It is well established that cancer is a progressive disease, occurring in a series of well-defined steps, typically arising as a consequence of activating mutations (oncogenes) or deactivating mutations (tumor suppressor genes) in proliferating cells. From studies exploiting cultured tumor cells, two-stage carcinogenesis protocols in mice, and transgenic models of tumorigenesis, it is now evident that a single mutagenic event does not result in formation of a malignant tumor 1. Additional genetic and epigenetic events are necessary for progression to the tumor state. Initiated cells therefore require alterations rendering them self-sufficient for growth, insensitive to growth-inhibitory signals, resistant to programs of terminal differentiation, senescence, or apoptosis, as well as endowing them with unlimited self-renewal capacity, the ability to orchestrate and direct sustained angiogenesis, and the ability to invade and thrive in ectopic tissue environments 1. In this issue, Lin et al. 2 report that CSF-1 expression is a critical factor in a transgenic mouse model of mammary cancer development. This study provides compelling data that one subset of inflammatory cells, macrophages, and the dynamic microenvironment in which they live facilitate malignant outgrowth and eventual metastatic spread of evolving neoplastic cells.

CSF-1, a dimeric polypeptide growth factor, acts through a cell surface tyrosine kinase receptor encoded by the cfms protooncogene 3. This growth factor–receptor complex is an important regulator of proliferation, differentiation, and survival of macrophages and their bone marrow progenitors 3. Interestingly, elevated expression of CSF-1 and cfms has long been associated with poor prognosis in several types of human epithelial cancer, eg, breast, uterine, and ovarian 4. Elevated expression of CSF-1 also correlates with intense leukocyte infiltration during development and progression of human breast and ovarian cancer 5, 6; however, the functional significance of increased CSF-1 and infiltrating leukocytes in neoplastic tissue has remained unclear. The study by Lin et al. provides a connection between autocrine CSF-1 expression, macrophage infiltration, and development of late-stage mammary carcinoma and its pulmonary metastases 2. The broader implications of this study are that inflammatory cells potentiate neoplastic progression via paracrine factors that are as important to tumor evolution as oncogenes and tumor suppressor genes (Fig. 1).