Heparin and hormonal regulation of mRNA synthesis and abundance of autocrine growth factors: relevance to clonal growth of tumors.

Zvibel, Isabel; Halay, E D; Reíd, Lola M.

doi:10.1128/mcb.11.1.108

Cited by 51 publications

(23 citation statements)

References 49 publications

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“…We first examined whether the adipogenesis-blocking chemicals impair the viability of human hepatocellular carcinoma cells that overexpress IGF2, a member of IGFs that is often produced at high levels in liver tumors (27). We identified three chemically analogous compounds that killed IGF2-overexpressing hepatocellular carcinoma cells (Hep-G2) but had milder effects on the cell line with low levels of IGF2 (SK-Hep-1) (28). Repeated experiments with three additional human hepatocellular carcinoma cell lines that we recently characterized 2 indicated that one of the three chemicals, 94G6, exhibited the highest cytotoxicity to IGF2-producing hepatocellular carcinoma cells with selectivity similar to that of a neutralizing antibody against IGF2 (Fig.…”

Section: Figmentioning

confidence: 99%

Identification of Bioactive Molecules by Adipogenesis Profiling of Organic Compounds

Choi

Kawazoe

Murakami

et al. 2003

Journal of Biological Chemistry

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An important step in the postgenomic drug discovery is the construction of high quality chemical libraries that generate bioactive molecules at high rates. Here we report a cell-based approach to composing a focused library of biologically active compounds. A collection of bioactive non-cytotoxic chemicals was identified from a divergent library through the effects on the insulin-induced adipogenesis of 3T3-L1 cells, one of the most drastic and sensitive morphological alterations in cultured mammalian cells. The resulting focused library amply contained unique compounds with a broad range of pharmacological effects, including glucose-uptake enhancement, cytokine inhibition, osteogenesis stimulation, and selective suppression of cancer cells. Adipogenesis profiling of organic compounds generates a focused chemical library for multiple biological effects that are seemingly unrelated to adipogenesis, just as genetic screens with the morphology of fly eyes identify oncogenes and neurodegenerative genes.

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Section: Figmentioning

confidence: 99%

Identification of Bioactive Molecules by Adipogenesis Profiling of Organic Compounds

Choi

Kawazoe

Murakami

et al. 2003

Journal of Biological Chemistry

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“…3 Heparin chains affected proliferation by transcriptionally inducing differentiation factors and inhibitory growth factors in the nonmetastatic cells. 4 Previously,we used human colorectal cancer cell lines to assess the role of liver ECM in regulating cell proliferation and found that hepatocyte-derived ECM stimulated the growth of cells that metastasize to the liver. 5 Enhancement of cell proliferation was accompanied by increased amounts of erb-B2 and erb-B3 in the colon cancer cells.…”

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confidence: 99%

Heparin‐derived disaccharides modulate proliferation and Erb‐B2–mediated signal transduction in colon cancer cell lines

Fishman

Brill

Papa

et al. 2002

Intl Journal of Cancer

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Organ-specific extracellular matrix (ECM) determines metastasis formation by regulating tumor cell proliferation. Hepatocyte-derived ECM enhances proliferation of colon cancer cell lines by increasing expression of tyrosine kinase receptors of the erb-B family. The active components in the ECM are the heparan sulfates, which are highly heterogenous in their chemistry and size. We determined the effect of heparan sulfate disaccharides, of defined chemistry and present in high amounts in the liver heparan sulfate chains, on the proliferation of colon cancer cell lines and investigated the mechanism involved. The low-metastatic cell line KM12 was stimulated to proliferate by a highly sulfated disaccharide, found in the highest amounts in hepatocyte-derived heparan sulfate. Growth of the highly metastatic cell line KM12SM was inhibited by the second most common disaccharide in hepatocyte-derived heparan sulfate. The effect of both disaccharides was not accompanied by changes in the expression of erb-B1, erb-B2, erb-B3 or heregulin-␣. We determined whether the disaccharides modified the signal-transduction pathways mediated by the erb-B receptors. The erb-B2-specific tyrosine kinase inhibitor AG825 abolished the enhancement of KM12 cell proliferation by the stimulatory disaccharide. This disaccharide increased tyrosine phosphorylation of erb-B1 and erb-B2 receptors, effects that were abolished by AG825. Moreover, the disaccharide caused increased expression of cyclin D1 and of activated MAP kinase, again reduced in the presence of the inhibitor AG825. The growth-inhibitory disaccharide reduced phosphorylation of erb-B1, but not of erb-B2, receptors in KM12SM cells. In conclusion, not only hepatocyte-derived heparan sulfate but also disaccharide molecules derived from heparan sulfate can affect colon cancer cell proliferation. Their effect is mediated by modulation of the erb-B signal transduction. © 2002 Wiley-Liss, Inc. Key words: heparin; erb-B2; signal transduction; colon cancer; disaccharide; heparan sulfateSite-specific metastasis, i.e., the propensity of each tumor type to metastasize to certain organs, is strongly dependent on the local environment of various organs colonized by metastatic tumor cells, in particular the extracellular matrix (ECM) of those organs. The organ-specific ECM may have either a stimulatory or an inhibitory effect on tumor cell proliferation. 1,2Previously, we showed that the ability of hepatomas and breast carcinomas to metastasize to a specific organ in vivo depended on in vitro survival of the cells at clonal densities on ECM derived from that organ. 3 The ECM components most active in regulating survival and proliferation were the organ-specific proteoglycans and their effect was due to their glycosaminoglycan chains. 3 Heparin chains affected proliferation by transcriptionally inducing differentiation factors and inhibitory growth factors in the nonmetastatic cells. 4 Previously,we used human colorectal cancer cell lines to assess the role of liver ECM in regulating cell prolifera...

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“…3,[6][7][8][26][27][28][29][30][31] Freshly isolated rat hepatocytes can bind to collagen via ␣ 1 ␤ 1 -integrin, 32 as shown by the ability of a monoclonal antibody to the ␣ 1 subunit to block binding to native type I collagen. 33 Hepatocyte binding to fibronectin, specifically at the amino acid sequence RGD, is mediated by ␣ 5 ␤ 1 -integrin.…”

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confidence: 99%

?3?1-integrin as a critical mediator of the hepatic differentiation response to the extracellular matrix

et al. 1998

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The extracellular matrix (ECM) promotes the differentiation of many cell types, and ECM remodeling in the liver has been implicated in embryonic development, tissue injury, and oncogenesis. Integrins are heterodimeric ECM receptors that play critical roles in transducing the composition of the ECM in the cell environment. We previously showed that mouse H2.35 cells, a conditionally transformed, liver-derived cell line, assume a more differentiated hepatocyte morphology and enhanced liver-specific gene expression when the cells are cultured on gelatinous ECM substrata. Here we show that H2.35 cells express relatively high levels of ␣ 3 ␤ 1 -integrins, similar to that previously shown for immature hepatocytes, transformed hepatocytes, and biliary cells. However, the cell morphological responses that depend on ␣ 3 ␤ 1 -integrin have not been defined. We found that transfecting H2.35 cells with antisense RNA construct directed to ␣ 3 -subunit messenger RNA perturbs the initial cell attachment to laminin and collagen, and strongly inhibits cell morphological, proliferative, and gene expression responses to a collagen gel substratum. In situ hybridization to mouse embryo tissues demonstrates the presence of ␣ 3 -subunit messenger RNAs in newly formed hepatocytes. We suggest that ␣ 3 ␤ 1 -integrins are important for immature and transformed hepatocytes to respond morphologically to the extracellular matrix. (HEPATOLOGY 1998;28:1095-1104.)Tissue-specific gene expression, morphogenesis, and cell migration are promoted by interactions between cells and the surrounding extracellular matrix (ECM). For example, early hepatocyte differentiation begins as foregut endodermal cells enter the new collagenous environment of the surrounding mesenchyme, 1 and the role of the ECM in adult hepatocyte differentiation is well established. [2][3][4][5][6][7][8] Other examples of ECMpromoted differentiation include the differentiation of keratinocytes, 9 gastrulation in Pleurodeles embryos, 10 and the epithelial conversion of kidney mesenchyme 11 (for review, see Adams and Watt 12 ). The ECM is present in all animals from the earliest stages of development and is composed of a mixture of proteins and proteoglycans such as collagens, laminin, and fibronectin. An important set of membrane receptors for ECM molecules is the integrin family of proteins. [13][14][15] Integrins are heterodimers of ␣ and ␤ subunits, with each subunit containing an N-terminal extracellular domain, a transmembrane domain, and a C-terminal intracellular domain. Integrins activate common as well as subgroupspecific intracellular signaling pathways in response to the ECM. 16,17 Membrane proximal events triggered by integrin ligation include the activation of the focal adhesion kinase 18 by the ␤ subunit and the recruitment of adapter protein Shc by certain ␣ subunits within heterodimers. 19 More ␣ subunits are known than ␤ subunits, and the particular combination of ␣ and ␤ partners determines the ligand specificity for ECM molecules. An ECM protein can be recognized...

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Heparin and hormonal regulation of mRNA synthesis and abundance of autocrine growth factors: relevance to clonal growth of tumors.

Cited by 51 publications

References 49 publications

Identification of Bioactive Molecules by Adipogenesis Profiling of Organic Compounds

Identification of Bioactive Molecules by Adipogenesis Profiling of Organic Compounds

Heparin‐derived disaccharides modulate proliferation and Erb‐B2–mediated signal transduction in colon cancer cell lines

?3?1-integrin as a critical mediator of the hepatic differentiation response to the extracellular matrix

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