Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: a systematic review

Abstract

The tumor microenvironment (TME) is comprised of many different cell populations, such as cancer-associated fibroblasts and various infiltrating immune cells, and non-cell components of extracellular matrix. These crucial parts of the surrounding stroma can function as both positive and negative regulators of all hallmarks of cancer development, including evasion of apoptosis, induction of angiogenesis, deregulation of the energy metabolism, resistance to the immune detection and destruction, and activation of invasion and metastasis. This review represents a summary of recent studies focusing on describing these effects of microenvironment on initiation and progression of the head and neck squamous cell carcinoma, focusing on oral squamous cell carcinoma, since it is becoming clear that an investigation of differences in stromal composition of the head and neck squamous cell carcinoma microenvironment and their impact on cancer development and progression may help better understand the mechanisms behind different responses to therapy and help define possible targets for clinical intervention.

Keywords: Epithelial-mesenchymal transition; Head and neck cancer; Tumor metabolism; Tumor microenvironment.

Fig. 1

Cellular constituents within the tumor microenvironment. In addition to the cancer cells, the tumor stroma is comprised of many other supporting cell populations as well as the extracellular matrix, which crucially contribute to the tumor progression. The characteristics and function of individual cell populations are described in the Table 1. Abbreviations: TAM tumor-associated macrophage, TAN tumor-associated neutrophil, MDSC myeloid-derived suppressor cell, NK natural killer cell, Treg regulatory T cell, CAF cancer-associated fibroblast, ECM extracellular matrix

Fig. 2

Metastatic cascade. a Acquisition of metastatic potential via epithelial-mesenchymal transition, degradation of the ECM (secretion of MMPs) and invasion through the basement membrane. Immune cells are recruited to the primary tumor site via cancer cell-derived and CAF-derived factors and cytokines. b Intravasation of cancer cells via invadopodia formation. Cancer cells acquire the resistance to anoikis. c Survival in the circulation. Cancer cells mediate the so-called tumor cell-induced platelet aggregation (TCIPA) to form a “platelet cloak” in order to be protected from TNF-α and to escape NK cells. Cancer cells evade the immune system by upregulation of indoleamine 2,3-dioxygenase (IDO). d Extravasation and formation of a secondary tumor site. Arrest of tumor cells on the endothelium, sequestration of tumor cells via NET formation, followed by transendothelial migration and invasion into the surrounding tissue. Abbreviations: TAM tumor-associated macrophage, TAN tumor-associated neutrophil, MDSC myeloid-derived suppressor cell, NK natural killer cell, Treg regulatory T cell, CAF cancer-associated fibroblast, ECM extracellular matrix, MMPs matrix metalloproteinases, MIF migration inhibitory factor, TGF-β transforming growth factor-β, EGF epithelial growth factor, HGF hepapocyte growth factor, TNF- α tumor necrosis factor-α, IDO indoleamine 2,3-dioxygenase, NET neutrophil extracellular trap