Site-specific metastasis is determined by the extracellular matrix (ECM) of the colonized organ. We have shown that hepatocyte-derived ECM stimulated proliferation of colon-cancer cells via induction of autocrine growth factors and their receptors. The ECM component responsible was heparin proteoglycan. We therefore investigated the effect of exogenously added heparin on colon cell lines of varying liver-colonizing potential. The cells were grown on typical liver matrix components, such as fibronectin and collagens type I and IV. We assessed the effect of these matrix components on clonal growth, proliferation and expression of autocrine growth factors and their receptors. The clonal growth of the KM12 cells was not affected by heparin, while the other cell lines were inhibited by heparin. Cell proliferation in weakly metastatic KM12, but not in strongly metastatic KM12SM, was inhibited by heparin on plastic. Weakly metastatic LS174T, but not strongly metastatic LiM6, was inhibited by heparin on fibronectin. Expression of erb-B2 was also differently modulated by heparin in weakly metastatic vs. highly metastatic cells. In weakly metastatic cells, heparin reduced erb-B2 levels when cells were on plastic and fibronectin, while in strongly metastatic cells, erb-B2 was induced by heparin. In all 4 cell lines, mRNA for cripto was induced by heparin when the cells were grown on fibronectin. In KM12SM cells, amphiregulin was induced by heparin in cells on fibronectin and collagen IV. We show that soluble heparin, similar in its carbohydrate chemistry to liver heparin proteoglycan, regulates the growth of colon-cancer cells. This effect depends on other matrix components found in the liver and is mediated in part by EGF family members.