Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.

The chemokines are a large family of small, structurally related cytokines. The physiological importance of most members of this family has yet to be elucidated, although some are inducible inflammatory mediators that determine leukocyte chemotaxis. Pre-B-cell growth-stimulating factor/stromal cell-derived factor-1 (PBSF/SDF-1) is a member of the CXC group of chemokines PBSF/SDF-1 stimulates proliferation of B-cell progenitors in vitro and is constitutively expressed in bone-marrow-derived stromal cells. Here we investigate the physiological roles of PBSF/SDF-1 by generating mutant mice with a targeted disruption of the gene encoding PBSF/SDF-1. We found that mice lacking PBSF/SDF-1 died perinatally and that although the numbers of B-cell progenitors in mutant embryos were severely reduced in fetal liver and bone marrow, myeloid progenitors were reduced only in the bone marrow but not in the fetal liver, indicating that PBSF/SDF-1 is responsible for B-cell lymphopoiesis and bone-marrow myelopoiesis. In addition, the mutants had a cardiac ventricular septal defect. Hence, we have shown that the chemokine PBSF/SDF-1 has several essential functions in development.

Vascularization of organs generally occurs by remodelling of the preexisting vascular system during their differentiation and growth to enable them to perform their specific functions during development. The molecules required by early vascular systems, many of which are receptor tyrosine kinases and their ligands, have been defined by analysis of mutant mice. As most of these mice die during early gestation before many of their organs have developed, the molecules responsible for vascularization during organogenesis have not been identified. The cell-surface receptor CXCR4 is a seven-transmembrane-spanning, G-protein-coupled receptor for the CXC chemokine PBSF/SDF-1 (for pre-B-cell growth-stimulating factor/stromal-cell-derived factor), which is responsible for B-cell lymphopoiesis, bone-marrow myelopoiesis and cardiac ventricular septum formation. CXCR4 also functions as a co-receptor for T-cell-line tropic human immunodeficiency virus HIV-1. Here we report that CXCR4 is expressed in developing vascular endothelial cells, and that mice lacking CXCR4 or PBSF/SDF-1 have defective formation of the large vessels supplying the gastrointestinal tract. In addition, mice lacking CXCR4 die in utero and are defective in vascular development, haematopoiesis and cardiogenesis, like mice lacking PBSF/SDF-1, indicating that CXCR4 is a primary physiological receptor for PBSF/SDF-1. We conclude that PBSF/SDF-1 and CXCR4 define a new signalling system for organ vascularization.

Although gastrointestinal stromal tumors (GISTs) are a rare type of cancer, they are the commonest sarcoma in the gastrointestinal tract. Molecularly targeted therapy, such as imatinib therapy, has revolutionized the treatment of advanced GIST and facilitates scientific research on GIST. Nevertheless, surgery remains a mainstay of treatment to obtain a permanent cure for GIST even in the era of targeted therapy. Many GIST guidelines have been published to guide the diagnosis and treatment of the disease. We review current versions of GIST guidelines published by the National Comprehensive Cancer Network, by the European Society for Medical Oncology, and in Japan. All clinical practice guidelines for GIST include recommendations based on evidence as well as on expert consensus. Most of the content is very similar, as represented by the following examples: GIST is a heterogeneous disease that may have mutations in KIT, PDGFRA, HRAS, NRAS, BRAF, NF1, or the succinate dehydrogenase complex, and these subsets of tumors have several distinctive features. Although there are some minor differences among the guidelines—for example, in the dose of imatinib recommended for exon 9-mutated GIST or the efficacy of antigen retrieval via immunohistochemistry—their common objectives regarding diagnosis and treatment are not only to improve the diagnosis of GIST and the prognosis of patients but also to control medical costs. This review describes the current standard diagnosis, treatment, and follow-up of GISTs based on the recommendations of several guidelines and expert consensus.

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