Abstract
During progression from single cancer cells to a tumor mass and metastases, tumor cells send signals that can subvert their tissue microenvironment. These signals involve soluble molecules and various extracellular vesicles, including a particular type termed exosomes. The specific roles of exosomes secreted in the tumor microenvironment, however, is unclear. The small GTPases RAB27A and RAB27B regulate exocytosis of multivesicular endosomes, which lead to exosome secretion, in human HeLa cells. Here, we used mouse models to show that Rab27a blockade in mammary carcinoma cells decreased secretion of exosomes characterized by endocytic markers, but also of matrix metalloproteinase 9, which is not associated with exosomes. Rab27a blockade resulted in decreased primary tumor growth and lung dissemination of a metastatic carcinoma (4T1), but not of a nonmetastatic carcinoma (TS/A). Local growth of 4T1 tumors required mobilization of a population of neutrophil immune cells induced by Rab27a-dependent secretion of exosomes together with a specific combination of cytokines and/or metalloproteinases. Our findings offer in vivo validation of the concept that exosome secretion can exert key pathophysiologic roles during tumor formation and progression, but they also highlight the idiosyncratic character of the tumor context.
Highlights
cell lysates (Cells)-autonomous acquisition of new properties such as proliferation and resistance to programmed death is not sufficient for a cell to become a tumor [1]
As previously done in the HeLa cell line, which expresses both genes at equivalent levels [13], we used lentiviruses expressing short hairpin RNA (shRNA) to mouse Rab27a or Rab27b, or a control nonmurine gene (Scr), to infect the 2 mammary carcinoma cell lines
We had previously shown in HeLa cells that RAB27A and RAB27B were required for efficient secretion of exosomes but not of a protein secreted through the regular secretion pathway [13]
Summary
Cell-autonomous acquisition of new properties such as proliferation and resistance to programmed death is not sufficient for a cell to become a tumor [1]. Transformed cells exchange signals with surrounding fibroblasts, endothelial cells and immune cells both through direct cell–cell interactions, and through secreted molecules. Tumors can secrete growth factors for endothelial cells, or chemokines and cytokines attracting and modifying the functions of Authors' Affiliations: 1Institut Curie Centre de Recherche, 2INSERM U932, 3CNRS UMR144, 4Institut Curie Departement de Chirurgie, Paris; 5Universite Paris-Descartes, Paris, France; 6Molecular and Cellular Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom; 7CEDOC, Faculdade de Cie^ncias Medicas, Universidade Nova de Lisboa; and 8Cell Biology of the Immune System Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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