Macrophage diversity enhances tumor progression and metastasis

Abstract

There is persuasive clinical and experimental evidence that macrophages promote cancer initiation and malignant progression. During tumor initiation, they create an inflammatory environment that is mutagenic and promotes growth. As tumors progress to malignancy, macrophages stimulate angiogenesis, enhance tumor cell migration and invasion, and suppress antitumor immunity. At metastatic sites, macrophages prepare the target tissue for arrival of tumor cells, and then a different subpopulation of macrophages promotes tumor cell extravasation, survival, and subsequent growth. Specialized subpopulations of macrophages may represent important new therapeutic targets.

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.

Figure 2. Macrophage Phenotypes and Tumorigenesis

Shown are six macrophage functions that provide extrinsic support to a tumor. Each of these extrinsic activities can be ascribed to a unique macrophage subpopulation. All of these macrophage subtypes are defined by the expression of the canonical markers Cd11b, F4/80 CSF-1R, and the absence of Gr1 but they are educated by microenvironmental cues to adopt a particular phenotype and perform the tasks as shown. The population listed as “perivascular” are probably the same as the invasive macrophage population as they have similar activities but they are localized to the abluminal surface of vessels often in cluster. * Populations whose transcriptomes have been analyzed

Figure 3. Macrophages Promote Seeding and Growth of Metastatic Cells

Myeloid cells, most likely macrophages, are recruited to the pre-metastatic niche in response to secreted products from the primary tumor. The metastatic target organs contain fibroblasts and elaborate extracellular matrix consisting of fibronectin and collagen. These niches direct and enhance tumor cell seeding in sites distant from the primary tumor. Once the tumor cells arrive at the metastatic site and begin to extravasate they recruit macrophages that are differentiated from blood borne monocytes. These macrophages enhance the ability of tumors cells to extravasate and promote their subsequent survival and growth. They continue to accumulate in metastatic lesions where they stimulate the growth and survival of the metastatic cells. Several growth factors and signaling pathways are important for these macrophage functions including vascular endothelial growth factor (VEGF) in the pre-metastatic site and colony stimulating factor-1 (CSF-1) for growth of the tumor cells.