Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protooncogene c-kit encodes a tyrosine kinase with a molecular weight of 145,000, highly related to the platelet derived growth factor/colony stimulating factor receptors. Mutations of the murine gene result in impairment of hematopoiesis, gametogenesis, and of the melanocyte cell lineage. In order to elucidate c-kit functions in development and oncogenesis we have analyzed immunohistochemically its expression in human normal and transformed nonlymphoid tissues. The receptor has been detected in spermatogonia, melanocytes, and unexpectedly, in astrocytes, renal tubules, parotid cells, thyrocytes, and breast epithelium. While the gene product is expressed in seminoma, lung tumors, and melanoma of low invasiveness, no detectable levels have been detected in thyroid and breast carcinomas, astrocytomas, and invasive melanomas. In breast tumors these findings were confirmed by paired, Northern blot analysis of RNA preparations from normal and transformed tissue. The present results demonstrate that the c-kit receptor plays a role in the development of a larger spectrum of cell lineages. Furthermore, on the basis of the transformation associated changes, we speculate that, while in some cell types, c-kit expression positively regulates mitogenesis and is selected for in neoplastic transformation, in other tissues the c-kit pathway is involved in morphogenesis and differentiation and is, therefore, negatively selected in the course of tumor progression.
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PMID:Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. 138 54

We have used proviral tagging in tumor-prone transgenic mice to identify collaborating oncogenes and genes contributing to tumor progression. This has yielded a series of oncogenes that could be assigned to different complementation groups in transformation: the myc, Pim, Bmi1, and Frat1 complementation groups. Frat1 is involved in tumor progression and appears to function in the Wnt signaling pathway. Overexpression of Fratl confers a growth advantage to transplanted tumor cells in vivo and to cells grown in vitro at high density. Frat1 might exert its activity by impairing the kinase activity of Gsk3beta, which is involved in the degradation of beta-catenin. Pim genes appear to act in tumor initiation and show strong synergism with myc in lymphomagenesis. Overexpression of Pim1 can also overcome some of the proliferative defects caused by defective interleukin signaling supporting a role of Pim1 in cell proliferation. We have applied proviral tagging in compound mutant Emu-myc/Pim1-/-/Pim2-/- mice to identify genes that can complement for the loss of Pim1 and Pim2 and, therefore, are able to synergize with c-myc in lymphomagenesis. A number of new as well as known genes have been found by this "complementation tagging." The latter included c-kit, Tp12, and cyclin D2, suggesting that Pim kinases might act upstream of or parallel to these known proto-oncogenes.
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PMID:Identification and characterization of collaborating oncogenes in compound mutant mice. 1019 95

The tumor suppressor p53 transcriptionally regulates a large number of target genes that may affect cell growth and cell death pathways. To better understand the role of p53 loss in tumorigenesis, we have developed a mouse mammary cancer model, the Wnt-1 TG/p53 model. Wnt-1 transgenic females that are p53-/- develop mammary adenocarcinomas that arise sooner, grow faster, appear more anaplastic, and have higher levels of chromosomal instability than their Wnt-1 transgenic p53+/+ counterparts. In this study, we used several assays to determine whether the presence or absence of p53 affects gene expression patterns in the mammary adenocarcinomas. Most of the differentially expressed genes are increased in p53+/+ tumors and many of these represent known target genes of p53 (p21WAF/C1P1, cyclin G1, alpha smooth muscle actin, and cytokeratin 19). Some of these genes (cytokeratin 19, alpha smooth muscle actin, and kappa casein) represent mammary gland differentiation markers which may contribute to the inhibited tumor progression and are consistent with the more differentiated histopathology observed in the p53+/+ tumors. Several differentially expressed genes are growth regulatory in function (p21, c-kit, and cyclin B1) and their altered expression levels correlate well with the differing growth properties of the p53+/+ and p53-/- tumors. Thus, while tumors can arise and progress in the presence of functioning wild type p53, p53 may directly or indirectly regulate expression of an array of genes that facilitate differentiation and inhibit proliferation, contributing to a more differentiated, slow growing, and genomically stable phenotype.
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PMID:Differential gene expression in mouse mammary adenocarcinomas in the presence and absence of wild type p53. 1114 50

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors develop at any site but are most commonly reported in the stomach. They originate from the neoplastic transformation of the intestinal pacemaker cell, the interstitial cell of Cajal. GISTs strongly express the receptor tyrosine kinase KIT and have mutations in the KIT gene, most frequently in exon 11 encoding the intracellular juxtamembranous region. Expression of KIT is seen in almost all GISTs, regardless of the site of origin, histologic appearance, or biologic behavior, and is therefore regarded as one of the key diagnostic markers. Distinction from smooth muscle tumors, such as leiomyosarcomas, and other mesenchymal tumors is very important because of prognostic differences and therapeutic strategies. Predicting the biologic behavior of GISTs is often difficult by conventional pathologic examination; tumor size and mitotic rate are the most important prognostic indicators. The prognostic significance of KIT mutations is controversial and thus far has not been clearly linked with biologic behavior. KIT mutations are associated with tumor development, and cytogenetic aberrations are associated with tumor progression. The pathogenesis of GISTs involves a gain-of-function mutation in the KIT proto-oncogene, leading to ligand-independent constitutive activation of the KIT receptor. KIT-wild-type GISTs have shown mutually exclusive platelet-derived growth factor receptor (PDGFR) mutation and activation. The use of imatinib mesylate (also known as Gleevec or STI-571) has greatly increased the therapeutic efficacy for this otherwise chemotherapy-resistant tumor. GISTs with very low levels of KIT expression may respond to imatinib mesylate therapy if the receptors are activated by specific mechanisms. KIT-activating mutations fall into two groups: the regulatory type and the enzymatic site type. The regulatory type of mutation is conserved at the imatinib binding site, whereas the enzymatic site mutation has a structurally changed drug-binding site, resulting in drug resistance. Resistance to the drug is the major cause of treatment failure in cancer therapy, emphasizing the need for researchers to understand KIT signaling pathways so as to identify new therapeutic targets. This review summarizes the pathologic features of GISTs, recent advances in understanding their molecular and biologic features, and therapy with imatinib mesylate.
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PMID:Gastrointestinal stromal tumors: overview of pathologic features, molecular biology, and therapy with imatinib mesylate. 1502 16

Vascular endothelial growth factor (VEGF) and C-KIT are involved in tumor progression in several human neoplasms. The aim of the present study has been to investigate their immunohistochemical expression in melanocytic lesions. We examined 11 compound nevi, 12 dysplastic nevi, and 18 melanomas. Immunostaining for VEGF was observed only in melanomas; c-kit expression was detected in melanomas (higher in radial than in vertical growth phase) and in nevi (predominantly in the junctional component). Our data indicate that assessment of VEGF expression might aid in the differential diagnosis between dysplastic nevi and melanomas. Moreover, VEGF might be a candidate for targeted therapy. The loss of c-kit expression might contribute to melanoma progression.
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PMID:Immunohistochemical expression of vascular endothelial growth factor (VEGF) and C-KIT in cutaneous melanocytic lesions. 1517 18

The proto-oncogene c-kit encodes a transmembrane tyrosine kinase growth factor receptor. Stem cell factor, the receptor ligand, plays an important role in the development of certain neoplasms. c-kit is selectively and competitively bound by STI-571, a newly developed tyrosine kinase inhibitor. Several investigators report conflicting results concerning its expression, especially in malignant breast lesions. The objective of this study was to better characterize the expression of c-kit within the spectrum of breast epithelium (normal breast epithelium, nonneoplastic lesions, and breast carcinoma). Seventy-seven randomly selected breast tissue samples, each containing normal breast epithelium (21), invasive breast carcinoma (41), in situ breast carcinoma (29), papilloma (8), fibroadenoma (5), fibrocystic change (11), and/or metastatic breast carcinoma (4), were immunostained with polyclonal rabbit antihuman c-kit (Dako, Carpenteria, CA) at a dilution of 1:200. The staining was interpreted as negative if no cells were immunoreactive, weak positive if 5% of the cells were immunoreactive, and positive if more than 5% of the cells were immunoreactive. Appropriate positive and negative controls were used. The observed staining was cytoplasmic, with highlighting of the nuclear membrane. Normal breast epithelium was positive in all cases. More than half of the cases of hyperplastic changes and benign neoplasms (fibroadenoma and papilloma) were positive. Only 10% of invasive and in situ carcinomas showed positivity for c-kit. c-kit is consistently expressed in normal breast epithelium, variably expressed in benign breast lesions, and poorly expressed in breast carcinoma. These data suggest that c-kit may play a role in breast tumor progression and may therefore have diagnostic, prognostic, and therapeutic implications.
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PMID:Expression of c-kit proto-oncogene product in breast tissue. 1523 91

The zinc-finger transcription factors Snail and Slug are involved in different processes controlling cell differentiation and apoptosis. They also appear to be involved in tumor progression. Their putative involvement in mammary gland development has not been specifically examined so far. Slug is expressed at a significant level in normal breast, and indirect evidence suggests it could be implicated in tubulogenesis. As an antiapoptotic agent, it could also protect epithelial cells from death during ductal lumen formation and during breast involution. In breast carcinomas, Snail transcription factors have been linked to tumor progression and invasiveness. Possible mechanisms include repression of the E-cadherin gene by Snail or Slug. However, it is not clear how this transcriptional activity is implicated in vivo. Other possible mechanisms involve maintenance of a plastic phenotype by Slug that could participate in local invasion of ductal carcinomas, and interference with apoptotic pathways that could contribute to global tumor growth and radioresistance. These processes probably also involve interactions with estrogen, EGF, or c-kit pathways.
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PMID:Roles of the transcription factors snail and slug during mammary morphogenesis and breast carcinoma progression. 1530 12

Ewing sarcoma is a small round blue cell tumor with a high incidence of metastasis and poor survival. The tyrosine kinase receptor, c-kit, is a growth factor receptor that is expressed in a variety of tumors including Ewing sarcoma. Blockade of c-kit by imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corp, East Hanover, NJ) has been successfully used in the treatment of chronic myelogenous leukemia and gastrointestinal tumors. Detection of c-kit expression in Ewing sarcoma indicates a possible role of c-kit in tumor progression and a potential use of anti-c-kit therapy in Ewing sarcoma. Ki-67 is a proliferation marker found at all stages of the cell cycle. Expression of c-kit and Ki-67 was studied in 17 patients with Ewing sarcoma. Sections from paraffin-embedded tumor samples were immunostained, using standard immunohistochemical protocols, with c-kit and Ki-67 monoclonal antibodies, polyclonal c-kit antibody without antigen retrieval, and c-kit polyclonal antibody with antigen retrieval. Eleven out of 17 cases (65%) stained with c-kit monoclonal antibody; the staining was diffuse in 6/17 (35%) cases. C-kit expression did not correlate with Ki-67 proliferation rates. Using the polyclonal c-kit-antibody without antigen retrieval methods, c-kit expression was demonstrated in 1/11 (9%) cases. Incorporating antigen retrieval methods, c-kit expression increased to 53%. Concordance between monoclonal antibodies in detecting c-kit expression was observed in 12/17 cases (71%). We conclude that c-kit is variably expressed in Ewing sarcoma, using either monoclonal or polyclonal antibodies. Detection of c-kit expression in Ewing sarcoma improves with the use of antigen retrieval methods.
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PMID:Expression of c-kit in Ewing family of tumors: a comparison of different immunohistochemical protocols. 1538 30

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin that is associated with a high incidence of recurrence and metastasis. The therapeutic arsenal for this malignancy is limited and once it spreads, there is no effective treatment. c-kit expression has been demonstrated previously in primary MCCs thus raising the possibility of treating MCCs with imatinib mesylate, the tyrosine kinase inhibitor that has shown promise in the management of c-kit expressing tumors. In this study we examine 25 additional primary MCCs and also 6 of their lymph node metastases. Formalin-fixed, paraffin-embedded tissues were stained immunohistochemically with an antibody directed against the KIT receptor. Percentage and intensity of staining were analyzed semiquantitatively using a three-tiered system. Twenty-one of the 25 (84%) primary tumors stained positively for KIT, of which 14 (67%) showed widespread positivity. Five of the 6 lymph nodes (83%) were similarly positive. High mitotic rate and vascular invasion in the primary tumors tended to be associated with prominent staining in the lymph node metastases. No association was found between c-kit expression and outcome. We confirm that the majority of primary MCCs express c-kit and further find that metastases are positive for the KIT receptor as well. Thus, c-kit expression may be an early event in the transformation of MCC, but not a marker for tumor progression.
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PMID:c-kit expression in primary and metastatic merkel cell carcinoma. 1561 26

The treatment strategy for mesenchymal tumors of the gastrointestinal tract is based upon typing of the tumor. Especially differential diagnosis of gastrointestinal stromal tumors (GISTs) to leiomyomas is crucial for determining radicality of surgery. L1 cell adhesion molecule (CD171) plays an essential role in tumor progression. The aim of this study was to determine expression of L1 in GISTs, smooth muscle tumors, desmoid-type fibromatosis and peripheral nerve sheath tumors (PNSTs). We retrospectively analyzed a total of 129 surgically resected primary tumors or metastases of 72 GISTs, 29 smooth muscle tumors, seven PNSTs and 21 desmoid-type fibromatosis by immunohistochemistry for c-kit, CD34, smooth muscle actin, desmin, vimentin, S-100 and L1 expression. L1 expression was detected in 53 (74%) of 72 GISTs but in none of 29 smooth muscle tumors or 21 desmoid-type fibromatosis (P<0.01 by Fisher's test). In all, four (57%) of seven peripheral nerve sheath tumors were L1-positive. Survival analysis of 55 surgically completely resected GISTs presenting without metastasis at initial diagnosis revealed no tumor-specific death among L1-negative patients (P=0.13 by log-rank test; median follow-up time 41 months) and one recurrence was observed (P=0.12). Interestingly high levels of L1 were seen in tumor vascular endothelial cells of smooth muscle tumors and PNSTs, but not in GISTs. Our data show that L1 is highly expressed in GISTs but not in smooth muscle tumors and desmoid-type fibromatosis being important differential diagnoses. The trend towards a reduced survival of L1-positive patients in this study has to be further evaluated in future trials with higher patient numbers.
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PMID:L1 (CD171) is highly expressed in gastrointestinal stromal tumors. 1640 Mar 20


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