Vasculogenic mimicry is associated with high tumor grade, invasion and metastasis, and short survival in patients with hepatocellular carcinoma

Abstract

Abstract. Vasculogenic mimicry (VM) has increasingly been recognized as a form of angiogenesis. In VM, epithelial cells are integrated into the malignant tumor vasculature. An association has been observed between VM and poor clinical prognosis in some malignant tumors. However, whether VM is present and clinically significant in hepatocellular carcinoma (HCC) is unknown. In this study, we determined whether VM was present in HCC and whether it was associated with tumor grade, invasion and metastasis, and survival duration. We collected paraffin-embedded HCC tumor samples, along with complete clinical and pathologic data for all the cases, and performed immunohistochemical staining for CD31, CD105 (endoglin), hepatocyte, vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9. The VM status was compared with the clinical and pathological data using statistical tests. Kaplan-Meier survival analysis and log-rank test were used to compare survival durations between patients with and without VM. The VM vessel cells were CD31 and CD105-negative and hepatocyte and vascular endothelial growth factor-positive, showing that they were not derived from endothelial cells but were HCC tumor cells. Patients with VM had a higher metastasis rate than did those without VM (P=0.003). Consistent with this finding, MMP-2 and MMP-9 were present in all the VM cases but were found less frequently in non-VM cases (P<0.05). The Kaplan-Meier survival analysis showed that patients in the VM group had a significantly shorter survival duration than did those in the non-VM group. In conclusion, VM is a marker of poor clinical prognosis in HCC: Its presence may be associated with a high tumor grade, invasion and metastasis, and short survival.

Doxycycline as an Inhibitor of the Epithelial-to-Mesenchymal Transition and Vasculogenic Mimicry in Hepatocellular Carcinoma

“…The molecular mechanisms underlying VM remain unclear; nevertheless, tumor cells lining VM networks secrete matrix metalloproteinases (MMP) and express vascular endothelial (VE)-cadherin to induce extracellular matrix (ECM) remodeling (4,5). Our previous studies also showed that VM occurs in HCC (6) and that EMT may be involved in VM formation in HCC (7). Previous research data indicated that VM was observed in 18 out of 97 patients with HCC (19%; ref.…”

Inhibition of tumor growth and vasculogenic mimicry by curcumin through down-regulation of the EphA2/PI3K/MMP pathway in a murine choroidal melanoma model

“…5,6 Our laboratory has begun to examine this process in detail using various strategies, resulting in the identification of several key signal transduction molecules critical for VM. 7,8 Anti-angiogenesis is a useful anticancer therapy that is widely accepted as a means for aggressive tumor therapy. However, recent findings have shown that routine single-targeted therapies using antiangiogenic drugs, such as angiostatin, endostatin and bevacizumab, which target endothelial cells have little effect on tumors exhibiting VM because of the absence of endothelial cells.…”

Overexpression of HIF-1α in primary gallbladder carcinoma and its relation to vasculogenic mimicry and unfavourable prognosis

“…Tumor cell plasticity underlies VM (8,37). Furthermore, VM channels and PAS patterns were associated with poor clinical outcome (10)(11)(12)14,18). VM was lined by tumor cells instead of endothelial cells without necrosis, hemorrhage, or inflammatory cells in the environment.…”

“…After these initial observations in melanoma (7,10), evidence for VM has been reported in other types of human cancers, including renal cell carcinoma (11) breast cancer (12), ovarian carcinoma (13), hepatocellular carcinoma (HCC) (14), laryngeal squamous cell carcinoma (LSCC) (15), glioblastomas (16), gastric adenocarcinoma (17) and colorectal cancer (18). Furthermore, tumors exhibiting VM related to more aggressive tumor biology and increased tumor-related mortality (10,11,19).…”