Dysregulation of Rab37-Mediated Cross-talk between Cancer Cells and Endothelial Cells via Thrombospondin-1 Promotes Tumor Neovasculature and Metastasis.
Purpose:Accumulating evidence indicates that factors secreted by cancer epithelial cells shape the tumor microenvironment to promote cancer invasion and metastasis. Recent studies also shed light on alterations of Rab small GTPase-mediated exocytosis in tumorigenesis. However, the mechanisms for Rab-mediated exocytosis in tumor microenvironment remain elusive. We aimed to investigate the interplay between Rab37-mediated exocytosis and tumor microenvironment, focusing on endothelial cell motility and angiogenesis.Experimental Design:We performed fluorescence IHC for Rab37, thrombospondin-1 (TSP1, an antiangiogenesis factor), and angiogenesis marker CD31 in 183 surgically resected esophageal squamous cell carcinoma (ESCC) patient samples. Cell migration, invasion, angiogenesis, and tumor metastasis were measured.Results:ESCC patients with low expression of Rab37 or TSP1 significantly correlated with high CD31 expression and were associated with worse progression-free survival. The multivariate Cox regression analysis showed that concordant low expression of both Rab37 and TSP1 was an independent prognostic factor of ESCC patients. Rab37-mediated exocytosis of TSP1 led to the inhibition of neovasculaturein vitroandin vivoSecreted TSP1 from cancer cells with Rab37 exocytic function inhibited the p-FAK/p-paxillin/p-ERK migration signaling in both cancer epithelial cells and their surrounding endothelial cells. Dysfunction of Rab37 or loss of TSP1 abrogated the suppressive effects on angiogenesis and metastasis.Conclusions:Our findings suggest that Rab37-mediated TSP1 secretion in cancer cells suppresses metastasis and angiogenesis via a cross-talk with endothelial cells and reveal a novel component of the vesicular exocytic machinery in tumor microenvironment and tumor progression. Dysregulation of Rab37/TSP1 axis has clinical implications for prognosis prediction.Clin Cancer Res; 23(9); 2335-45. ©2016 AACR.
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Hong-Tai
HT
Tzeng
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Chung-Han
CH
Tsai
Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yi-Ting
YT
Yen
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Hung-Chi
HC
Cheng
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yi-Chieh
YC
Chen
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Shih-Wen
SW
Pu
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yu-Shiuan
YS
Wang
Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yan-Shen
YS
Shan
Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yau-Lin
YL
Tseng
Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Wu-Chou
WC
Su
Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Wu-Wei
WW
Lai
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. liwhawu@mail.ncku.edu.tw ycw5798@mail.ncku.edu.tw.|Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Li-Wha
LW
Wu
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. liwhawu@mail.ncku.edu.tw ycw5798@mail.ncku.edu.tw.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yi-Ching
YC
Wang
D000368:Aged; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002465:Cell Movement / Q000235:genetics; D018572:Disease-Free Survival; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics; D019700:Thrombospondin 1 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D020691:rab GTP-Binding Proteins / Q000235:genetics*
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019700:Thrombospondin 1; C000611726:thrombospondin-1, human; C571080:Rab37 protein, human; D020691:rab GTP-Binding Proteins