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 non-receptor tyrosine kinase c-Src has been implicated in the development of numerous human cancers. c-Src is activated in colon cancers, particularly in highly metastatic cells, and its overexpression strongly correlates with tumor progression. C-terminal Src kinase (Csk) has been demonstrated to negatively regulate Src family tyrosine kinases through tyrosine phosphorylation at the C-terminal regulatory site (Tyr-527). We report herein that down-regulation of Src kinase activity by adenovirus-mediated csk gene transfer abrogated the highly metastatic phenotype of colon cancer cells. Overexpression of Csk decreased Src tyrosine kinase activity in NL-17 cells, the highly metastatic clone of mouse colon adenocarcinoma 26. Importantly, Csk overexpression in NL-17 cells resulted in significant suppression of in vivo metastasis, without affecting its tumorgenicity. Csk overexpression decreased the invasiveness of NL-17 cells through Matrigel, in vitro reconstituted basement membrane. Gelatin zymography confirmed the decreased protein levels of MMP-2 (gelatinase A) in the supernatants of Csk-overexpressed NL- 17 cells. These results provide a therapeutic basis for interfering with metastasis of colon cancer by csk gene-mediated down-regulation of Src kinase activity.
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PMID:Overexpression of the csk gene suppresses tumor metastasis in vivo. 1105 67

Our studies on glycosphingolipids (GSLs) were initiated through isolation and structural characterization of lacto-series type 1 and 2 GSLs, and globo-series GSLs. Lacto-series structures included histo-blood group ABH and I/i antigens. Our subsequent studies were focused on GSL changes associated with: (i) ontogenic development and differentiation; (ii) oncogenic transformation and tumor progression. Various novel types of GSLs such as extended globo-series, sialyl-Le(x) (SLe(x)), sialyl-dimeric-Le(x) (SLe(x)-Le(x)), dimeric-Le(x) (Le(x)-Le(x)), Le(y)-on-Le(x), dimeric-Le(a) (Le(a)-Le(a)), Le(b)-on-Le(a), etc. were identified as tumor-associated antigens. These studies provide an essential basis for up- or down-regulation of key glycosyltransferase genes controlling development, differentiation, and oncogenesis. GSL structures established in our laboratory are summarized in Table 1, and structural changes of GSLs associated with ontogenesis and oncogenesis are summarized in Sections 2 and 3. Based on these results, we endeavored to find out the cell biological significance of GSL changes, focused on (i) cell adhesion, e.g., the compaction process of preimplantation embryo in which Le(x)-to-Le(x), Gb4-to-GalGb4 or -nLc4 play major roles; and (ii) modulation of signal transduction through interaction of growth factor receptor tyrosine kinase with ganglioside, e.g., EGF receptor tyrosine kinase with GM3. Recent trends of studies on i and ii lead to the concept that GSL clusters (microdomains) are organized with various signal transducer molecules to form 'glycosignaling domains' (GSD). GSL-dependent adhesion occurs through clustered GSLs, and is coupled with activation of signal transducers (cSrc, Src family kinase, Rho A, etc.). Clustered GSLs involved in cell adhesion are recognized by GSLs on counterpart cells (carbohydrate-to-carbohydrate interaction), or by lectins (e.g., siglecs, selectins). Our major effort in utilization of GSLs in medical science has been for: (i) cancer diagnosis and treatment (vaccine development) based on tumor-associated GSLs and glycoepitopes; (ii) genetically defined phenotype for susceptibility to E. coli infection; (iii) clear identification of physiological E-selectin epitope (myeloglycan) expressed on neutrophils and myelocytes; (iv) characterization of sialyl poly-LacNAc epitopes recognized as male-specific antigens. Utilization of these GSLs or glycoepitopes in development of anti-adhesion approach to prevent tumor metastasis, infection, inflammation, or fertilization (i.e., contraceptive) is discussed. For each approach, development of mimetics of key GSLs or glycoepitopes is an important subject of future study.
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PMID:Traveling for the glycosphingolipid path. 1142 54

Growth and metastasis of solid tumors depend on the formation of new blood vessels which originate from the existing vascular system. These blood vessels grow into the tumor and thus provide the necessary nutrients and growth factors for tumor progression. At the same time, the newly formed blood vessels allow tumor cells to disseminate and form metastases in distant organs. Normally, vascular homeostasis is regulated by a balance of angiogenic and antiangiogenic mechanisms. Tumor-induced angiogenesis is mainly sustained by the production and secretion of angiogenic factors originating from tumor and stroma cells. The most prominent angiogenic factor is the vascular endothelial growth factor (VEGF). Recently, additional angiogenic factors and their respective receptors have been identified and related to tumor angiogenesis. Among these, the angiopoietins and their receptor TIE-2 have been investigated to some detail. Angiopoietin-1 which binds to and activates TIE-2 is obviously responsible for the stabilization of vessels under homeostatic conditions. Angiopoietin-2 binds to the same receptor as angiopoietin-1 but is antagonistic with respect to angiopoietin-1. It destabilizes blood vessels and, under appropriate conditions, induces complete regression. In the similar situation angiopoietin-2 induces the destabilization of blood vessels, and the angiogenic factor VEGF produced by the tumor induces the massive formation of new vessels. When human melanoma cells A375 are stably transfected to produce the soluble variant of the angiopoietin receptor TIE-2 (sTIE-2), they show a substantial inhibition of tumor growth on nude mice. Similar effects have been seen with the soluble variant of the VEGF receptor FLT-1 (sFLT-1). In both cases, the vessel density of the tumors is significantly reduced. These experiments show that the inhibition of the angiopoietin/TIE-2 system, similar to the inhibition of the VEGF/VEGF receptor system, has an antitumoral effect, most probably due to the inhibition of tumor angiogenesis. Thus, inhibition of both signalling systems seem to be a valid strategy for the development of novel antiangiogenic therapies. Recently, the inhibition of the VEGF receptor tyrosine kinase by the compound PTK787/ZK222584 has been shown to substantially inhibit tumor growth and metastases formation. This compound has now entered clinical trials at the Tumor Biology Center in Freiburg i.Br. A preliminary evaluation of phase I study shows a very promising clinical outcome.
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PMID:[Tumor angiogenesis: new approaches to cancer therapy]. 1144 5

MUC4 is a one of the membrane mucins of the mucin gene (MUC) family, characterized by mucin tandem repeat domains and a transmembrane domain which associates it with the cell plasma membrane. Although MUC4 is encoded by a single gene, it is produced by epithelial cells as a heterodimer through a proteolytic cleavage mechanism. This heterodimer is found in both membrane and soluble forms associated with epithelia. Functionally, MUC4 is proposed to provide a protective mechanism for vulnerable epithelia, such as those of the airway, eye, female reproductive tract and mammary gland. The protective mechanism(s) may be highjacked by some carcinomas, such as those of the breast, to increase tumor progression. Two mechanisms are proposed to contribute to the MUC4 functions. First, MUC4 acts as an anti-adhesive or anti-recognition barrier at epithelial or tumor cell surfaces. Second, MUC4 can bind the receptor tyrosine kinase ErbB2 and alter its cellular signaling. Expression of MUC4 in mammary gland is repressed by posttranscriptional mechanisms involving basement membrane and TGF-beta, which are relieved during pregnancy to permit secretion of MUC4 into milk. These mechanisms are also abrogated in some breast cancers, providing a scenario for promotion of tumor progression. These observations imply important functions for MUC4 in both normal mammary function and in breast cancer.
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PMID:Muc4/sialomucin complex in the mammary gland and breast cancer. 1154 1

Activation of the Met receptor tyrosine kinase through its ligand, hepatocyte growth factor, stimulates cell spreading, cell dispersal, and the inherent morphogenic program of various epithelial cell lines. Although both hepatocyte growth factor and epidermal growth factor (EGF) can activate downstream signaling pathways in Madin-Darby canine kidney epithelial cells, EGF fails to promote the breakdown of cell-cell junctional complexes and initiate an invasive morphogenic program. We have undertaken a strategy to identify signals that synergize with EGF in this process. We provide evidence that the overexpression of the CrkII adapter protein complements EGF-stimulated pathways to induce cell dispersal in two-dimensional cultures and cell invasion and branching morphogenesis in three-dimensional collagen gels. This finding correlates with the ability of CrkII to promote the breakdown of adherens junctions in stable cell lines and the ability of EGF to stimulate enhanced Rac activity in cells overexpressing CrkII. We have previously shown that the Gab1-docking protein is required for branching morphogenesis downstream of the Met receptor. Consistent with a role for CrkII in promoting EGF-dependent branching morphogenesis, the binding of Gab1 to CrkII is required for the branching morphogenic program downstream of Met. Together, our data support a role for the CrkII adapter protein in epithelial invasion and morphogenesis and underscores the importance of considering the synergistic actions of signaling pathways in cancer progression.
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PMID:Crk synergizes with epidermal growth factor for epithelial invasion and morphogenesis and is required for the met morphogenic program. 1213 61

Members of the Eph family of receptor tyrosine kinase have been implicated in cell-cell communication and tissue integrity during embryogenesis. We have previously demonstrated cell type specific and hormone dependent EphB4 expression in the mouse mammary parenchyma suggesting involvement in the homeostasis of this organ. Since disruption of tissue organization is crucial for metastatic dissemination, we have investigated the expression of EphB4 during carcinogenesis of the human breast. Immunohistochemical analysis of 24 normal human breast samples and 124 consecutive breast carcinomas was correlated with tumor characteristics (stage, histology, grade, lymph node involvement) and the expression of ER, PR, Ki-67, p53 and HER2. In normal breast tissue, the EphB4 protein was expressed exclusively in parenchymal cells. Strikingly, a drastic reduction in the number of EphB4 protein expressing cells was observed in almost all invasive carcinomas analyzed, irrespective of the tumor type (p<0.0001). Furthermore, we found a highly significant correlation between EphB4 positivity and low histological grading of the tumor cells (p=0.002) suggesting that in breast cancer, EphB4 expression is not compatible with tumor progression. This raises the possibility that EphB4 could represent a potent tool for therapeutic intervention.
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PMID:Loss of EphB4 receptor tyrosine kinase protein expression during carcinogenesis of the human breast. 1216 60

The erbB2 receptor tyrosine kinase and the CD44 transmembrane glycoprotein interact with one another in numerous cell types. This interaction helps to maintain erbB2 activity that contributes to tumor progression. We investigated whether CD44 and erbB2 similarly interact in endometrial carcinomas in vitro and in situ. In contrast to other carcinomas, CD44 did not colocalize with erbB2 in any of the 51 cases of endometrial cancer analyzed. CD44 also did not coimmunoprecipitate or colocalize with erbB2 in two endometrial carcinoma cell lines. We propose that the lack of CD44-erbB2 interactions may reduce the contribution of erbB2 to endometrial carcinoma progression.
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PMID:Endometrial carcinoma cells are nonpermissive for CD44-erbB2 interactions. 1237 51

Most gastrointestinal stromal tumors (GISTs) have activating mutations in the KIT receptor tyrosine kinase, and most patients with GISTs respond well to Gleevec, which inhibits KIT kinase activity. Here we show that approximately 35% (14 of 40) of GISTs lacking KIT mutations have intragenic activation mutations in the related receptor tyrosine kinase, platelet-derived growth factor receptor alpha (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.
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PMID:PDGFRA activating mutations in gastrointestinal stromal tumors. 1252 57

Studies on signal transduction pathways have generated various promising molecular targets for therapeutic inhibition in cancer therapy. Receptor tyrosine kinases represent an important class of such therapeutic targets. c-Met is a receptor tyrosine kinase that has been shown to be overexpressed and/or mutated in a variety of malignancies. A number of c-Met activating mutations, many of which are located in the tyrosine kinase domain, have been detected in various solid tumors and have been implicated in invasion and metastasis of tumor cells. It is known that stimulation of c-Met via its natural ligand, hepatocyte growth factor (also known as scatter factor, HGF/SF) results in a plethora of biological and biochemical effects in the cell. Activation of c-Met signaling can lead to scattering, angiogenesis, proliferation, enhanced cell motility, invasion, and eventual metastasis. In this review, the role of c-Met dysregulation in tumor progression and metastasis is discussed in detail with particular emphasis on c-Met mutations. Moreover, we summarize current knowledge on various pathways of c-Met signal transduction, highlighting the central role in the cytoskeletal functions. In this summary is included recent data in our laboratory indicating that phosphorylation of focal adhesion proteins, such as paxillin, p125FAK, and PYK2, occurs in response to c-Met stimulation in lung cancer cells. Most importantly, current data on c-Met suggest that when mutated or overexpressed in malignant cells, c-Met would serve as an important therapeutic target.
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PMID:c-Met: structure, functions and potential for therapeutic inhibition. 1288 8

Although relatively little is known about the molecular mechanisms underlying tumor progression, recently CD44 glycoproteins and the c-Met receptor tyrosine kinase have been identified as potentially important components of the metastatic cascade. CD44 is a family of transmembrane receptors generated from a single gene by alternative splicing and differential glycosylation. Important biological processes involving CD44 glycoproteins include cell adhesion, lymphocyte homing, hematopoiesis, tumor progression and metastasis. The precise mechanism via which CD44 promotes tumorigenesis have not yet been elucidated. We evaluated the expression of adhesion molecule CD44 variant 6 in pulmonary metastases from colorectal carcinomas and its correlation with clinicopathological parameters. Twenty patients were randomly selected from the patients who had undergone a resection of pulmonary metastasis from colorectal cancer. Formalin-fixed, paraffin-embedded archival specimens of tumor tissues and adjacent normal mucosa from these patients were the subjects of the present study. Immunoreactivity for CD44 was quantified. Specimens were considered positive if almost 25% of the neoplastic cells were stained. CD44 v6 expression was related to the interval between colon resection and metastases diagnosis, the number of pulmonary metastases, and the survival after lung resection. No statistical correlation was found between CD44 v6 positivity and disease-free interval after colon resection, number of metastases or 2-year survival after lung resection. Probably CD44 v6 is necessary and sufficient to confer metastatic potential to carcinoma cells increasing the migration capacity and participating in invasion via changes in adhesion to the extracellular ligands, but is not necessary to modify the clinical history of the metastases. Therefore the evaluation of CD44 v6 expression in lung metastases does not influence the therapeutic scheme.
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PMID:Evaluation of CD44 variant 6 expression and clinicopathological factors in pulmonary metastases from colon carcinoma. 1453 11


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