A large group of small Rab GTPases which mediate secretory and endosomal membrane transport, as well as autophagosome biogenesis, are essential components of vesicle trafficking machinery. Specific Rab protein together with the cognate effectors coordinates the dynamics of trafficking pathway and determines the cargo proteins destination. Functional impairments of Rab proteins by mutations or post-translational modifications disrupting the regulatory network of vesicle trafficking have been implicated in tumorigenesis. Therefore, the vesicle transport regulators play essential roles in the mediation of cancer cell biology, including uncontrolled cell growth, invasion and metastasis. The context-dependent role of the same Rab to act as either an oncoprotein or tumor suppressor in different cancers is found. Such discrepancies may be due in part to the interaction of specific Rab protein with different effectors or cargos in various tumors. Here, we review recent advances in the roles of Rab GTPases in communicating with other effectors in tumor progression. In this review, we also emphasize dysregulation of Rab-mediated membrane delivery shifting normal cell behaviors toward malignancy. Thus, recovery of the dysregulated vesicle trafficking systems in cancer cells may provide future directions for potential strategy to restrain tumor progression.

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. .

Interplay between cancer epithelial cells and the surrounding immune cells shape the tumor microenvironment to promote cancer progression. Tumor-associated macrophages are well recognized for their roles in cancer progression. Accumulating evidence also indicates implication of Rab small GTPase-mediated exocytosis in tumorigenesis. However, the mechanism for Rab-mediated exocytosis in regulation of macrophage polarization is not clear. We have previously identified Rab37 as a metastasis suppressor in lung cancer. In our study, we identified a novel Rab37 trafficking cargo soluble ST2 (sST2), which skewed macrophage polarization toward anti-tumoral M1-like phenotype in vitro. We further demonstrated that Rab37-mediated sST2 secretion significantly increased the ratio of M1 vs. M2 in xenografts and thus reduced tumor growth. Moreover, lung cancer patients with low Rab37, low sST2 and low ratio of M1 vs. M2 macrophages expression profile correlated with worse overall survival examined by Kaplan-Meier survival analysis. Multivariate Cox regression analysis showed that this Rab37-sST2-M1/M2 expression profile predicted poor prognosis. Our findings reveal a novel regulation of cancerous Rab37 in microenvironmental macrophages polarization, which preferentially shifts to anti-tumoral phenotype and thereby suppresses lung tumor growth.

We previously identified a novel Rab small GTPase protein, Rab37, which plays a critical role in regulating exocytosis of secreted glycoproteins, tissue inhibitor of metalloproteinases 1 (TIMP1) to suppress lung cancer metastasis. Patients with preserved Rab37 protein expression were associated with better prognosis. However, a significant number of the patients with preserved Rab37 expression showed poor survival. In addition, the molecular mechanism for the regulation of Rab37-mediated exocytosis remained to be further identified. Therefore, we investigated the molecular mechanism underlying the dysregulation of Rab37-mediated exocytosis and metastasis suppression. Here, we report a novel mechanism for Rab37 inactivation by phosphorylation. Lung cancer patients with preserved Rab37, low TIMP1, and high PKCα expression profile correlate with worse progression-free survival examined by Kaplan-Meier survival, suggesting that PKCα overexpression leads to dysfunction of Rab37. This PKCα-Rab37-TIMP1 expression profile predicts the poor outcome by multivariate Cox regression analysis. We also show that Rab37 is phosphorylated by protein kinase Cα (PKCα) at threonine 172 (T172), leading to attenuation of its GTP-bound state, and impairment of the Rab37-mediated exocytosis of TIMP1, and thus reduces its suppression activity on lung cancer cell motility. We further demonstrate that PKCα reduces vesicle colocalization of Rab37 and TIMP1, and therefore inhibits Rab37-mediated TIMP1 trafficking. Moreover, Phospho-mimetic aspartate substitution mutant T172D of Rab37 significantly promotes tumor metastasis in vivo. Our findings reveal a novel regulation of Rab37 activity by PKCα-mediated phosphorylation which inhibits exocytic transport of TIMP1 and thereby enhances lung tumor metastasis.