226 HOXB9, a gene overexpressed in breast cancer, induces angiogenesis, invasion, and lung metastasis

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The secretion of soluble factors and extracellular matrix (ECM) proteins by tumor cells and surrounding stromal cells creates a tumor microenvironment (TME). Here, we reviewed a key role of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs or M2 macrophages) in the development and metastasis of head and neck squamous cell carcinoma (HNSCC).Interactions between HNSCC cells and CAFs induce overexpression of TGF-β, VEGF, TNF-α, HGF, IL-1α, IL1-β, IL-6, IL33, CXCL12, and MMPs in both cell types. Elevated concentrations of these soluble factors contribute to the growth, migration, and invasion of HNSCC cells. Periostin, an ECM protein, is also upregulated in CAFs during HNSCC, and it has been shown to accelerate HNSCC progression. Macrophages are a double-edged weapon, and any imbalance in the regulatory mechanisms may cause a shift from tumoricidal to tumorigenic activity of these cells. TAMs are common infiltrated inflammatory cells in HNSCC. Such TAMs express M2 markers, including FR-β, CD206, and TGF-β. TAMs contribute to HNSCC progression through various mediators. Increased levels of TGF-β, IL-10, and macrophage inflammatory protein-3 alpha (MIP-3α/CCL20) expression were found in TAMs in HNSCC. These soluble factors play a key role in the migration and invasion of HNSCC cells.CAFs can promote HNSCC progression through direct contact and/or paracrine signaling. Interactions between HNSCC cells and CAFs stimulate expression of various growth factors, cytokines, chemokines, MMPs, and periostin. TAMs in HNSCC upregulate the production of IL-1β, IL-10, and MIP-3α/CCL20, which are involved in tumorigenic processes.