Targeting the tumor microenvironment (Stroma) for treatment of metastasis

The major cause of death from cancer is metastases that are resistant to conventional therapies. Metastases can be located in different organs and in different regions of the same organ that influence the response to therapy. Primary tumor in general and metastatic lesions in particular are biologically heterogeneous and contain multiple cell populations with diverse characteristics of growth rate, karyotype, cell surface receptors, antigenicity, immunogenicity, enzymes, hormone receptors, sensitivity to different cytotoxic drugs, production of extracellular matrix proteins, adhesion molecules, angiogenic potential, invasiveness, and metastatic potential. The outcome of metastasis depends on multiple interactions of metastatic cells with homeostatic mechanisms, which tumor cells often usurp. At the primary metastatic sites, tumor cells interact with host cells, such as endothelial cells, pericytes, epithelial cells, fibroblasts, myoepithelial cells, and leukocytes. The tissues composed by these normal cells are biologically unique, and the organ microenvironments they provide for tumor cells are also unique. The pathogenesis of a metastasis consists of many sequential steps that must be completed to produce clinically relevant lesions. Preferential metastasis of tumor cells to certain organs is independent of vascular anatomy, rate of blood flow, and number of tumor cells delivered to each organ. The outcome of metastasis depends on multiple continuous interactions between unique subpopulations of tumor cells (seed) and specific host factors within the organ microenvironment, such as vasculature (soil). Understanding the mechanisms responsible for the development of biological heterogeneity in primary cancers and metastases, and the processes that regulate tumor cell dissemination to and proliferation in distant tissues, is a major goal of research. For many years, all of our efforts to treat cancer metastases have concentrated on the inhibition or destruction of tumor cells. Because all cells in the body depend on an adequate supply of oxygen and nutrients, and on the ability of the circulatory system to remove toxic molecules, therapeutic regimens directed against tumor-associated endothelial cell can destroy tumor cells regardless of their biologic heterogeneity. New strategies to treat tumor cells by modulating their interaction with the organ microenvironment and by targeting receptors expressed on tumor-associated endothelial cells present unprecedented possibilities for the treatment of cancer metastasis.