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

• Published in: Cancer science Vol. 110; no. 7; pp. 2296 - 2308
• Main Authors: Iida‐Norita, Rie, Kawamura, Minaho, Suzuki, Yasuhiro, Hamada, Shin, Masamune, Atsushi, Furukawa, Toru, Sato, Yasufumi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2019; John Wiley and Sons Inc
• Subjects: Adenocarcinoma; Angiogenesis; Angiogenic Proteins - genetics; Angiogenic Proteins - metabolism; Animals; Carboxypeptidase; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell division; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement; Cell Proliferation; Chemokines; Cloning; Cytokines; Cytokines - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Granulocytes; Humans; MDSC; Medical prognosis; Metastases; Metastasis; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Original; Pancreatic cancer; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Peritoneum; Suppressor cells; Tubulin; Tubulin - metabolism; tubulin detyrosination; Tumor Microenvironment; Up-Regulation; vasohibin‐2; United States > US; Japan; tubulin detyrosination; MDSC; vasohibin-2; angiogenesis; pancreatic ductal adenocarcinoma
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14041

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. VASH2‐dependent increase in tubulin detyrosination directly accelerates migration of PDAC cells. In the tumor microenvironment, VASH2 promotes tumor angiogenesis as a result of paracrine activity and evasion of tumor immunity as a result of altered gene expression in PDAC cells.