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

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‐medi...

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Bibliographic Details
Published in:International journal of cancer 2018-10, Vol.143 (7), p.1753-1763
Main Authors: Tzeng, Hong‐Tai, Su, Ching‐Chin, Chang, Chih‐Peng, Lai, Wu‐Wei, Su, Wu‐Chou, Wang, Yi‐Ching
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Cancer
Cell Movement
Cell Proliferation
Epithelial cells
Exocytosis
Genotype & phenotype
Guanosine triphosphatases
Humans
Interleukin-1 Receptor-Like 1 Protein - metabolism
Lung cancer
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
macrophage
Macrophages
Macrophages - metabolism
Macrophages - pathology
Medical prognosis
Medical research
Metastases
Mice
Mice, Inbred BALB C
Mice, Nude
Phenotype
Phenotypes
Polarization
Prognosis
rab GTP-Binding Proteins - metabolism
Rab37
Regression analysis
ST2
Survival analysis
Survival Rate
Tumor Cells, Cultured
tumor microenvironment
Tumorigenesis
Xenograft Model Antitumor Assays
Xenografts
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Summary: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. What's new? Cancer cells shape the tumor microenvironment to promote malignancy through secretion of soluble factors. However, little is known about the suppression of tumor progression via cancer‐secreted factors. Here, the authors provide evidence from cell‐based, animal, and clinical studies that a small GTPase Rab37 mediates the exocytosis of soluble ST2 from lung cancer cells to skew macrophages towards M1‐like tumor‐suppressive phenotype, thus reducing tumor growth. Low expression of Rab37 and ST2 together with low ratio of M1/M2 macrophages correlates with poor overall survival. The Rab37/sST2 axis provides a link for the crosstalk between cancer and immune cells in the tumor microenvironment.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.31569