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

The desmoplastic response to human breast carcinoma is a host myofibroblast-mediated collagenous response exhibiting synergistic effects on tumor progression. Although many paracrine interactions between breast carcinoma cells and myofibroblasts have been characterized, the event(s) which initiate desmoplasia have remained undefined. Our studies utilized c-rasH transfected MCF-7 cells which overexpress ras p2l and which are weakly tumorigenic in ovariectomized nude mice. The xenografts are desmoplastic and comprised of 30% myofibroblasts and 60 mg/g of interstitial collagen. In situ hybridization studies of these xenografts reveal a stromal gene expression pattern (stromelysin-3, IGF-II and TIMP-1) identical to that observed in human tumor desmoplasia. 17-beta estradiol increases c-rasH MCF-7 growth but abolishes desmoplasia. c-rasH MCF-7 in vitro constitutively produce myofibroblast mitogenic activity which competes with PDGF in a receptor binding assay. This myofibroblast mitogenic activity is unaltered by 17-beta estradiol/tamoxifen pretreatment in vitro. Transfection of c-rasH MCF-7 with a PDGF-A dominant negative mutant, 1308, produced by site-directed mutagenesis (serine-->cysteine129) reduces both homo- and heterodimer secretion of PDGF by as much as 90% but does not interfere with the secretion of other growth factors. Clones with low PDGF, though tumorigenic, are non-desmoplastic. Our results suggest that breast carcinoma-secreted PDGF is the major initiator of tumor desmoplasia.
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PMID:Human breast carcinoma desmoplasia is PDGF initiated. 1098 Jun 9

The DAP (Death Associated Protein) kinase family is a novel subfamily of pro-apoptotic serine/threonine kinases. All five DAP kinase family members identified to date are ubiquitously expressed in various tissues and are capable of inducing apoptosis. The sequence homology of the five kinases is largely restricted to the N-terminal kinase domain. In contrast, the adjacent C-terminal regions are very diverse and link individual family members to specific signal transduction pathways. There is increasing evidence that DAP kinase family members are involved in both extrinsic and intrinsic pathways of apoptosis and may play a role in tumor progression. This review will focus on structural composition and subcellular localization of DAP kinase family members and on signal transduction pathways leading to their activation. Potential mechanisms of DAP kinase family-mediated apoptosis will be discussed. BioEssays 23:352-358, 2001.
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PMID:The DAP kinase family of pro-apoptotic proteins: novel players in the apoptotic game. 1126 41

DAP-kinase is a pro-apoptotic Ca(2+) calmodulin-regulated serine/threonine kinase that participates in a wide array of apoptotic systems initiated by interferon-gamma, TNF-alpha, activated Fas, and detachment from extracellular matrix. It was isolated by an unbiased functional approach to gene cloning aimed at hitting central mediators of the apoptotic process. This 160 Kd protein kinase is localized to actin microfilaments and carries interesting modules such as ankyrin repeats and the death domain. The death promoting effects of DAP-kinase depend on its intact catalytic activity, the correct intracellular localization, and on the presence of the death domain. A few mechanisms restrain the killing effects of the protein in healthy cells. The enzyme's active site is negatively controlled by an adjacent CaM regulatory domain whose effect is relieved by binding to Ca(2+)-activated calmodulin. A second mode of autoinhibition engages the serine-rich C-terminal tail, spanning the last 17 amino acids of the protein. A link between DAP-kinase and cancer has been established. It was found that the mRNA and protein expression is frequently lost in various human cancer cell lines. Analysis of the methylation status of DAP-kinase's 5' UTR in DNA extracted from fresh tumor samples, showed high incidence of hypermethylation in several human carcinomas and B cell malignancies. The anti-tumorigenic effect of DAP-kinase was also studied experimentally in mouse model systems where the re-introduction of DAP-kinase into highly metastatic mouse lung carcinoma cells who had lost the protein, strongly reduced their metastatic capacity. Thus, it appears that loss of DAP-kinase confers a selective advantage to cancer cells and may play a causative role in tumor progression. A few novel kinases sharing high homology in their catalytic domains with DAP-kinase have been recently identified constituting altogether a novel family of death promoting serine/threonine kinases.
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PMID:DAP-kinase: from functional gene cloning to establishment of its role in apoptosis and cancer. 1131 98

Thrombospondin-1 (TSP-1) is a 450 kDa matrix bound glycoprotein involved in tumor invasion, metastasis, and angiogenesis. One of the receptors involved in TSP-1 mediated tumor cell adhesion and metastasis is the cysteine-serine-valine-threonine-cysteine-glycine (CSVTCG) receptor. One mechanism of TSP-1 in promoting tumor cell metastasis involves the up-regulation of matrix metalloproteinase-9 (MMP-9) expression, specifically through the CSVTCG TSP-1 receptor. TSP-1 and its CSVTCG receptor has been implicated in tumor progression in a variety of cancers including breast adenocarcinomas, head and neck squamous cell carcinomas, and pancreatic carcinomas. In this study, we examined 99 cases of colorectal cancer by immunohistochemical analysis to investigate 1) the localization of TSP-1 and CSVTCG TSP-1 receptor, 2) the relationship with MMP-9, and 3) the correlation of expression with clinical staging. Strong expression of TSP-1 was observed in the submucosa or the serosa adjacent to the tumor. Positive staining for CSVTCG TSP-1 receptor was observed in tumor cells and microvessels. MMP-9 was also expressed in tumor cells. In addition, staining intensity of CSVTCG TSP-1 receptor was higher in poorly differentiated adenocarcinoma than well or moderately differentiated adenocarcinoma. Tumors in which inflammatory cells stained strongly for CSVTCG TSP-1 receptor correlated with decreased incidence of distant metastasis and angiogenesis. These data were consistent with our previous studies for breast, pancreatic, and head and neck carcinoma. They suggest an important role for TSP-1 and CSVTCG TSP-1 receptor in tumor progression in colorectal cancer.
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PMID:The localization of thrombospondin-1 (TSP-1), cysteine-serine-valine-threonine-cysteine-glycine (CSVTCG) TSP receptor, and matrix metalloproteinase-9 (MMP-9) in colorectal cancer. 1133 89

Acquisition of invasive metastatic potential through protease expression is a key event in tumor progression. In carcinomas, the production of metalloproteinases and serine proteinases is regulated by a cross talk between stromal cells and cancer cells. Paradoxically, high rather than low levels of their inhibitors predict poor survival of patients suffering from a variety of cancers. Recent observations suggest a much more complex role of these inhibitors in tumor progression than expected initially.
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PMID:New functions of stromal proteases and their inhibitors in tumor progression. 1138 95

Megakaryocytic genes such as alphaIIbbeta3 can be expressed by malignant cells as part of the disturbances in their gene regulation. However, the function of the gene product greatly depends on the interaction of the ectopic protein with the new environment. The outside-in signaling of the ectopically expressed alphaIIbbeta3 integrin was studied in B16a murine melanoma cells using a monoclonal antibody, specifically directed to the activated conformation of alphaIIbbeta3, PAC-1 and the physiological ligand, fibrinogen. Ligation of alphaIIbbeta3 induced down-regulation of FAK but serine phosphorylation of three protein bands, 20/21, 85 and 140 kDa within 1-15 min. Flow cytometry indicated that the ligation of the receptor in B16a cells induces approximately 50% increase in phosphoserine positive cells within 5-15 min. 12-lipoxygenase is placed downstream in the signaling pathway, since ligation of alphaIIbbeta3 induces 12-HETE production within 5 min and pretreatment of tumor cells with select lipoxygenase inhibitior, Baicalein, prevents the increase in serine phosphorylation. Confocal microscopy of adherent tumor cells demonstrated rearrangement of actin filaments upon alphaIIbbeta3 ligation paralleled by downregulation of p125FAK and phoshotyrosine+ adhesion plaques and translocation of PKCalpha to stress fibers and cortical actin. PKC appears to be the major effector serine kinase of the alphaIIbbeta3-coupled signaling pathway, since pretreatment of tumor cells with a select PKC inhibitor, Calphostin C, prevents the ligation-induced serine phosphorylation. Previous studies have indicated a role for the 12-lipoxygenase-PKC signaling pathway in platelet aggregation as well as tumor invasion, therefore the involvement of this cascade in the signaling of the ectopic alphaIIbbeta3 integrin may partially explain its role in tumor progression.
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PMID:Ectopic alphaIIbbeta3 integrin signaling involves 12-lipoxygenase- and PKC-mediated serine phosphorylation events in melanoma cells. 1143 81

Proteoglycans that modulate the activities of growth factors, chemokines, and coagulation factors regulate in turn the vascular endothelium with respect to processes such as inflammation, hemostasis, and angiogenesis. Endothelial cell-specific molecule-1 is mainly expressed by endothelial cells and regulated by pro-inflammatory cytokines (Lassalle, P., Molet, S., Janin, A., Heyden, J. V., Tavernier, J., Fiers, W., Devos, R., and Tonnel, A. B. (1996) J. Biol. Chem. 271, 20458-20464). We demonstrate that this molecule is secreted as a soluble dermatan sulfate (DS) proteoglycan. This proteoglycan represents the major form either secreted by cell lines or circulating in the human bloodstream. Because this proteoglycan is specifically secreted by endothelial cells, we propose to name it endocan. The glycosaminoglycan component of endocan consists of a single DS chain covalently attached to serine 137. Endocan dose-dependently increased the hepatocyte growth factor/scatter factor (HGF/SF)-mediated proliferation of human embryonic kidney cells, whereas the nonglycanated form of endocan did not. Moreover, DS chains purified from endocan mimicked the endocan-mediated increase of cell proliferation in the presence of HGF/SF. Overall, our results demonstrate that endocan is a novel soluble dermatan sulfate proteoglycan produced by endothelial cells. Endocan regulates HGF/SF-mediated mitogenic activity and may support the function of HGF/SF not only in embryogenesis and tissue repair after injury but also in tumor progression.
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PMID:Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity. 1159 Jan 78

Grb7 family adaptor molecules consist of Grb7, Grb10 and Grb14, each of which has several splicing variants. Like other adaptor molecules, Grb7 family proteins function to mediate the coupling of multiple cell surface receptors to downstream signaling pathways in the regulation of various cellular functions. They share significant sequence homology with each other and a conserved molecular architecture including an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes a PH domain and shares sequence homology with the Caenorhabditis elegans protein, Mig-10, involved in embryonic migration, and a carboxyl-terminal SH2 domain. Grb7 family proteins are differentially expressed in a variety of tissues. They are phosphorylated on serine/threonine as well as tyrosine residues, although the kinases responsible have not been well characterized. Grb7 family proteins are mainly localized in the cytoplasm, but have been observed at the plasma membrane, focal contacts, or mitochondria under certain conditions. A large number of receptor tyrosine kinases and other signaling molecules can associate with Grb7 family proteins, mostly through the SH2 domains. Various isoforms of Grb10 have been shown to regulate cell proliferation and apoptosis, whereas Grb7 has been found to regulate cell migration and also implicated in tumor progression. Future studies of interests will include identification of potential downstream effectors of Grb7 family proteins as well as understanding of the mechanisms of specificity of the different family members in signal transduction.
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PMID:The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions. 1160 34

Galectin-3, a beta-galactoside-binding protein, is implicated in cell growth, adhesion, differentiation, and tumor progression by interactions with its ligands. Recent studies have revealed that galectin-3 suppresses apoptosis and anoikis that contribute to cell survival during metastatic cascades. Previously, it has been shown that human galectin-3 undergoes post-translational signaling modification of Ser(6) phosphorylation that acts as an "on/off" switch for its sugar-binding capability. We questioned whether galectin-3 phosphorylation is required for its anti-apoptotic function. Serine to alanine (S6A) and serine to glutamic acid (S6E) mutations were produced at the casein kinase I phosphorylation site in galectin-3. The cDNAs were transfected into a breast carcinoma cell line BT-549 that innately expresses no galectin-3. Metabolic labeling revealed that only wild type galectin-3 undergoes phosphorylation in vivo. Expression of Ser(6) mutants of galectin-3 failed to protect cells from cisplatin-induced cell death and poly(ADP-ribose) polymerase from degradation when compared with wild type galectin-3. The non-phosphorylated galectin-3 mutants failed to protect cells from anoikis with G(1) arrest when cells were cultured in suspension. In response to a loss of cell-substrate interactions, only cells expressing wild type galectin-3 down-regulated cyclin A expression and up-regulated cyclin D(1) and cyclin-dependent kinase inhibitors, i.e. p21(WAF1/CIP1) and p27(KIP1) expression levels. These results demonstrate that galectin-3 phosphorylation regulates its anti-apoptotic signaling activity.
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PMID:Galectin-3 phosphorylation is required for its anti-apoptotic function and cell cycle arrest. 1172 77

Mast cells (MC) have been associated with diverse human cancers. The primary function of these cells is to store and release a number of biologically active mediators, including the serine proteases tryptase and chymase. These proteases have been closely related with angiogenesis and tumor invasion, two critical steps during tumor progression. In the present work we analyzed the presence of MC in human uterine cervix from both normal and neoplastic tissues by using metachromatic, immunohistochemical, and enzymohistochemical staining. Tryptase-positive (MCT)- and tryptase/chymase-positive (MCTC)-mast cells were found in both normal and neoplastic tissues. The phenotype predominantly expressed in normal tissues as well as in benign and malignant lesions of the uterine cervix was the MCT. The total number of MC remained constant through the different stages of malignant transformation (cervical intraepithelial neoplasia grade 1-3) but a significant increase in the invasive carcinoma (IC) group was observed, this increase being mainly due to the MCT phenotype. Furthermore, we detected abundant MCT but not MCTC infiltrating tumors in sections of IC. Regarding the potent angiogenic properties described for tryptase, these findings suggest that in advanced stages of malignancy the significant number of MCT distributed within the cervical tissues could provide an effective mechanism to create the abundantly vascularized microenvironment required for tumor cells to proliferate and disseminate.
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PMID:Characterization of mast cells according to their content of tryptase and chymase in normal and neoplastic human uterine cervix. 1186 May 42


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