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GIST

Gastrointestinal stromal tumors (GISTs) are neoplasms that arise either from the mesenchymal (non-epithelial) tissue of the gastrointestinal tract or, rarely, from other intra-abdominal soft tissues. They probably originate from—or share a common stem cell with—the interstitial cells of Cajal. These cells, which are located in the myenteric plexus of the gastrointestinal tract, are pacemaker cells that cause gut peristaltic contractions. Following surgical resection, GISTs often recur locally, spread diffusely throughout the serosal surfaces of the abdomen and/or metastasize to the liver. Advanced disease is associated with metastases to distant sites, including the lung and bone. Prior to the advent of targeted therapies, the prognosis for advanced GISTs was poor owing to their inherent resistance to both chemotherapy and radiation therapy.

Most (75–80%) GISTs have KIT mutations, typically affecting the juxtamembrane domain encoded by exon 11. The alterations might be in-frame deletions or insertions, missense mutations, or combinations thereof. Mutations also arise in the extracellular domains of KIT and in the kinase I and II domains. 20–25% of GISTs do not have KIT mutations, and of these tumors about a third have PDGFRA mutations in domains homologous to those in KIT (prevalence of PDGFRA mutations is about 10%). KIT and PDGFRA mutations are mutually exclusive. KIT and PDGFRA kinase domains are activated normally through binding of their respective ligands (stem-cell factor or platelet-derived growth factor), leading to receptor dimerisation. The juxtamembrane regions of these kinases serve to regulate dimerisation, thus, mutations in these domains disrupt this function. By contrast, alterations in the kinase II domains of KIT and PDGFRA alter the activation loop that conformationally regulates the ATP-binding pocket of each kinase. Through these and probably other mechanisms, mutations of KIT and PDGFRA promote oncogenic signaling through the mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase (PI3K) pathways.

10–15% of GISTs do not have a detectable KIT or PDGFRA mutation. These so-called wild-type tumors form a heterogeneous group, some of which are driven by oncogenic mutations acting downstream of the receptor kinases. Wild-type GISTs include neurofibromatosis 1 (NF1 gene mutation), Carney-Stratakis syndrome (rare), Carney’s triad (rare), BRAF mutation (rare), succinate dehydrogenase subunit mutations (SDHA, SDHB, SDHC, SDHD), and RAS-family mutations (NRAS, HRAS, KRAS). In wild-type GISTs without succinate dehydrogenase activity, upregulation of hypoxia-inducible factor α (HIF1α) might lead to increased growth signaling through insulin-like growth factor receptor 1 (IGF1R) and vascular endothelial growth factor receptor 2 (VEGFR2).

During the past decade, GISTs have served as an important model in the emerging field of molecularly targeted therapies for solid tumors. The nearly simultaneous discovery of oncogenic kinase mutations in GISTs and the introduction of kinase inhibitor therapies have led to a rapid evolution in our understanding of these tumors and the biology that defines them. Currently, many agents are under investigation in clinical trials of advanced GIST. These include multikinase inhibitors (masitinib, regorafenib, dasatinib, nilotinib, pazopanib, sorafenib), immunomodulating agents (interferon alfa, ipilimumab), inhibitors of heat-shock protein, a phosphoinositide-3-kinase inhibitor, and an insulin-like growth factor 1 receptor inhibitor. In summary, new insights into the origin and progression of GISTs are setting the stage for further therapeutic innovations, with the goal not only of controlling disease growth, but also of eliminating all tumor cells at the time of initial therapy.

Creative Biogene, as a leading biotechnology company, is able to offer various GIST pathway related products including stable cell lines, viral particles and clones for your pathogenesis study and drug discovery projects.

References:

  1. Joensuu H, Hohenberger P, Corless C L. Gastrointestinal stromal tumour. The Lancet, 2013, 382(9896): 973-983.
  2. Corless C L, Barnett C M, Heinrich M C. Gastrointestinal stromal tumours: origin and molecular oncology. Nature Reviews Cancer, 2011, 11(12): 865.
  3. Eisenberg B L, Pipas J M. Gastrointestinal stromal tumor—background, pathology, treatment. Hematology/Oncology Clinics, 2012, 26(6): 1239-1259.

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