, a KPS of 60 or less, a large tumor burden are significant prognostic factors for patient survival. Our data suggest that VM might be an independent adverse prognostic factor in newly diagnosed GBM, further prospective studies are needed to answer this question.

Vasculogenic mimicry is a marker of poor prognosis in prostate cancer

We investigated the role of vasculogenic mimicry (VM) in the progression of prostate cancer (PCa). Ninety-six patients who had undergone prostatectomy for treatment of PCa and for whom a complete record of clinical and follow-up data were available were reviewed. VM and matrix metalloproteinase-2 (MMP-2) were detected by immunohistochemical staining in frozen tissue sections. Relationship between VM and clinicopathological variables was analyzed statistically. Multivariate analyses were performed to assess the prognostic significance of VM. Results showed that out of the 96 PCa cases studied here, VM was detectable in 24 (25%) and was positively correlated with preoperative prostate-specific antigen (PSA) level, Gleason score, pathological stage, lymph node metastasis, seminal vesicle invasion, distant metastasis and PSA doubling time (PSADT). Univariate analysis showed that VM, PSA level, Gleason score, distant metastasis and PSADT were correlated with overall survival (OS), while VM, Gleason score, distant metastasis, local recurrence and PSADT were correlated with disease-free survival (DFS). Multivariable analysis indicated that the presence of VM, higher Gleason score and distant metastasis were the adverse predictors of OS and DFS. A higher widespread staining for MMP-2 was correlated with the VM-positive subgroup. In conclusion, VM mainly exists in the high risk PCa patients and is an independent marker of poor prognosis.

Vasculogenic mimicry and its clinical significance in medulloblastoma

Vasculogenic mimicry (VM), a process involving the formation of a tubular structure by highly invasive and genetically dysregulated tumor cells, can supplement the function of blood vessels to transport nutrients and oxygen to maintain the growth of tumor cells in many malignant tumors. We aimed to explore the existence of VM and its clinical significance in medulloblastoma in this study. VM was identified in 9 out of 41 (22%) medulloblastoma tissues. Immunohistochemical studies revealed that the presence of VM was associated with the expression of MMP-2, MMP-14, EphA2 and laminin 5γ2. Tumor tissues with VM were associated with lower microvessel density (MVD), which was indirect evidence of the blood supply function of VM. Survival analysis and log-rank tests showed that patients with VM had shorter overall survival time than those without VM. Multivariate analysis and the Cox proportional hazards model identified VM as independent prognostic factor for overall survival. Our results confirmed the existence of VM for the first time and revealed that VM is a strong independent prognostic factor for survival in patients with medulloblastoma.

Zinc finger E‐box binding homeobox 1 promotes vasculogenic mimicry in colorectal cancer through induction of epithelial‐to‐mesenchymal transition

Our previous studies have shown that epithelial-mesenchymal transition (EMT) may be involved in the vasculogenic mimicry (VM) formation in hepatocellular carcinoma. Here, we hypothesize that zinc finger E-box binding homeobox 1 (ZEB1) promotes VM formation in colorectal carcinoma (CRC) by inducing EMT. We identified VM in 39 (19.2%) out of 203 CRC patients. The presence of VM was associated with aggressive biological behavior and was an unfavorable prognostic indicator. By immunohistochemical analysis, we found that the VM-positive CRC samples showed increased ZEB1 expression compared with the VM-negative samples and the ZEB1 expression occurred concomitantly with features of EMT. In vitro, knockdown of ZEB1 in poorly differentiated HCT116 CRC cells destroyed the vessel-like structures in the 3-D culture, a property associated with VM formation. Knockdown of ZEB1 resulted in restoration of epithelial phenotypes and significantly inhibited the ability to migrate and invade. In addition, ZEB1 underexpression decreased the expression of vascular endothelial (VE)-cadherin and Flk-1, which are characteristics of endothelial cells. Taken together, our results suggest that ZEB1 can promote VM formation by inducing EMT in CRC and might represent an important target in CRC.

Demonstration of vasculogenic mimicry in astrocytomas and effects of Endostar on U251 cells

Angiogenesis is an important process for the cell growth of normal and tumor tissues. Vasculogenic mimicry (VM) is a newly described vascular network structure that was first described in aggressive melanomas. To find out whether VM also exists in astrocytomas and to examine its clinical significance, we studied 80 malignant astrocytoma samples using immunohistochemistry coupled with periodic acid–Schiff (PAS) staining. To explore the possible therapeutic methods of anti-VM formation, we cultured astrocytoma cells using three-dimensional Matrigel and investigated the effects of Endostar, an endothelial cell growth inhibitor, on astrocytoma cell growth, invasion, and VM formation. VM structures were found in 8 samples of malignant astrocytomas, seven of which were grade IV astrocytomas. Glioblastoma U251 cells cultured in Matrigel formed vessel-like loops and networks, mimicking the features of VM in vivo, whereas such structures were not found in cultured normal astrocytes or well-differentiated astrocytoma SHG44 cells. In addition, treatment with Endostar led to a dose- and time-dependent inhibition of proliferation and invasion of both U251and SHG44 cells, but VM formation by U251 cells in vitro was not prominently affected. In conclusion, VM is frequently detected in aggressive glioblastomas, and the presence of VM may constitute a new predictor for poor prognosis in astrocytoma patients. Although Endostar has broad anti-tumor effects due to anti-angiogenesis and anti-tumor cell mechanisms, its inhibitory effects on VM formation by U251cells in vitro are not remarkable.

Investigation of vasculogenic mimicry in intracranial hemangiopericytoma

Vasculogenic mimicry (VM) has increasingly been recognized as a form of angiogenesis. Previous studies have shown that the existence of VM is associated with poor clinical prognosis in certain malignant tumors. However, whether VM is present and clinically significant in intracranial hemangiopericytoma (HPC) is unknown. The present study was therefore designed to examine the expression of VM in intracranial HPC and its correlation with matrix metalloprotease-2 (MMP-2) and vascular endothelial growth factor (VEGF). A total of 17 intracranial HPC samples, along with complete clinical and pathological data, were collected for our study. Immunohistochemistry was performed to stain tissue sections for CD34, periodic acid-Schiff, VEGF and MMP-2. The levels of VEGF and MMP-2 were compared between tumor samples with and without VM. The results showed that VM existed in 12 of 17 (70.6%) intracranial HPC samples. The presence of VM in tumors was associated with tumor recurrence (P<0.05) and expression of MMP-2 (P<0.05). However, there was no difference in the expression of VEGF between groups with and without VM.

Abstract 5158: Plastic tumor cells engaged in vasculogenic mimicry produce PDGF-B and attract structural support

Abstract In developmental angiogenesis, pericytes are recruited by PDGF-B-expressing endothelial cells to remodel, stabilize and support the immature blood vessel. In a process called vasculogenic mimicry (VM) highly aggressive tumor cells gain the unique ability to dedifferentiate into multiple cellular phenotypes, and obtain endothelial-like characteristics. This process can lead to the formation of vasculogenic-like matrix-embedded networks, i.e. vascular-like structures, contributing to circulation. The presence of VM is associated with increased tumor malignancy. Interestingly, also the expression of PDGF in tumor cells has been demonstrated to be associated with an increased grade of malignancy. As plastic, highly aggressive tumor cells form vasculogenic-like structures resembling immature vessels, we hypothesize that plastic tumor cells engaged in VM also functionally resemble endothelial cells by seeking structural support. We demonstrate that plastic, aggressive melanoma cells transcribe and secrete PDGF-B, while in poorly aggressive melanoma cells, PDGF-B is absent. Myofibroblasts, acquired from the human vena saphena, cultured in the presence of plastic tumor cell conditioned medium display an activated phenotype. Additionally, in vitro analysis of 3D-culture on Matrigel demonstrated the functional contribution of myofibroblasts to plastic tumor cells as they structurally support the VM-characteristic networks formed. Immunohistochemical analysis of a series of cutaneous melanoma tissues showed a gradient PDGF-B staining towards the outer surface of the nest structures, i.e. the tumor cells aligning the VM-characteristic matrix networks. Consistent with the above described data, we observed staining for alpha-smooth muscle actin (α-SMA), a pericyte-specific marker, within the VM-characteristic matrix networks, thereby revealing the presence of pericytes inside these networks. Together our results demonstrate that highly aggressive, VM-positive tumor cells do not solely resemble endothelial cells phenotypically, but also actively behave like endothelial cells by producing PDGF-B and attracting structural support to their immature structures. The current findings suggest that targeting of pericytes may have an unexpected anti-tumor activity through affecting vasculogenic mimicry. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5158. doi:10.1158/1538-7445.AM2011-5158

Vasculogenic Mimicry: a New Prognostic Sign of Gastric Adenocarcinoma

Vasculogenic mimicry (VM) has been generally recognized as a new pattern of tumor neovascularization. It presents in many human malignancies. Till now, there is no report about VM in gastric adenocarcinoma (GAC). In this study, we collected 173 paraffin-embedded human GAC samples, with detailed follow-up and clinicopathologic data. CD31/ periodic acid-Schiff (PAS) double staining, immunohistochemical staining of CK8 & 18 and laminin were performed to validate the existence of VM in GAC. Microvascular density (MVD) and vasulogenic mimicry density (VMD) were counted respectively. VM was observed in 40 of the 173 GAC patients, especially in poorly differentiated GAC (P = 0.014). Patients with VM were prone to hematogenous metastasis and distant recurrence compared with patients without VM (P = 0.020, 0.029). Higher VMD values was also associated with hematogenous metastasis (P = 0.003). Immunohistochemical staining index (SI) of hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, and MMP-9 were compared between the VM and non-VM group. The SI of four factors were all higher in the VM group than those of non-VM group (P = 0.000, 0.000, 0.004, 0.009, respectively). The Kaplan-Meier survival analysis showed that the VM group has shorter life span compared with non-VM group (P = 0.022). Cox proportional hazards model indicated that the presence of VM and TNM stage were independent predictors of poor prognosis (P = 0.039 and 0.004) for GAC. In conclusion, VM exists in GAC, especially in poorly differentiated GAC. Additionally, it is an unfavorable prognostic indictor for GAC. Hypoxia may play a role in VM formation in GAC.

Prognostic Role of Vasculogenic Mimicry in Colorectal Cancer

Angiogenesis, as measured by degree of microvessel density, has been associated with tumor progression in many tumor types but does not always correlate with clinical outcome. In 1999, aggressive tumor cells were shown to form blood-conducting tubes not lined by endothelial cells, and this phenomenon was termed vasculogenic mimicry. We investigated angiogenesis and the presence of vasculogenic mimicry in colorectal carcinoma in relation to tumor stage, patient survival, and genetic indicators of tumor cell plasticity. Paraffin-embedded tissue samples were examined from a study of 117 patients with colorectal carcinoma with a 12-year follow-up. Immunohistochemical analysis was used to measure microvessel density and proliferating endothelial cells and to detect vasculogenic mimicry (scored by 3 independent observers). Cell cultures from 7 colon cell lines, real-time polymerase chain reaction (PCR) on cell lines, frozen tissue material from 4 colorectal cancer patients with and 4 without vasculogenic mimicry, and fresh colorectal cancer tissue from 2 patients were used to investigate the relationship between vasculogenic mimicry and tumor cell plasticity. Microvessel density was not a prognostic marker in our patients. We found vasculogenic mimicry in 23 (19.7%) of 117 colorectal tumor samples. Cell culture experiments and real-time PCR on human colorectal carcinoma material showed evidence for vasculogenic mimicry with overexpression of EPHA2 and LAMC2, known to be important for the tube-forming capacity of melanoma tumor cells. The presence of vasculogenic mimicry was associated with significantly shortened survival, both overall (P < 0.0001) and within intermediate cancer stages (Dukes B, P = 0.0277; Dukes C, P < 0.0001). Vasculogenic mimicry can occur in colorectal carcinoma and appears to be comparable to vasculogenic mimicry described in other tumors. Moreover, vasculogenic mimicry in colorectal carcinoma may be a strong independent prognostic marker for survival.

Role and mechanism of vasculogenic mimicry in gastrointestinal stromal tumors

Vasculogenic mimicry (VM) is the formation of fluid-conducting channels by highly invasive and genetically dysregulated tumor cells. In this study, we collected specimens of 84 human gastrointestinal stromal tumors (GISTs) along with clinicopathologic data and another 42 GISTs with fresh tissue that was used for gelatin zymography. VM was found in 21 of the 84 GISTs using CD31/periodic acid-Schiff double staining and CD117 and CD31 immunohistochemical staining. There was a significant difference in the VM-positive rate between the lesions with a mitotic rate > or =5/50 high-power fields and those with a lower mitotic rate (P = .000) and between the cases with and without liver metastasis (P = .008). There was a significant difference in the VM-positive rate between the high-risk group (5.9%) and the very low/low-risk group (12.5%) (P = .010) or the intermediate-risk group (39.5%) (P = .020). Kaplan-Meier survival analysis showed VM indicated a poor prognosis (P = .0000). Cox proportional hazards model indicated that the presence of VM, tumor size 10 cm or greater, and hemorrhage were independent predictors of a poor prognosis (P = .000, .005, .032, respectively). The staining indexes of matrix metalloproteinase (MMP)-2 and MMP-9 were higher in the VM-positive than in the VM-negative group (P = .024 and .037, respectively). Gelatin zymography showed that the activity of MMP-2 and MMP-9 was significantly higher in the VM-positive lesions (P = .013 and .033, respectively). We conclude that VM in GISTs is an unfavorable prognostic sign and that patients with VM-positive tumors are prone to suffer liver metastasis. Both MMP-2 and MMP-9 play an important role in VM formation in GISTs.