Molecular mechanisms of tumor dissemination in primary and metastatic brain cancers

Cancer is characterized by dysregulated growth control, overcoming of replicative senescence, and metastasis formation. Tumor dissemination distinguishes malignant from benign neoplasms and is mediated by homing receptors, their ligands, and proteinases. The homing receptor CD44 is frequently expressed on primary brain tumors and brain metastases, Its engagement by osteopontin physiologically induces macrophage chemotaxis, a mechanism that may be utilized by metastatic brain tumors in the process of dissemination, In host defense, osteopontin and its receptors, CD44 and integrin alpha (V)beta (3), play key roles in mediating delayed type hypersensitivity responses by activating macrophages to induce Th1 cytokines while inhibiting Th2 cytokines, Other metastasis associated gene products similarly contribute to host defenses. Hence, cancer spread is regulated by a set of developmentally nonessential genes which physiologically mediate stress responses, inflammation, wound healing, and neovascularization. Function of the relevant gene products is extensively modified post-transcriptionally and their dysregulation in cancer occurs on the levels of expression and splicing. Consistent patterns of organ preference by malignancies of particular tissue origin suggest a necessary connection between loss of growth control and senescence genes and expression of genes mediating the dissemination of tumor cells. (C) 2000 Elsevier Science Inc.