Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases

Abstract

Tumor-associated macrophages (TAM) play pivotal roles in cancer initiation and progression. Monocytes, the precursors of TAMs, normally undergo spontaneous apoptosis within 2 days, but can subsist in the inflammatory tumor microenvironment for continuous survival and generation of sufficient TAMs. The mechanisms underlying tumor-driving monocyte survival remain obscure. Here we report that cancer cell-derived exosomes were crucial mediators for monocyte survival in the inflammatory niche. Analysis of the survival-promoting molecules in monocytes revealed that cancer cell-derived exosomes activated Ras and extracellular signalregulated kinases in the mitogen-activated protein kinase (MAPK) pathway, resulting in the prevention of caspase cleavage. Phosphorylated receptor tyrosine kinases (RTKs), such as phosphorylated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), were abundantly expressed in cancer cell-derived exosomes. Knock-out of EGFR or/and HER-2, or alternatively, inhibitors against their phosphorylation significantly disturbed the exosome-mediated activation of the MAPK pathway, inhibition of caspase cleavage, and increase in survival rate in monocytes. Moreover, the deprived survival-stimulating activity of exosomes due to null expression of EGFR and HER-2 could be restored by activation of another RTK, insulin receptor. Overall, our study uncovered a mechanism of tumor-associated monocyte survival and demonstrated that cancer cell-derived exosomes can stimulate the MAPK pathway in monocytes through transport of functional RTKs, leading to inactivation of apoptosis-related caspases. This work provides insights into the long sought question on monocyte survival prior to formation of plentiful TAMs in the tumor microenvironment.Clinical and experimental evidences suggest that a particular type of macrophage population is present within the tumor microenvironment (1). Tumor-associated macrophages (TAMs) 4 are derived from recruited monocytes or resident tissue macrophages (2), and play essential roles in tumor initiation, progression, and metastasis (3). Monocyte recruitment, survival, and differentiation are fundamental steps for continuous generation of TAMs. Previous studies are focused on understanding the complicated mechanisms of monocyte recruitment and differentiation within tumor tissues (2). However, investigations regarding how monocytes maintain survival before differentiation into sufficient TAMs have never been reported.As key components of the innate immune system, monocytes are continuously produced by bone marrow but normally undergo spontaneous apoptosis within 48 h in blood circulation (4, 5). Monocyte apoptosis can be prevented in vitro by serum at high concentrations (Ͼ20%), differentiation factors, and a wide range of inflammatory stimuli such as lipopolysaccharide (LPS) and interferon-␥ (IFN-␥), all of which reduce the activation of caspases and trigger the differentiation of monocytes into macrophages or dendritic cells (5-10). However, i...

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