Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we reported that high concentrations of eosinophils in human colonic carcinomas are associated with better prognoses, that sections taken 1 cm remote from (deep to) the margin of tumor (SRM) and sections contiguous to the margin (SCM) of tumor and adjacent uninvolved colon contain significantly different concentrations of eosinophils, and that concentrations of eosinophils in SCM and SRM are both useful and complementary for the prediction of prognosis. As a first step towards studying the ecology of the eosinophil in colonic carcinoma and with the goal of identifying other kinds of cells that might be useful for the prediction of prognosis, we counted cells in SCM and SRM that expressed histochemically demonstrable acid phosphatase, alpha-naphthylbutyrate esterase, and peroxidase. The tumors of patients with and without metastases at the time of resection of the primary tumor contained different (P = 0.0314) concentrations of cells with histochemically demonstrable alpha-naphthylbutyrate esterase in SCM but not in SRM. In contiguous 1- to 2-micron sections, morphologically macrophage-like cells with histochemically demonstrable acid phosphatase and cells with histochemically demonstrable alpha-naphthylbutyrate esterase were found to be present in different concentrations both in SCM (P less than 0.01) and in SRM (P less than 0.01); i.e., these phenotypic markers appear to identify different subpopulations of macrophages in tumors. In contrast to our previous study of human pulmonary alveolar macrophages, examination of sections stained sequentially for these phenotypic markers that are commonly used for the identification of macrophages in tumors revealed numerous cells in the same sections that expressed histochemically demonstrable acid phosphatase (red) but not alpha-naphthyl butyrate esterase (brown) and vice versa. Several of these markers promise to be useful and complementary for the prediction of prognosis.
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PMID:Heterogeneity and prognostic significance of macrophages in human colonic carcinomas. 402 96

Abetalipoproteinemia (ABL [Bassen-Kornzweig syndrome]) is characterized by marked hypolipidemia with absence of low-density lipoproteins, fat-soluble vitamin deficiency, spinocerebellar ataxia, and retinitis pigmentosa. Our patient had ABL, severe neurologic disease, and spinal cord malignancy, as well as disseminated CNS and extraneural metastases. It is possible that patients with this disorder and long-standing fat-soluble vitamin deficiency may have increased risk for CNS malignancy.
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PMID:Abetalipoproteinemia and metastatic spinal cord glioblastoma. 632 13

Overexpression of the RHAMM gene by transfection into fibroblasts is transforming and causes spontaneous metastases in the lung. H-ras-transformed fibrosarcomas transfected with a dominant suppressor mutant of RHAMM exhibit a so-called revertant phenotype and are completely nontumorigenic and nonmetastatic. Conversely, fibroblasts stably expressing low levels of RHAMM as a result of antisense transfection are resistant to ras transformation. Collectively, these results indicate that RHAMM acts downstream of ras. The loss of functional RHAMM ablates signaling within focal adhesions, in particular changes in focal adhesion kinase phosphorylation, and as a result these focal adhesions are unable to turn over in response to hyaluronan. These results provide evidence of the oncogenic potential of a novel extracellular matrix receptor and establish a functional link between transformation by ras and signaling within focal adhesions that are required for transformation by this oncogene.
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PMID:Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. 984 61

CAI (NSC 609974; L651582), a new agent that has demonstrated antimetastatic activity in vitro and in vivo, was not very cytotoxic toward EMT-6 mouse mammary carcinoma cells in culture or toward FSaIIC fibrosarcoma cells in vivo. Coexposure of EMT-6 cells to CAI and antitumor alkylating agents under various environmental conditions did not markedly increase the cytotoxicity of cisplatin (CDDP), melphalan, or carmustine (BCNU). However, the combination of CAI and 4-hydroperoxycyclophosphamide (4-HC) produced much greater than additive killing of EMT-6 cells. CAI also increased the sensitivity of hypoxic EMT-6 cells to X-rays. CAI increased the cytotoxicity of cyclophosphamide toward FSaIIC tumor cells when animals were treated with single doses of both drugs. The effect of CAI on tumor cell killing by cyclophosphamide was greatest at high doses of the antitumor alkylating agent. CAI administration appeared to result in increased serum levels of prostaglandin E2 and leukotriene B4 in animals bearing the Lewis lung tumor. Administration of CAI on days 4-18 did not alter the growth of the Lewis lung carcinoma but did result in an increase in the tumor-growth delay produced by treatment with CDDP, cyclophosphamide, melphalan, BCNU, and fractionated radiation. Although CAI did not reduce the number of lung metastases present in Lewis lung carcinoma-bearing mice on day 20, it did appear to reduce the number of large (vascularized) metastases present on that day.
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PMID:CAI: effects on cytotoxic therapies in vitro and in vivo. 792 63

Tetrahydrocortisol, beta-cyclodextrin tetradecasulfate, and minocycline used alone or in combination are not very cytotoxic toward EMT-6 mouse mammary tumor cells growing in monolayer. Tetrahydrocortisol (100 microM, 24 h) and beta-cyclodextrin tetradecasulfate (100 microM, 24 h) protected EMT-6 cells from the cytotoxicity of CDDP, melphalan, 4-hydroperoxycyclophosphamide, BCNU, and X-rays under various conditions of oxygenation and pH. Minocycline (100 microM, 24 h) either had no effect upon or was additive with the antitumor alkylating agents or X-rays in cytotoxic activity toward the EMT-6 cells in culture. The combination of the three modulators either had no effect upon or was to a small degree protective against the cytotoxicity of the antitumor alkylating agents or X-rays. The Lewis lung carcinoma was chosen for primary tumor growth-delay studies and tumor lung-metastases studied. Tetrahydrocortisol and beta-cyclodextrin tetradecasulfate were given in a 1:1 molar ratio by continuous infusion over 14 days, and minocycline was given i.p. over 14 days, from day 4 to day 18 post tumor implantation. The combination of tetrahydrocortisol/beta-cyclodextrin tetradecasulfate diminished the tumor growth delay induced by CDDP and melphalan and produced modest increases in the tumor growth delay produced by cyclophosphamide and radiation. Minocycline co-treatment increased the tumor growth delay produced by CDDP, melphalan, radiation, bleomycin, and, especially cyclophosphamide, where 4 of 12 animals receiving minocycline (14 x 5 mg/kg, days 4-18) and cyclophosphamide (3 x 150 mg/kg, days 7, 9, 11) were long-term survivors. The 3 modulators given in combination produced further increases in tumor growth delay with all of the cytotoxic therapies, and 5 of 12 of the animals treated with the 3-modulator combination and cyclophosphamide were long-term survivors. Although neither tetrahydrocortisol/beta-cyclodextrin tetradecasulfate, minocycline, nor the three modulator combination impacted the number of lung metastases, there was a decrease in the number of large lung metastases. Treatment with the cytotoxic therapies alone reduced the number of lung metastases. Addition of the modulators to treatment with the cytotoxic therapies resulted in a further reduction in the number of lung metastases. These results indicate that agents that inhibit the breakdown of the extracellular matrix can be useful additions to the treatment of solid tumors.
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PMID:beta-cyclodextrin tetradecasulfate/tetrahydrocortisol +/- minocycline as modulators of cancer therapies in vitro and in vivo against primary and metastatic Lewis lung carcinoma. 826 4

Cell motility, a primary component of tumor cell invasion, is a continuum of sequential events in which the cell extends pseudopodia, forms nascent attachments, assembles and contracts the cytoskeleton, and finally, as it translocates forward, disengages distal adhesions. What triggers cells to move? Substratum contact mediated by integrin adhesion receptors is important, but other signals such as chemokinetic factors appear to be required for continued crawling. It is now apparent that integrins do not simply bind cells to matrix in a Velcro-like fashion, but also are potent signaling molecules. Initial engagement of integrins induces their condensation into focal contacts, forming anchors to the extracellular matrix and discrete signal-transducing complexes on the cytoplasmic surface. A number of growth factors, through either autocrine or paracrine pathways, can activate the cellular machinery that mobilizes the cell. Thus, these two classes of receptors--the integrin receptors that bind specific extracellular adhesion molecules, and growth factor receptors that bind their respective ligands--can regulate cell locomotion. Not surprisingly, there is 'cross-talk' between integrin and growth factor receptors that occurs through their common intracellular signaling pathways. In this way, each receptor type can either amplify or attenuate the other's signal and downstream response. An example of growth factor-induced motility is the epithelial-mesenchymal transition induced by hepatocyte growth factor/scatter factor (HGF/SF). When bound to its receptor, the c-met proto-oncogene product, HGF/SF induces a phenotypic conversion that appears to be an important aspect of tumor progression in malignant carcinomas. The motogenic response produced by HGF/SF in carcinoma cells occurs in discrete steps in which integrins and focal adhesion kinase (p125FAK) are first recruited to focal contacts. This is rapidly followed by cell spreading, disruption of focal adhesions and cell-cell contacts, and, finally, cell crawling. The precise mechanism by which growth factors such as HGF/SF and its receptor induce this motogenic response and modulate integrin function has not been clearly defined but appears to involve several signaling pathways. Understanding the process by which growth factor and integrin receptors interact and regulate motility may suggest novel targets for therapeutic intervention.
Cancer Metastasis Rev 1995 Sep
PMID:Growth factor regulation of integrin-mediated cell motility. 854 69

A human myeloid leukemia cell line, KBM-7, was developed from a patient in the blastic phase of chronic myeloid leukemia (CML). We characterized its morphology, immunophenotype, cytogenetics, and proliferative capacity. Developed in the absence of exogenous lymphokines, KBM-7 in vitro cloning capacity actually decreased when colony-stimulating factors were added. The cells had an aberrant immature myeloid phenotype, a doubling time of 22 h in suspension cultures and a high cloning efficiency in semisolid system (24 +/- 3)%. Early passages contained one near-haploid (predominant) and one hyperdiploid stem line. Gradually the hyperdiploid stem line became predominant, reaching an average of 49 chromosomes per cell. Cells from passage 89 had two Philadelphia chromosomes [t(9;22)(q34;q11)] and lacked normal copies of chromosomes 9 and 22. Detailed molecular characterization of the breakpoint in the t(9;22)(q34;q11) revealed that KBM-7 had the BCR 2/ABL II splice junction. The cells had high protein kinase (p210BCR-ABL) activity and carried two identified variants of an ABL-BCR message. There was no evidence that normal BCR or c-ABL messages were expressed, assessed with the reverse-transcriptase polymerase chain reaction. When KBM-7 cells were heterotransplanted into nude mice without immunosuppressive pretreatment, one of three mice injected with 1 x 10(7) cells and all mice injected with 1 x 10(8) cells developed slowly growing granulocytic sarcomas within 6-8 weeks. These tumors were locally invasive but did not metastasize. We conclude that the KBM-7 cell line will be of value for investigating molecular events underlying neoplastic transformation in CML, in particular for studying the effects of BCR-ABL and ABL-BCR on the proliferation of CML cells in the absence of normal BCR and c-ABL messages.
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PMID:KBM-7, a human myeloid leukemia cell line with double Philadelphia chromosomes lacking normal c-ABL and BCR transcripts. 860 23

Arginine-derived nitric oxide (NO) has been identified in some tumor cell lines and solid human tumors. The effect of tumor cell NO on tumor biology is poorly understood. The purpose of this study was to investigate the effect of NO production by EMT-6 murine breast cancer cells on tumor cell growth in vitro and subcutaneous tumor growth and experimental pulmonary metastasis in vivo. EMT-6 cells were incubated with endotoxin (LPS, 10 microgram/ml) and interferon-gamma (IFN, 50 U/ml), in the presence or absence of the NO synthase inhibitor, omega-nitro-L-arginine methyl ester (L-NAME, 2 mM), and NO production and cell number were assessed 24 hr later. EMT-6 cells were also treated overnight with LPS/IFN, in the presence or absence of L-NAME, washed and injected either subcutaneously in the dorsal flank (n = 40) or via the tail vein (n = 40) of syngeneic BALB/c mice. Two weeks following tumor cell injection, tumor size and number of pulmonary metastases were assessed. LPS/IFN stimulated NO production in EMT-6 cells and inhibited cell growth in vitro by 50%. L-NAME blocked LPS/IFN stimulation of NO production and restored cell growth to near control levels. When injected into BALB/c mice, LPS/IFN-stimulated tumor cells demonstrated a two-fold increase in subcutaneous tumor growth and experimental pulmonary metastases over control cells. L-NAME reduced tumor size and number of lung metastases to control levels, suggesting that tumor cell NO production was responsible for this effect. In summary, LPS/IFN-stimulated NO production in EMT-6 tumor cells inhibits tumor cell growth in vitro, yet paradoxically augments tumor growth and metastasis in vivo.
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PMID:Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo. 866 Nov 71

Lck protein is expressed in some colon carcinoma cell lines but its expression in colon cancer cells in vivo has not been clarified. LCK transcription is regulated from two distinct promoters and initiated exclusively from the downstream promoter in colon carcinoma cell lines in contrast to peripheral lymphocytes. We investigated the expression of the downstream promoter-initiated LCK transcript in 18 colorectal primary cancer and normal mucosae, and two hepatic metastases, using a RNase protection assay with the EcoRI-BglII fragment of human LCK cDNA, YT16. In normal tissues, only traces of the LCK transcript were detected. The expression of the LCK transcript was augmented in 3/18 cancer specimens. The relative level of the LCK transcript in the cancer tissue compared to the average value of normal adjacent tissue was 10-60 in 3 cases, and 3-10 in 7 cases. One hepatic metastasis expressed more LCK message than the primary lesion. Our results indicate that the LCK message is strongly expressed in some colorectal cancers.
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PMID:Augmented expression of LCK message directed from the downstream promoter in human colorectal cancer specimens. 886 6

The isoflavinoid genistein is a protein-tyrosine kinase inhibitor which has been identified as a putative cancer prevention agent. Its consumption is associated with a low incidence of clinical metastatic prostate cancer in the face of a sustained high incidence of organ-confined prostate cancer. We therefore undertook studies to examine genistein's effect upon cell adhesion as one possible mechanism by which it could be acting as an antimetastatic agent. A morphogenic analysis revealed that genistein caused cell flattening in a variety of cell lines: PC3-M, PC3, and DU-145 prostate carcinoma cells, as well as MCF-7 breast carcinoma cells. Mechanistic studies focused on the highly metastatic PC3-M cell line, and revealed that cell flattening was accompanied by an increase in cell adhesion. Further investigations demonstrated that focal adhesion kinase (FAK) accumulated in areas of focal cell attachment, and that this accumulation occurred only when cells were actively undergoing genistein-mediated morphologic change. Concurrent formation of a complex between the cell attachment molecule, beta-1-integrin, and FAK was shown to occur, and to correlate with transient activation of FAK activity. Genistein is presented as a novel investigative tool for use in the study of molecular events involved in the process of cell adhesion.
Clin Exp Metastasis 1996 Sep
PMID:Genistein-stimulated adherence of prostate cancer cells is associated with the binding of focal adhesion kinase to beta-1-integrin. 887 13


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