PARACRINE GROWTH-REGULATION OF HUMAN COLON-CARCINOMA ORGAN-SPECIFIC METASTASIS

The process of cancer metastasis consists of a series of steps resulting in the spread of malignant cells beyond the site of origin and formation of metastases in distant organs. The outcome of this nonrandom process depends, in part, on the interaction of unique tumor cells with a compatible organ microenvironment. The molecular basis of the intrinsic capacity of distinct malignant cells to colonize specific organs and the degree to which host factors influence this process is under intense investigation. Biological analyses of human colon carcinoma tumors obtained from surgical specimens and implanted orthotopically into athymic nude mice revealed that these tumors are heterogeneous for metastatic properties. Moreover, recent evidence using this model suggest that whereas nonmetastatic and highly metastatic cells can grow at local sites, growth in the secondary liver-specific site was associated only with highly metastatic HCC cells. These cells also respond to mitogenic signals produced by damaged normal tissues, suggesting that physiological signals can be utilized by neoplastic cells. Molecular characterization of highly metastatic HCC cells selected in the nude mouse model as well as in situ mRNA hybridization of archival HCC surgical specimens for specific growth factor receptors correlated with the malignant cell's ability to respond to organ-specific growth factors. This article will focus on biological and molecular evidence supporting the hypothesis that organ-derived, paracrine growth factors regulate the site-specific growth of receptive malignant cells that possess the appropriate receptors.