Macrophages and Extracellular Matrix in Breast Cancer: Partners in Crime or Protective Allies?

Abstract

Solid cancers such as breast tumors comprise a collection of tumor, stromal and immune cells, embedded within a network of tumor-specific extracellular matrix. This matrix is associated with tumor aggression, treatment failure, chemo- and radio-resistance, poor survival and metastasis. Recent data report an immunomodulatory role for the matrix in cancer, via the creation of niches that control the migration, localization, phenotype and function of tumor-infiltrating immune cells, ultimately contributing to escape of immune surveillance. Macrophages are crucial components of the immune infiltrate in tumors; they are associated with a poor prognosis in breast cancer and contribute to shaping the anti-tumor immune response. We and others have described how matrix molecules commonly upregulated within the tumor stroma, such as tenascin-C, fibronectin and collagen, exert a complex influence over macrophage behavior, for example restricting or enhancing their infiltration into the tumor, and driving their polarization towards or away from a pro-tumoral phenotype, and how in turn macrophages can modify matrix production in the tumor to favor tumor growth and metastasis. Targeting specific domains of matrix molecules to reinstate an efficient anti-tumor immune response, and effectively control tumor growth and spread, is emerging as a promising field offering a new angle for cancer therapy. Here, we review current knowledge on the interactions between tumor-associated macrophages and matrix molecules that occur within the tumor microenvironment of breast cancer, and discuss how these pathways can be targeted for new immunotherapies for hard to treat, desmoplastic tumors.

Keywords: breast cancer; extracellular matrix; immune infiltrate; immunotherapy; macrophages; tumor microenvironment.

Figure 1

Interactions between the ECM and macrophages in the tumor microenvironment. The tumor-specific ECM network has a panel of possible interaction pathways with macrophages, all of which ultimately impact the evolution of cancer growth and prognosis. ECM molecules including tenascin-C, collagen, fibronectin, osteopontin, hyaluronan, versican, and thrombospondin, are highly upregulated in primary and metastatic breast cancer and embed epithelial tumor cells, and are produced by tumor cells, CAF, or immune cells. The ECM presence is associated with an increased migration of macrophages to the tumor site, with which they directly interact via the expression of integrins including αMβ2, α2β2, α2β1, αvβ5, or α9β1, or are guided by patterns of chemokine-matrix gradients. On site, macrophages are able to degrade the ECM fibers by secreting MMP2, 9, 13, and 14, and reorganize the collagen fibers. Together with their capacity to help cancer cell migration, intra- and extravasation, and initiating the EMT process, ECM help TAM contribute to accelerated metastasis. The ECM network is able to drive TAM towards either pro-angiogenic, anti-tumor M1-like or anti-tumor M2-like phenotype depending of the local contexture. Moreover, the EDA and FBG domains of fibronectin and tenascin-C respectively are TLR4 ligands that can trigger inflammatory responses in myeloid cells.

Figure 2

In vivo blockade of the FBG domain of tenascin-C diminishes TAM numbers and restrict their presence to tumor edge in a mammary tumor model. Mammary tumors from mice that were treated with a blocking anti-FBG antibody (upper panels) or a control isotype (lower panels) were collected 21 days after engraftment and stained with anti-CD206 (light blue), anti-F4/80 (red), and anti-TNC (green) antibodies.