Abstract
Vasculogenic mimicry (VM) is a blood supply modality that occurs independently of endothelial cell angiogenesis. Hypoxia and the epithelial-mesenchymal transition (EMT) induce VM formation by remodeling the extracellular matrix. Our previous study demonstrated that hypoxia-inducible factor-2 alpha (HIF-2α) promotes the progress of EMT in pancreatic cancer; however, whether HIF-2α promotes VM formation in pancreatic cancer remains unknown. In this study, we investigated HIF-2α expression and VM by immunohistochemistry in 70 pancreatic cancer patients as well as the role of Twist1and Twist2 in HIF-2α-induced VM in vitro and in vivo. We found that the overexpression of HIF-2α and VM were correlated with poor tumor differentiation, late clinical stage and lymph node metastasis, and a poor prognosis in pancreatic cancer. Moreover, the upregulation of HIF-2α in SW1990 cells induced VM formation, whereas the opposite results were found after silencing HIF-2α in AsPC-1 cells. A mechanistic study indicated that HIF-2α might regulate the binding of twist1 to vascular endothelial cadherin (VE-cadherin) to promote VM formation in pancreatic cancer cells, and that the P1 (-421bp) and P4 (-2110bp) regions of the Twist1 binding sequences are positive regulatory elements for VE-cadherin. In addition, we confirmed that the overexpression of HIF-2α increased Twist1 expression and promoted tumor growth and VM formation in pancreatic cancer xenografts in nude mice. These findings indicated that HIF-2α might play a critical role in VM and that HIF-2α and the pathway of HIF-2α inducing VM formation are potential therapeutic targets for pancreatic cancer.
Highlights
Pancreatic cancer, one of the most lethal cancers among all malignances, is characterized by aggressive local invasion and metastatic spread, with a median overall survival of less than 1year and a 5-year survival of approximately 5% [1]
We found that the overexpression of Hypoxia-inducing factors (HIF)-2α and Vasculogenic mimicry (VM) were correlated with poor tumor differentiation, late clinical stage and lymph node metastasis, and a poor prognosis in pancreatic cancer
These results indicated that HIF-2α might be involved in poor differentiation and advanced clinical stages of pancreatic cancer
Summary
Pancreatic cancer, one of the most lethal cancers among all malignances, is characterized by aggressive local invasion and metastatic spread, with a median overall survival of less than 1year and a 5-year survival of approximately 5% [1]. Pancreatic cancer is a complex, multifactorial disease involving mutations in cancer-associated genes, and has a poor prognosis because traditional radiation or chemotherapy strategies yield disappointing results [1, 3]. [7] described an angiogenesis-independent pathway called “Vasculogenic Mimicry (VM),” which is a newly-defined pattern of tumor blood supply in which highly aggressive tumor cells mimic endothelial cells and form extracellular matrix (ECM)-rich structures to supply red cells and plasma without the appearance of endothelial cells. VM formation is a multistep and complex process, including activation and proliferation of tumor cells, differentiation of tumor cells into endothelial-like cells and appearance of new vessels. VM occurs first, whereas endothelium-dependent vessels provide the tumor with sufficient blood and promote cancer progression [18]. Several key proteins are necessary for the formation of VM, among which VE-cadherin is the most critical for VM channels [19, 20]
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