Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

Abstract

Vasohibin‐2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL‐KrasG12D; LSL‐Trp53R172H; Pdx‐1‐Cre (KPC) mice, a mouse model of pancreatic ductal adenocarcinoma (PDAC), and cells isolated from them (KPC cells). Knockdown of Vash2 from PDAC cells did not affect their proliferation, but decreased their migration. When Vash2‐knockdown PDAC cells were orthotopically inoculated, liver metastasis and peritoneal dissemination were reduced, and the survival period was significantly prolonged. When KPC mice were crossed with Vash2‐deficient mice, metastasis was significantly decreased in Vash2‐deficient KPC mice. VASH2 was recently identified to have tubulin carboxypeptidase activity. VASH2 knockdown decreased, whereas VASH2 overexpression increased tubulin detyrosination of PDAC cells, and tubulin carboxypeptidase (TCP) inhibitor parthenolide inhibited VASH2‐induced cell migration. We next clarified its role in the tumor microenvironment. Tumor angiogenesis was significantly abrogated in vivo when VASH2 was knocked down or deleted. We further examined genes downregulated by Vash2 knockdown in KPC cells, and found chemokines and cytokines that were responsible for the recruitment of myeloid derived suppressor cells (MDSC). Indeed, MDSC were accumulated in PDAC of KPC mice, and they were significantly decreased in Vash2‐deficient KPC mice. These findings suggest that VASH2 plays an essential role in the metastasis of PDAC with multiple effects on both cancer cells and the tumor microenvironment, including tubulin detyrosination, tumor angiogenesis and evasion of tumor immunity.

Landscape of Myeloid-derived Suppressor Cell in Tumor Immunotherapy

“…SDF-1 in the microenvironment upregulates CCR4+MDSC infiltration in the lung, and accumulated MDSC in turns secrete more SDF-1 to form a positive feedback, which promotes the metastasis of CCR4+ prostate cancer cells [ 107 ]. Vashibin-2 (vash2) expressed in pancreatic ductal adenocarcinoma (PDAC) can induce MDSC attraction by secreting chemokines including CXCL2, CXCL5, CCL2, and CCL5, which promotes angiogenesis and metastasis [ 108 ]. In a mouse model of lung adenocarcinoma, signal transduction by TLR7 on the surface of cancer cells can also recruit MDSCs to promote cancer progression and metastasis [ 109 ].…”

Molecular mediators of peritoneal metastasis in pancreatic cancer

“…VASH2 stimulation of angiogenesis is related to decrease of mir-200b [210]. Like ovarian cancer, PDA expresses VASH2 [211]. VASH2 expression is associated with poor prognosis in PDA patients [212].…”

“…VASH2 expression is associated with poor prognosis in PDA patients [ 212 ]. VASH2 effects both PDA cells and the tumor microenvironment by promoting tubulin detyrosination-lead tumor cell migration, tumor angiogenesis, as well as induction of myeloid derived suppressor cells [ 211 ]. Many anti-angiogenic agents are approved or under clinical development for patients with ovarian cancer.…”

epiLiver a novel tumor specific, high throughput and cost-effective blood test for specific detection of liver cancer (HCC)

“…Vasohibin 2 (VASH2) gene was implicated in angiogenesis in invasive tumors [32] and was previously shown to be methylated in HCC [33]. Vash2 is a promoter of an angiogenesis gene it is therefore expected to promote cancer and indeed higher expression of Vash2 is associated with poor progression of pancreatic cancer [34], esophageal squamous cell carcinoma [35], breast cancer [36] and epithelial-mesenchymal transition (EMT) in HCC [37]. We would therefore expect hypomethylation of the 5'regulatory region of the gene rather than the observed hypermethylation of the1st exon.…”