MET Promotes Antitumor Neutrophil Recruitment and Cytotoxicity

Amplification or mutation of the proto-oncogene MET is required for the growth and survival of many tumors, making it a promising therapeutic target. However, MET expression and function in tumor-associated stromal cells is not well characterized. Finisguerra and colleagues found that deletion of Met in the hematopoietic compartment or specifically in neutrophils resulted in enhanced growth and metastasis of various hepatocyte growth factor (HGF)–secreting tumors, including lung and hepatocellular carcinomas, melanomas, fibrosarcomas, and mammary and colorectal cancers. Met deficiency resulted in reduced numbers of tumor-associated neutrophils (TAN) in primary tumors and metastases, whereas reconstitution of MET expression in neutrophils increased their recruitment and blocked tumor growth, supporting the idea that MET is critical for antitumor neutrophil infiltration into tumors. Specific knockdown of MET in cancer cells more effectively suppressed tumor growth compared with systemic administration of MET inhibitors, revealing that MET blockade in antitumor neutrophils limits the therapeutic efficacy of systemic MET inhibition. The expression of MET in neutrophils was enhanced in tumor-bearing mice and human non–small cell lung tumors compared with healthy tissue and was induced by inflammatory stimuli such as TNFα. Systemic inactivation of TNFα inhibited MET expression in TANs and prevented TAN accumulation in tumors by blocking neutrophil chemotaxis toward HGF and transendothelial migration of neutrophils to inflammatory sites. Furthermore, Met deletion in neutrophils reduced the expression of inducible nitric oxide synthase, a marker of antitumor neutrophils, and impaired nitric oxide production, resulting in decreased cancer cell killing capacity. Together, these data demonstrate that, whereas MET promotes cancer cell proliferation and survival, it enhances the recruitment and cytotoxic function of antitumor neutrophils, suggesting that MET inhibition specifically in cancer cells may improve the efficacy of MET-targeted therapies.

Finisguerra V, Di Conza G, Di Matteo M, Serneels J, Costa S, Thompson AA, et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature 2015 May 18 [Epub ahead of print].

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