Dysregulation of Rab37-Mediated Cross-talk between Cancer Cells and Endothelial Cells via Thrombospondin-1 Promotes Tumor Neovasculature and Metastasis

Abstract

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. 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. 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 and 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. 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. .

Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages toward tumor‐suppressing phenotype

“…We previously reported that Rab37 was a metastasis suppressor . Here, we provide compelling evidence from cell‐based, animal and clinical studies that Rab37 functions as a modulator of macrophage polarization via regulating the exocytosis of sST2, resulting in the preferential shift of macrophages phenotype from M2‐like to M1‐like, and thereby inhibiting tumor growth.…”

“…We previously reported that Rab37 was a metastasis suppressor. 33,34 Here, we provide compelling evidence from cellbased, animal and clinical studies that Rab37 functions as a modulator of macrophage polarization via regulating the exocytosis of sST2, resulting in the preferential shift of macrophages phenotype from M2-like to M1-like, and thereby inhibiting tumor growth. Silencing of Rab37 reduced sST2 secretion into the extracellular compartment and thus resulted in pro-tumoral M2 macrophages activation in tumor microenvironment ( Figs.…”

“…32 We also showed that the small GTPase Rab37 regulates exocytosis of tumor cells to suppress metastasis by inhibiting cell motility through tissue inhibitor of metalloproteinase 1 (TIMP1) secretion and blocking neovasculature by releasing thrombospondin-1 (TSP1). 33,34 These results suggest that Rab37 mediates the cross-talk between cancer cells and their surrounding stroma via exocytosis of specific cargos. Since the interplay between cancer cells and macrophages is the major determinant in the shaping of tumor microenvironment, little is known about the regulation of macrophages polarization by cancer cell-triggered exocytosis.…”

“…Low level of Rab37 mRNA expression was associated with tumor metastasis . We also showed that the small GTPase Rab37 regulates exocytosis of tumor cells to suppress metastasis by inhibiting cell motility through tissue inhibitor of metalloproteinase 1 (TIMP1) secretion and blocking neovasculature by releasing thrombospondin‐1 (TSP1) . These results suggest that Rab37 mediates the cross‐talk between cancer cells and their surrounding stroma via exocytosis of specific cargos.…”

Identification of prognostic genes in adrenocortical carcinoma microenvironment based on bioinformatic methods

“…Increasing evidence revealed that dysregulated Rab proteins were related to cancer progression . RAB37 was a metastasis suppressor by regulating exocytosis to the extracellular compartment, resulting in inhibition of cancer metastasis and neo‐angiogenesis …”