Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors.
c-Kit tyrosine kinase receptor and its ligand stem cell factor have multiple functions during development, whereas in adulthood they are mostly needed for stem cell (SC) maintenance and mast cell (MC) biology. c-Kit plays an essential tumor-cell-intrinsic role in many types of cancer, either providing the tumorigenic force when aberrantly activated or conferring stem-like features characterizing the most aggressive variants. A tumor-cell-extrinsic role occurs through c-Kit-dependent accessory cells (such as MCs) that infiltrate tumors and deeply influence their progression. c-Kit-targeted therapy with tyrosine kinase inhibitors (TKIs) may ideally work against both tumor and stromal cells. Here, we summarize the tumor-intrinsic and -extrinsic roles of c-Kit in cancer and discuss TKIs with their on- and off-targets, with a special emphasis on MCs as paradigmatic c-Kit-dependent accomplices for tumor progression.
Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008415:Mastocytosis / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats; D019089:Stem Cell Factor / Q000378:metabolism*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit