Cancer Progression and Growth: Relationship of Paracrine and Autocrine Growth Mechanisms to Organ Preference of Metastasis

Abstract

The progression of cancer cells to highly malignant phenotypes that ultimately invade and metastasize to near and distant sites requires that metastatic cells respond to mitogenic signals in new microenvironments. The successful growth of metastases is due to their ability to respond to local paracrine growth factors and inhibitors and to produce and respond to autocrine growth factors. Solid tumors of the same histologic class, however, may respond differently to combinations of paracrine and autocrine growth signals at metastatic sites. At early stages of tumor dissemination there is a tendency for certain cancers to metastasize to and grow preferentially at particular sites, suggesting that paracrine growth mechanisms may dominate the growth signals processed by metastatic cells. In contrast, at later stages of progression where widespread dissemination of cancer occurs, autocrine growth mechanisms may dominate the positive growth signals processed by metastatic cells and the cells may fail to respond to negative growth signals. Ultimately progression of cancer cells to completely autonomous (acrine) growth states can occur, and metastatic cell proliferation may be completely independent of growth factors or inhibitors. This suggests that pharmacologic intervention using analogs of specific growth inhibitors or antagonists of growth factors, such as genetically altered growth factors, monoclonal antibodies, or other agents, to block growth signaling mechanisms may be useful only at stages of cancer progression before widespread metastasis of acrine malignant cells occurs.