Adriamycin-induced inhibition of melanoma cell invasion is correlated with decreases in tumor cell motility and increases in focal contact formation.

Tumor cell adhesion to the extracellular matrix (ECM) is closely linked with tumor cell invasion and metastasis. In this study, we demonstrate that low levels of adriamycin, a widely used anticancer drug, can inhibit the invasion of highly metastatic K1735-M2 mouse melanoma cells in vitro through a reconstituted basement membrane extract. Adriamycin-induced inhibition of melanoma cell invasion occurred at levels of the drug (i.e. 1 ng/ml) that did not inhibit tumor cell growth, suggesting that the observed inhibition in tumor cell invasion was not due to the well-documented ability of adriamycin to interfere with DNA and/or RNA synthesis. Rather, these studies indicated that adriamycin-induced inhibition of melanoma cell invasion was accompanied by a corresponding decrease in the ability of adriamycin-treated tumor cells to migrate in response to several isolated ECM components including fibronectin, laminin and basement membrane (type IV) collagen. The decreased migration of adriamycin-treated tumor cells was not accompanied by a decrease in the adhesion or spreading of the adriamycin-treated cells on substrata coated with these ECM components. Instead, adriamycin-treated cells actually exhibited a slightly increased propensity (compared to untreated control cells) to adhere on fibronectin-, laminin-, and type IV collagen-coated substrata. Additionally, adriamycin treatment caused a dramatic increase in focal contact formation by these melanoma cells, as assessed by fluorescent microscopy of actin and vinculin. In addition to providing a useful model for which to study the molecular and cellular basis for focal contact formation, these results further emphasize the results of several other investigators that have suggested an important role for focal contacts in modulating tumor cell motility, invasion and metastasis.

Expression of collagen binding integrins during cardiac development and hypertrophy.

The interaction between components of the extracellular matrix and the cell surface of cardiac myocytes appears to be regulated in part by receptors belonging to the integrin superfamily. The expression of the integrins was investigated at different stages of development of the heart as well as during cardiac hypertrophy. The characterization of the membrane proteins showed that a beta 1-integrin and associated alpha-chains were responsible for the interaction with collagen, laminin, and fibronectin. Immunoprecipitation data indicated that the presence of specific alpha-chains varied with development. These data were correlated with the ability of the isolated myocytes to attach to specific components of the extracellular matrix. The expression of the alpha 1-chain was prominently associated with the recognition of interstitial collagens. The presence of the alpha 1-chain was also associated with stages when collagen synthesis was increased, especially during fetal and neonatal growth and cardiac hypertrophy. Immunohistochemical localization with the antiserum against beta 1-integrin demonstrated its specific localization near the Z lines of cardiac myocytes. The localization both in vitro and in vivo indicated that the beta 1-integrin may play a role in myofibrillogenesis during development. The present immunohistochemical, cell adhesion, and biochemical data clearly indicate that integrins play a major role in the regulation of the interaction between cardiac myocytes and the extracellular matrix during development and disease.