Fibroblasts and macrophages: Key players in the head and neck cancer microenvironment  Kusumawadee Utispan, Sittichai Koontongkaew  Journal of Oral Biosciences  Volume 59, Issue 1, Pages 23-30 (February 2017) DOI: 10.1016/j.job.2016.11.002 Copyright © 2016 Japanese Association for Oral Biology Terms and Conditions

Fig. 1 Schematic representation of tumor microenvironment (TME) components. TME consists of tumor cells, stromal cells such as carcinoma-associated fibroblast (CAF), tumor associated macrophage (TAM), pericyte and endothelial cell, extracellular matrix and soluble factors. Journal of Oral Biosciences 2017 59, 23-30DOI: (10.1016/j.job.2016.11.002) Copyright © 2016 Japanese Association for Oral Biology Terms and Conditions

Fig. 2 Heterogeneous origins of CAFs. CAFs of HNSCC could be derived from 1) resident fibroblasts, 2) bone marrow derived mesenchymal stem cells (BM MSCs) and 3) endothelial cell. However it is not clear whether BM MSCs and endothelial cells are the precursors of CAFs in HNSCC. Journal of Oral Biosciences 2017 59, 23-30DOI: (10.1016/j.job.2016.11.002) Copyright © 2016 Japanese Association for Oral Biology Terms and Conditions

Fig. 3 Schematic showing trans-differentiation of resident fibroblasts into CAFs. HNSCC-derived cytokines, chemokines and growth factors mediated paracrine trans-differentiation of resident normal fibroblasts into cancer associated fibroblasts (CAFs). TGF-β1, TGF-β3, TNF-α, IL-β and IL-6 constitute the most important soluble factors in CAF induction. Vimentin, α-SMA, FAP-1, FSP-1, Snail, CXCR4/CXCL12, IL-33 and PDGFR were upregulated whereas CAV-1, PTEN and p21 were downregulated in CAFs. Journal of Oral Biosciences 2017 59, 23-30DOI: (10.1016/j.job.2016.11.002) Copyright © 2016 Japanese Association for Oral Biology Terms and Conditions

Fig. 4 Interplay between tumor-associated macrophage (TAMs) and HNSCC cells. HNSCC cells could drive polarization of macrophage to TAMs. The expression of M2 surface markers (CD68, CD163, CD206 and FR-β) was increased in the polarized macrophages. TAMs upregulated anti-inflammatory cytokines such as IL-10 and TGF-β; and MIP-3α/CCL20. MIP-3α/CCL20 contributes the migration and invasion of HNSCC cells. Journal of Oral Biosciences 2017 59, 23-30DOI: (10.1016/j.job.2016.11.002) Copyright © 2016 Japanese Association for Oral Biology Terms and Conditions

Fig. 5 Effector mechanisms how CAFs and TAMs can enhance HNSCC cell progression. CAFs can affect HNSCC cells proliferation and invasion indirectly via paracrine signaling mediated by secreting soluble factors and/or direct contact. These direct and indirect effects are mediated by several soluble factors, cell-cell contacts and synthesized extracellular matrixes as shown in this figure. Cancer cells and CAFs attract each other, leading to a direct physical interaction that may be mediated by cell-surface adhesion molecules. TAMs enhance HNSCC cell progression through the signaling of TGF-β, IL-10 and MIP-3α/CCL20 receptors on HNSCC cell. Arrows point from the cell that secretes the mediator to the cell it acts upon. Journal of Oral Biosciences 2017 59, 23-30DOI: (10.1016/j.job.2016.11.002) Copyright © 2016 Japanese Association for Oral Biology Terms and Conditions

Journal of Oral Biosciences 2017 59, 23-30DOI: (10. 1016/j. job. 2016 Copyright © 2016 Japanese Association for Oral Biology Terms and Conditions