Figure 1. Macrophages Promote Tumor Initiation, Progression, and Malignancy.

A) Chronic smoldering inflammation in response to pathogens or chronic irritants creates a mutagenic and growth-promoting environment in the subepithelial stroma. This environment potentiates the acquisition of oncogenic mutations in the overlying epithelial cells. Central to the inflammatory process are activated macrophages, which are the major producers of reactive oxygen and nitrogen species as well as a wide range of growth factors. B) Spontaneous or hereditary mutations cause tumor initiation and progression in cancers not associated with inflammation. C) The hyperplastic lesions progress to an intraepithelial neoplasia. This process results in the recruitment of monocytes by chemoattractants from the blood, such as colony stimulating factor-1 (CSF-1) and the chemokine CCL-2. These monocytes differentiate into macrophages in the tumor. These macrophages, unlike those in the initiating inflammatory environment, are not classically activated but instead resemble trophic, immunomodulatory macrophages found during development. D) The transition from an intraepithelial neoplasia/adenoma to an early carcinoma is promoted by macrophages in part through their stimulation of the angiogenic switch. Macrophages deliver vascular endothelial growth factor (VEGF) and other angiogenic molecules in a temporal and spatial fashion to avascular areas resulting in angiogenesis. In addition, macrophages produce growth factors and proteases that facilitate the escape of tumor cells from their constraining basement membranes. Furthermore, macrophages suppress cytotoxic T cell responses to the invading tumor cells. E) After progression to malignancy, and as tumors because late carcinomas, macrophages are continuously recruited through similar mechanisms as before. In the tumor they differentiate into different subpopulations that have functions in: (1) angiogenesis, (2) tumor cell invasion and intravasation, and (3) immunosuppression. The dotted box designates an invasive microenvironment as defined in mouse models of breast cancer. In this model tumor cell motility and invasion is sparked by the production of growth factors/chemokines, such as CXCL12 that binds to its receptor (CXCR4) expressed on both macrophages and tumor cells. Once motility is initiated it is driven by an obligate epidermal growth factor (EGF)-CSF-1 paracrine loop with macrophages and tumor cells moving in lock step. Invasion also requires matrix formation and destruction through cathepsins and SPARC. Macrophages promote vasculogeneisis through angiogenic factors such as VEGF. Tumor cells egress through macrophage clusters on the blood vessels thus the macrophages increase both the invasion/intravasation of tumor cells and the number of vascular targets. This allows increased numbers of tumor cells to enter the circulation and thereby enhance tumor metastasis.