Fibronectin and its integrin receptors in cancer.

The adhesive extracellular matrix protein fibronectin and its integrin receptors play important roles at several stages of tumor development. Tumor cells are generally less adhesive than normal cells and deposit less extracellular matrix. The loosened matrix adhesion that results may contribute to the ability of tumor cells to leave their original position in the tissue. Normal cells, when detached, stop growing and undergo anoikis (apoptosis caused by loss of adhesion). Integrin-activated pathways mediated by focal adhesion kinase (FAK) and the adapter protein She seem to be particularly important in anchorage dependence; many oncoproteins are capable of shunting these pathways. Malignant cells circumvent anchorage dependence with the help of oncoproteins. Once invading tumor cells have gained access to the circulation, adhesion to the endothelia and other tissue components facilitates the establishment of tumor colonies at distant sites. Specific tissue affinities may underlie the tendency of some tumors to metastasize preferentially to certain tissues. Interfering with tumor cell attachment with integrin-binding peptides has been shown to be an effective antimetastatic strategy in animal experiments. Tumor angiogenesis is yet another aspect of malignancy wherein extracellular matrices and integrins are important. Angiogenic endothelial cells in tumor vessels depend on the alpha v family of integrins for survival. Inhibiting angiogenesis with compounds that block the activity of alpha v integrins, and targeting drugs into tumors through these integrins, show promise as new anticancer strategies.