Angiogenesis and colonization in the tumor metastatic process: basic and applied advances

Tumor metastasis is a major cause of death for cancer patients. This review proposes that the final steps in the development of a distant metastasis may be the most productive targets for clinical development. It cannot be guaranteed that, in "metastasis-free" patients, tumor cells have not invaded out of the primary lesion, intravasated and extravasated from the circulatory system, and are sitting at distant sites as occult micrometastases. The remaining processes involved in outgrowth at metastatic sites, colonization and angiogenesis, are reviewed. Colonization is thought to be accomplished by clonally dominant cell populations through progressive independence from exogenous growth factors, production of growth factors, and stimulatory proliferative responses to traditionally inhibitory cytokines. Therapeutic efforts aimed at interrupting the switch in tumor cell responsiveness to cytokines, rather than to any one specific cytokine, may be most successful at inhibiting metastatic colonization. Angiogenesis has been demonstrated to be directly or indirectly induced by a plethora of cytokines. Partial suppression of neovascularization can be achieved in tissue culture and animal models using various natural and pharmaceutical angiostatic agents. However, as with clonal dominance, such agents must be able to suppress the redundant effects of angiogenesis-promoting factors. This review discusses the current literature on colonization and angiogenesis, emphasizing its underlying mechanisms and potential therapeutic applications.