Current and future strategies to block tumor angiogenesis, invasion, and metastasis.

Progression of malignancy involves a series of sequential steps that ultimately lead to cancer-cell dissemination. In addition to the loss of growth control, an imbalanced regulation of motility and proteolysis is a prerequisite for invasion and metastasis. These factors are also necessary for angiogenesis-an integral process occurring at both the primary and the metastatic sites. Investigators have elucidated in detail many of the molecular mechanisms involved in the sequential steps of the metastatic cascade and have thereby provided new targets for therapeutic intervention. For each step, different model systems have been developed and various strategies for antimetastatic therapy have been tested in vitro as well as in murine systems. Difficulties in translating results obtained in preclinical models into the clinical setting have become apparent and have not been unexpected in light of the sometimes highly artificial interaction in the experimental setting. Nevertheless, continued development of model systems and further research into the genetic control of malignancy should lead to the identification of common signal-transduction pathways. Interference at such sites promises to be particularly effective in inhibiting proliferation and metastasis.