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

Abstract

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...

Effects of CRM197, a specific inhibitor of HB-EGF, in oral cancer

“…It has also been implicated in increased proliferation and metastasis. [11][12][13][14][15][16][17][18][19] CRM197 is a nontoxic mutant of diphtheria toxin that shares immunological properties with the native molecule. CRM197 binds to human HB-EGF and blocks its mitogenic activity by the inhibition of EGFR binding.…”

Helicobacter pylori Can Induce Heparin-Binding Epidermal Growth Factor Expression via Gastrin and Its Receptor

“…Overexpression of HB-EGF has been identified in a large number of different cancer cell lines, including colon, breast, and bladder (25)(26)(27)(28)(29). Additionally, soluble HB-EGF has been identified as a potent inducer of tumor growth and angiogenesis (30).…”

Heparin regulates colon cancer cell growth through p38 mitogen‐activated protein kinase signalling

“…In a recent study, we have shown that heparin dose‐dependently stimulates the proliferation of HT29, SW1116 and HCT116 cells (47). Furthermore, in liver‐colonizing colon cell lines, HS disaccharides were found to stimulate the division of weakly metastatic cells and to inhibit the proliferation of strongly metastatic colon cancer cell lines, grown on fibronectin substrate, depending on their structure and sulphation patterns (20). These data highlight the importance of HS‐dependent pathways on colon cancer cell growth and metastasis.…”

“…On the other hand, some investigations show that heparin can stimulate cell growth (16–18). In our recent study, heparin was demonstrated to stimulate colon cancer cell proliferation (19), whereas previously liver HS‐derived disaccharides have been shown to both inhibit and to enhance colon cancer cell proliferation in a sulphation pattern‐dependent manner (20).…”

“…Tel ⁄ Fax: 00302810394719; E-mail: tzanakak@med. uoc.gr cell proliferation in a sulphation pattern-dependent manner (20).…”