Dysregulation of Rab37-mediated cross-talk between cancer cells and endothelial cells via thrombospondin-1 promotes tumor neovasculature and metastasis

Hong Tai Tzeng, Chung Han Tsai, Yi-Ting Yen, Hung-Chi Cheng, Yi Chieh Chen, Shih Wen Pu, Yu Shiuan Wang, Yan-Shen Shan, Yau-Lin Tseng, Wu-Chou Su, Wu-Wei Lai, Li-Wha Wu, Yi-Ching Wang

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Abstract

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 neovasculature in vitro and in vivo. Secreted 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.

Original languageEnglish
Pages (from-to)2335-2345
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number9
DOIs
Publication statusPublished - 2017 May 1

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Thrombospondin 1
Endothelial Cells
Neoplasm Metastasis
Tumor Microenvironment
Exocytosis
Neoplasms
Cell Movement
Epithelial Cells
rab GTP-Binding Proteins
Paxillin
Monomeric GTP-Binding Proteins
Cell Shape
Angiogenesis Inducing Agents
Disease-Free Survival
Carcinogenesis
Research Design
Fluorescence
Regression Analysis

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

@article{86011ac38b4846ba98b1cd153836d2c6,
title = "Dysregulation of Rab37-mediated cross-talk between cancer cells and endothelial cells via thrombospondin-1 promotes tumor neovasculature and metastasis",
abstract = "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 neovasculature in vitro and in vivo. Secreted 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.",
author = "Tzeng, {Hong Tai} and Tsai, {Chung Han} and Yi-Ting Yen and Hung-Chi Cheng and Chen, {Yi Chieh} and Pu, {Shih Wen} and Wang, {Yu Shiuan} and Yan-Shen Shan and Yau-Lin Tseng and Wu-Chou Su and Wu-Wei Lai and Li-Wha Wu and Yi-Ching Wang",
year = "2017",
month = "5",
day = "1",
doi = "10.1158/1078-0432.CCR-16-1520",
language = "English",
volume = "23",
pages = "2335--2345",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
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TY - JOUR

T1 - Dysregulation of Rab37-mediated cross-talk between cancer cells and endothelial cells via thrombospondin-1 promotes tumor neovasculature and metastasis

AU - Tzeng, Hong Tai

AU - Tsai, Chung Han

AU - Yen, Yi-Ting

AU - Cheng, Hung-Chi

AU - Chen, Yi Chieh

AU - Pu, Shih Wen

AU - Wang, Yu Shiuan

AU - Shan, Yan-Shen

AU - Tseng, Yau-Lin

AU - Su, Wu-Chou

AU - Lai, Wu-Wei

AU - Wu, Li-Wha

AU - Wang, Yi-Ching

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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 neovasculature in vitro and in vivo. Secreted 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.

AB - 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 neovasculature in vitro and in vivo. Secreted 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.

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U2 - 10.1158/1078-0432.CCR-16-1520

DO - 10.1158/1078-0432.CCR-16-1520

M3 - Article

VL - 23

SP - 2335

EP - 2345

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 9

ER -