Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastrointestinal stromal tumors (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. GIST is currently defined as a gastrointestinal tract mesenchymal tumor containing spindle cells (less commonly epitheloid cells or rarely both) and showing CD 117 (c-kit protein) positivity in more than 95% of cases. Although they may arise throughout the gut, the commonest site are stomach (60-70%), small intestine (20-30%), colorectum (5%) and esophagus (up to 5%). Rarely, GISTs develop in the retroperitoneum, omentum or mesentery. GIST originates from the intestinal cell of Cajal (ICC). ICCs are located in and around the myenteric plexus and are thought to function as intestinal pacemaker cells. Historicaly, GIST were often misclassified as leiomyomas or leiomyosarcomas. Subsequently, it has been determined that GISTs have distinct ultrastructural features and immunophenotypical markers compared with smooth muscle and smooth muscle tumors. GIST predominantly occur in middle aged and older patients, with no significant difference in the sex incidence. Data from the recent population study suggest an incidence of about 10-22 cases per million persons per year. Clinical presentation of GIST varies widely, and depends on tumor size and location. GISTs that caused symptoms tended to be larger with an average size of 6cm versus 2cm for asymptomatic GISTs. Symptoms are most commonly related to mass effect or bleeding. GISTs can grow very large before producing symptoms. Commonest symptom of gastric GIST is manifest or occult bleeding. Abudant, life-threateting bleeding that require urgent surgery is rare. For patient with primary, localized, nonmetastatic GIST, complete surgical resection represents the only chance for cure. Lymhadenectomy is not necessary, because lymph node metastasis is very rare. The 5 year survival rate in patients with resected primary GISTs ranges from 48-65%. Conventional chemotherapy and radiation therapy is ineffective in the treatment of GIST. Imatinib mesilate (a tyrosine kinase inhibitor) was confirmed to be effective against metastatic or unresectable GISTs.
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PMID:[Gastrointestinal stromal tumors (GIST) of the stomach as a cause of upper gastrointestinal bleeding]. 1763 70

The so-called interstitial cells of Cajal myenteric plexus (ICC-MP), interstitial cells of Cajal intramuscular (ICC-IM) and interstitial cells of Cajal deep muscular plexus (ICC-DMP) are the three types of ICC endowed within the intestinal muscle coat where they play different roles in gut motility. Studies on ICC ontogenesis showed ICC-MP in the human ileum by 7-9 weeks while information on ICC-IM and ICC-DMP in foetuses and newborns are not exhaustive. Functional recordings in the fasting state of prematurely born babies aged 28-37 weeks showed immature ileal motility. To gain more information on the time of appearance of the three ICC types in the human ileum and on the steps of the acquisition of mature features, we studied by c-kit immuno-histochemistry foetuses aged 17-27 weeks and newborns aged 36-41 weeks. In parallel, the maturative steps of enteric plexuses and muscle layers were immunohistochemically examined by using anti-neuron specific enolase (NSE), anti-S-100 and anti-alpha smooth muscle actin (alphaSMA) antibodies. The appearance and differentiation of all the ICC types were seen to occur in concomitance with those of the related nerve plexuses and muscle layers. ICC-MP appeared first, ICC-IM and ICC-DMP later and their differentiation was incomplete at birth. In conclusion, the ICC-MP, the intestinal pacemaker cells, in spite of absence of food intake, are already present during the foetal life and the ICC-IM appear by pre-term life, thus ensuring neurotransmission. The ICC-DMP and their related nerve plexus and smooth muscle cells, i.e. the intestinal stretch receptor, begin to differentiate at birth. These findings might help in predicting neonatal ileal motor behaviour and in interpreting the role of ICC abnormalities in the pathophysiology of intestinal motile disorders of neonates and young children.
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PMID:Morphology of the interstitial cells of Cajal of the human ileum from foetal to neonatal life. 1763 40

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gut and are distinguished by expression of CD117 (c-Kit). Oncogenic mutations in the KIT or PDGFRA gene are detected in approximately 85% of sporadic GISTs. In recent years, examples of familial GIST have been reported in which germline mutations of KIT or PDGFRA result in multiple GISTs, skin disorders, and other abnormalities. The most common germline mutations are in KIT exon 11, mutations in exons 8 and 17 have also been described, and there are 2 families with germline PDGFRA mutations. We present a case in which a germline KIT exon 13 mutation (K642E) was discovered in a patient with multiple GISTs of rectum, small intestine, and esophagus, as well as diffuse hyperplasia of the interstitial cells of Cajal. To our knowledge, this is only the second germline example of this particular mutation. The patient's esophageal tumors were stabilized with imatinib.
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PMID:Imatinib in the management of multiple gastrointestinal stromal tumors associated with a germline KIT K642E mutation. 1782 95

Gastro-intestinal stromal tumours (GIST) are a biologically distinct heterogenous group of tumours of the gut. They are said to arise from interstitial cells of Cajal in gut wall. The turnour results from mutation of c-kit gene which codes for CD117 containing tyrosine kinase receptor of Cajal cells. Identification of this mutation by immunohistochemistry (IHC) is the key to the diagnosis of these tumours. CD117 negative GISTs develop from gene mutation through alternate pathway (PDGFRA). The accurate diagnosis is important as specific chemotherapeutic agents are now available for their management. We have studied 8 cases of GISTs during last 2 years in our institute. Half of the cases were female, six cases were in the age group between 35 to 50 years, the other two being of 19 and 70 years. On histology, 5 cases were categorized as high grade on the basis of their size and mitotic count. All cases were subjected to IHC. Only 4 cases were CDll7 positive, one case was positive for S100 and one case for SMA. Remaining 2 cases, negative for CD117, S100 and SMA, histologically resembled GISTs. CD117 positive cases are ideal candidates for treatment with molecularly targeted specific chemotherapeutic agents, e.g., imatinib as these tumours are non-responsive to conventional chemotherapy. Histologically diagnosed stromal tumours of the gut should be subjected to immunostain for CD117 so that specific medical management can be provided to prevent recurrence and metastasis as well as pre-operative debulking of the tumour.
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PMID:Gastro-intestinal stromal tumour--role of CD117 in diagnosis and management. 1788 45

A considerable body of evidence has revealed that interstitial cells of Cajal (ICC), identified with c-Kit-immunoreactivity, act as gut pacemaker cells, with spontaneous Ca(2+) activity in ICC as the probable primary mechanism. Namely, intracellular (cytosolic) Ca(2+) oscillations in ICC periodically activate plasmalemmal Ca(2+)-dependent ion channels and thereby generate pacemaker potentials. This review will, thus, focus on Ca(2+)-associated mechanisms in ICC in the gastrointestinal (GI) tract, including auxiliary organs.
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PMID:Calcium-associated mechanisms in gut pacemaker activity. 1797 77

In the development of mouse gut, longitudinal smooth muscle cells (LMC) and interstitial cells of Cajal (ICC) originate from common precursor cells expressing c-Kit. Recently, some gastrointestinal stromal tumours, which develop from smooth muscle layers of the gut and have gain-of-function mutations of c-kit, have been reported to have gain-of-function mutations of platelet-derived growth factor (PDGF) receptor alpha gene. These data raise the possibility that PDGF signalling might be involved in the development of LMC. Therefore, we examined the expression pattern of the PDGF signal family of embryonic gut by immunohistochemistry and in situ hybridization, and investigated the role of PDGF signals in the development of smooth muscle layers in mouse gut using a new organ culture system. During embryonic development, the circular muscle layer expressed PDGF-A, enteric neurons expressed PDGF-B and common precursor cells of LMC and ICC expressed both PDGF receptor alpha and beta. The selective PDGF receptor inhibitor AG1295 suppressed the differentiation of LMC in gut explants. We conclude that PDGF signals play critical roles in the differentiation of LMC in mouse embryonic gut.
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PMID:Platelet-derived growth factor signals play critical roles in differentiation of longitudinal smooth muscle cells in mouse embryonic gut. 1819 51

The molecular mechanisms underlying the regulation of vas deferens (VD) motility and semen emission are still poorly understood. Interstitial cells of Cajal (ICC), which harbour the c-kit receptor (CD117), provide the basis of coordinated gut motility. We investigated whether c-kit receptor-positive cells also exist in the normal human VD. Enzyme and fluorescence immunohistochemical techniques were applied on serial sections of human proximal, middle, and distal VD segments (n=49) employing 13 different monoclonal and polyclonal antibodies recognizing the c-kit receptor. The c-kit receptor was detected in either round- or spindle-shaped cells. On account of their antigenic profile, the round- and oval-shaped c-kit receptor-positive cells were identified as mast cells (MC) occurring in all layers of the VD except the epithelium. In contrast, two distinct populations of exclusively c-kit receptor-positive spindle-shaped cells were found within the lamina propria and, rarely, in the inner and outer smooth muscle layers, as well as within the epithelium. Different shaped c-kit receptor-positive MC and IC were present in all layers of the human VD. Our findings demonstrate the presence of different c-kit receptor-positive cells also in the human VD. Their rather ubiquitous distribution within the lamina propria and muscle layers suggests that IC and MC may modulate the neuromuscular transmission and the propagation of electrical signals in multiple systems involved in the draining of fluids. The importance of the c-kit receptor-positive interepithelial cells remains unclear.
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PMID:C-kit receptor in the human vas deferens: distinction of mast cells, interstitial cells and interepithelial cells. 1829 31

Interstitial cells of Cajal (ICC) are specialized mesenchyme-derived cells that regulate contractility and excitability of many smooth muscles with loss of ICC seen in a variety of gut motility disorders. Maintenance of ICC numbers is tightly regulated, with several factors known to regulate proliferation. In contrast, the fate of ICC is not established. The aim of this study was to investigate whether apoptosis plays a role in the regulation of ICC numbers in the normal colon. ICC were identified by immunolabelling for the c-Kit receptor tyrosine kinase and by electron microscopy. Apoptosis was detected in colon tissue by immunolabelling for activated caspase-3, terminal dUTP nucleotide end labelling and by ultrastructural changes in the cells. Apoptotic ICC were identified and counted in double-labelled tissue sections. They were identified in all layers of the colonic muscle. In the muscularis propria 1.5 +/- 0.2% of ICC were positive for activated caspase-3 and in the circular muscle layer 2.1 +/- 0.9% of ICC were positive for TUNEL. Apoptotic ICC were identified by electron microscopy. Apoptotic cell death is a continuing process in ICC. The level of apoptosis in ICC in healthy colon indicates that these cells must be continually regenerated to maintain intact networks.
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PMID:Apoptotic cell death of human interstitial cells of Cajal. 1879 96

To examine the origin of intestinal mucosal T cells and, in particular, unconventional CD8 alpha alpha(+) T cells, we have undertaken a thorough analysis of the gut immune compartment in euthymic and athymic mice carrying either wild-type or mutant transcription factor retinoic acid-related orphan receptor-gamma t (ROR gamma t). We identified a previously unrealized complexity of gut cryptopatch (CP) cells that challenges the previous assertion that CP cells comprise ROR gamma t-expressing adult counterparts of fetal lymphoid tissue inducer (Lti) cells. We showed that many CP cells express intermediate T cell differentiation markers, whether or not they express ROR gamma t, and found that CPs are not completely dependent on ROR gamma t, as previously reported, but merely fewer in number in the ROR gamma t-deficient condition. Indeed, c-kit(+)IL-7R(+)Lin(-)ROR gamma t(-) cells inside the CP and c-kit(+)IL-7R(+)Lin(-)ROR gamma t(-) and c-kit(+)IL-7R(+)Lin(-)ROR gamma t(low) cells outside the CP basically remain in the gut mucosa of ROR gamma t-deficient ROR gamma t(EGFP/EGFP) mice. Consistent with these non-Lti-like c-kit(+)IL-7R(+)Lin(-) cells being gut T cell progenitors, ROR gamma t-deficient mice develop the normal number of intestinal mucosal T cells. These results clearly reassert the intraintestinal differentiation of the body's largest peripheral T cell subpopulation.
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PMID:ROR gamma t is dispensable for the development of intestinal mucosal T cells. 1907 76

A strict regulation of contractility in the uterus and fallopian tube is essential for various reproductive functions. The uterus contributes, through either increased contractility or periods of relative quiescence, to: (i) expulsion of menstrual debris, (ii) sperm transport, (iii) adequate embryo placement during implantation, (iv) enlarging its capacity during pregnancy and (v) parturition. The dominant cell population of the uterine wall consists of smooth muscle cells that contain the contractile apparatus responsible for the generation of contractile force. Recent interest has focused on a new population of cells located throughout the myometrium on the borders of smooth muscle bundles. These cells are similar to interstitial cells of Cajal (ICC) in the gut that are responsible for the generation of electrical slow waves that control peristalsis. A precise role for myometrial Cajal-like interstitial cells (m-ICLC) has not been identified. m-ICLC express the c-kit receptor, involved in creating and maintaining the ICC phenotype in the gastrointestinal tract. However, both acute and prolonged inhibition of this receptor with the c-kit antagonist imatinib mesylate does not appear to affect the spontaneous contractility of myometrium. Calcium imaging of live tissue slices suggests that contractile signalling starts on the borders of smooth muscle bundles where m-ICLC are located and recently the possible role of extracellular ATP signalling from m-ICLC has been studied. This manuscript reviews the evidence regarding tissue-level signalling in the myometrium with a particular emphasis on the anatomical and possible functional aspects of m-ICLC as new elements of the contractile mechanisms in the uterus.
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PMID:Myometrial interstitial cells and the coordination of myometrial contractility. 1973 38


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