Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase

Abstract

Oncogenic Kit mutations are found in somatic gastrointestinal (GI) stromal tumors (GISTs) and mastocytosis. A mouse model for the study of constitutive activation of Kit in oncogenesis has been produced by a knock-in strategy introducing a Kit exon 11-activating mutation into the mouse genome based on a mutation found in a case of human familial GIST syndrome. Heterozygous mutant Kit V558⌬ ͞؉ mice develop symptoms of disease and eventually die from pathology in the GI tract. Patchy hyperplasia of Kit-positive cells is evident within the myenteric plexus of the entire GI tract. Neoplastic lesions indistinguishable from human GISTs were observed in the cecum of the mutant mice with high penetrance. In addition, mast cell numbers in the dorsal skin were increased. Therefore Kit V558⌬ ͞؉ mice reproduce human familial GISTs, and they may be used as a model for the study of the role and mechanisms of Kit in neoplasia. Importantly, these results demonstrate that constitutive Kit signaling is critical and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal. Kit encodes a growth factor receptor with ligand-dependent tyrosine kinase activity (1-3). Kit ligand (KitL) is the only known ligand of the Kit receptor (4). KitL binding to the receptor mediates receptor dimerization, activation of kinase activity, and autophosphorylation. Subsequently, Kit activates several signaling cascades, leading to cell proliferation, cell survival, and other cellular responses. Kit and KitL are encoded at the White spotting (W) and Steel (Sl) loci in the mouse, respectively (4-6). Mutations at the murine W and Sl loci generate deficiencies in several major cell systems during embryogenesis and in the postnatal animal: in hematopoiesis, melanogenesis, gametogenesis, and intestinal pacemaker cells. In hematopoiesis Kit receptor signaling is critical in the stem cell hierarchy, erythropoiesis, mast cell development and function, megakaryopoiesis, and lymphopoiesis (7-10). Interstitial cells of Cajal (ICC) function as pacemaker cells in the gastrointestinal (GI) tract and they mediate inputs from the enteric nervous system to smooth muscle cells. ICC express the Kit receptor tyrosine kinase and inhibition of Kit function interferes with the autonomous movement of the GI tract (11-13).GI stromal tumor (GIST) is the most common mesenchymal neoplasm of the human intestinal tract. GISTs are a heterogeneous group of tumors, which historically had been classified either as leiomyoma, leiomyosarcoma, or GI autonomic nerve tumors (14). GISTs express Kit and they are thought to derive from a Kit ϩ or Kit low ICC progenitor or ICC through somatic mutation, based on immunophenotypic and ultrastructural similarities (15).Originally, we had identified Kit as the oncogene of an acute transforming feline retrovirus, the HZ4-FeSV (1). However, a role for Kit in human neoplasia has been emerging only more recently. First, human and murine mast cell lines were found to carry Kit-activating mutations in the activation loop of the kinas...

Gastrointestinal stromal tumors: what do we know now?

“…7,25 Finally, mice engineered to express KIT with mutations of the type found in human GISTs develop diffuse ICC hyperplasia within the muscular wall of the stomach and intestine. 26,27 These mice also develop GIST-like tumors. This histologic picture is similar to that seen in individuals with inherited KIT-activating mutations.…”

“…Mice engineered to express KIT with mutations of the type found in human GISTs develop diffuse ICC hyperplasia within the muscular wall of the stomach and intestine. 26,27 These mice also develop GIST-like tumors. Diffuse ICC hyperplasia has been described in several kindreds with heritable mutations in KIT (Table 2), and is associated with dysphagia and the development of multiple GISTs, 26,29,53,[73][74][75][76][77][78] although many of the tumors do not follow a malignant course.…”

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…By contrast, TAM polarization may be important for the response to targeted therapies in other cancer types and can even result in adverse effects. Imatinib treatment of tumorbearing Kit V558/+ mice -which carry a gain-of-function point mutation on one allele of the Kit receptor gene predisposing them to spontaneous gastrointestinal stromal tumor (GIST) development [107] -has been shown to repolarize TAMs from their normal anti-tumorigenic, T cell-stimulating phenotype to a more pro-tumorigenic phenotype [108]. However, the consequence of TAM skewing by imatinib, whether this is beneficial or detrimental for tumor progression, remains untested.…”

A mutation-created novel intra-exonic pre-mRNA splice site causes constitutive activation of KIT in human gastrointestinal stromal tumors

“…Through these diverse signal transduction pathways and tissue-specific regulations, KIT plays important roles in hematopoiesis, melanogenesis, gametogenesis, and peristalsis. Gain-of-function KIT mutations have been implicated in mastocytosis, hematologic disorders, germ cell tumors, and GISTs (Hirota et al, 1998Taniguchi et al, 1999;Isozaki et al, 2000;Allander et al, 2001;Sandberg and Bridge, 2002;Heinrich et al, 2003a, b;Kinoshita et al, 2003;Sommer et al, 2003;Koh et al, 2004). Loss-of-function mutations in KIT result in human piebaldism (Syrris et al, 2002).…”