REVIEW Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors P Pittoni 1,3 , S Piconese 1,3 , C Tripodo 2 and MP Colombo 1 1 Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and 2 Department of Human Pathology, University of Palermo, Palermo, Italy 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 acces- sory 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. Oncogene (2011) 30, 757–769; doi:10.1038/onc.2010.494; published online 8 November 2010 Keywords: c-Kit; mast cells; tyrosine kinase inhibitors; off-target; mouse mutants Introduction c-Kit (CD117) is a tyrosine kinase (TK) receptor of the class III subfamily, which also includes the receptor for platelet-derived growth factor (PDGFR), the receptor for macrophage colony-stimulating factor-1 and FMS- like TK 3. Kit was originally described in its viral form (v-Kit), as the oncogene responsible for the transform- ing activity of the Hardy–Zuckerman IV feline sarcoma virus (Besmer et al., 1986), whereas its human protein counterpart was first identified as a cell-surface marker of human acute myeloid leukemia cells (Gadd and Ashman, 1985). Nonetheless, the strongest evidence of the crucial role in physiology of c-Kit receptor and its ligand stem cell factor (SCF), also known as Kit ligand, steel factor and mast cell growth factor, came from the mapping of these two molecules to the White spotting (W) (Chabot et al., 1988; Geissler et al., 1988) and Steel (Sl) (Zsebo et al., 1990) loci, respectively. Mice with spontaneous mutations at either W or Sl locus display indeed a very similar and pleiotropic phenotype, including severe macrocytic anemia, mast cell (MC) deficiency, sterility and pigmentation defects (Silvers, 1979). Since then, the SCF/c-Kit axis has been extensively studied and many reports have contributed to elucidate its essential role in haematopoiesis, melanogenesis and gametogenesis, but have also extended its extreme biological relevance to the fields of stem cells (SCs) and cancer cell biology. Among the c-Kit-dependent cells, interest is renewed for MCs that, beyond classical histamine-releasing cells in allergic reactions, are now viewed as multifunctional and plastic cells intervening in a variety of reactions, such as protection from patho- gens, autoimmune and inflammatory disorders, trans- plantation tolerance, metabolic diseases, and, most importantly, cancer progression (Kinet, 2007; Galli et al., 2008; Beaven, 2009). This review focuses on the SCF/c-Kit axis in physiological and pathological conditions, especially cancer. Tumor-cell-intrinsic and -extrinsic roles of c-Kit are discussed, with emphasis on MCs, accomplices for tumor progression that, strongly relying on c-Kit, represent the primary off-target of c-Kit-directed cancer therapy. Biology of the SCF/c-Kit axis Expression of c-KIT and SCF As a member of the PDGFR family, c-Kit receptor is characterized by an extracellular ligand-binding region containing five immunoglobulin-like repeats, a trans- membrane sequence, an autoinhibitory juxtamembrane domain and two intracellular TK domains: an ATP- binding pocket and a kinase activation loop (Liu et al., 2007) (Figure 1). SCF is produced as a glycosylated transmembrane protein. Alternative splicing originates two isoforms, one containing a cleavage site, leading to its proteolysis and release as a soluble homodimer, and the other remaining cell associated (Anderson et al., 1991). During embryonic life, c-Kit and SCF are expressed along the migratory pathways and in the homing locations of primordial germ cells and melanocytes, in Received 13 August 2010; revised 9 September 2010; accepted 18 September 2010; published online 8 November 2010 Correspondence: Dr MP Colombo, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo, 42 20133 Milan, Italy. E-mail: mario.colombo@istitutotumori.mi.it 3 These authors contributed equally to this work. Oncogene (2011) 30, 757–769 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc