Understanding GIST
Etiology
Interstitial cells of Cajal (ICCs), which are intercalated between the autonomic nerves and muscle walls of the gut, are believed to function as "pacemaker" cells for GI tract motility. ICCs have been shown to express the KIT proto-oncogene receptor (KIT, CD117) on their surface. This receptor, a transmembrane tyrosine kinase, binds the stem-cell factor and is believed to be essential for development of normal haematopoiesis, proliferation, and migration of primordial germ cells during embryogenesis, as well as for pacemaker functions in ICCs.1 Similarly, GISTs express the tyrosine kinase receptor KIT in most cases, unlike GI leiomyomas and leiomyosarcomas, which do not express KIT receptors.1 The ultrastructure of ICCs is also consistent with GIST cells,2 both of which have abundant mitochondria, intermediate filaments, microtubules, and cytoplasmic interdigitating projections.1,2 The shared histologic morphology and immunohistochemical reactivity of ICCs and GISTs suggest that GIST is derived from ICCs or their stem-cell precursors.1
Cellular Origins of GIST
Image reproduced with permission from Thomsen L, et al. Nature Med. 1998;4:848-851.3
In the majority of GISTs, the ICCs, which mediate peristalsis in the upper intestine, undergo uncontrolled growth. Growing tumours stimulate angiogenesis or formation of new blood vessels via production of cytokines, such as vascular endothelial growth factor (VEGF). Cells located within the growing blood vessels then secrete other cytokines, including platelet-derived growth factors (PDGFs). These bind to associated PDGF receptors on pericytes, resulting in increased vascular and endothelial cell stability.
References:
1. Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998;152:1259-1269.
2. Torihashi S, Horisawa M, Watanabe Y. c-Kit immunoreactive interstitial cells in the human gastrointestinal tract. J Auton Nerv Syst. 1999;75:38-50.
3. Thomsen L, Robinson TL, Lee JC, et al. Interstitial cells of Cajal generate a rhythmic pacemaker current. Nat Med. 1998;4:848-851.