Microbial Colonization and Inflammation as Potential Contributors to the Lack of Therapeutic Success in Oral Squamous Cell Carcinoma

Abstract

This review discusses the microenvironment of evolving and established conventional oral squamous cell carcinoma, by far the most common oral cancer. The focus of this paper is mainly on the more recent data that describe the role of microorganisms, host-microbial interactions, and in particular, the contributions of cell-surface toll-like receptors on immune system cells and on normal and malignant epithelial cells to their functions that support carcinogenesis. Because carcinomas arising at various host surfaces share much in common, additional information available from studies of other carcinomas is included in the discussion. Accumulating evidence reveals the complex toll-like receptor-mediated tumor-supporting input into many aspects of carcinogenesis via malignant cells, stromal immune cells and non-immune cells, complicating the search for effective treatments.

Keywords: carcinogenesis; inflammation; microbiome; oral epithelial dysplasia; oral mucosa; oral squamous cell carcinoma; toll-like receptors; tumor microenvironment.

Figure 1

Overview of the oral mucosal environment in the evolution of oral squamous carcinogenesis. (A) Icons used to depict components of the figures in this review. PMN, neutrophil; Eo, eosinophil; mo, monocyte; MC, mast cell; B, B cell; T, T cell; NK, NK cell; mph, macrophage; DC, dendritic cell; L, lymphocyte; TLR, toll-like receptor; EC, epithelial cell; CC, cancer cell; CSC, cancer stem cell. (B) Oral mucosa is colonized by microbes, increasing in amount and penetration with carcinogenesis. Normal basal keratinocytes express high levels of TLR2, possibly both cell-surface and cytoplasmic, according to immunohistochemistry. High levels of TLR2 (as well as TLR5) are found in epithelial dysplasia keratinocytes and OSCC cells. The infiltrating immune system cells increase with progression to dysplasia and OSCC and acquire pro-tumor phenotypes in the TME of established OSCC.

Figure 2

Summary of TLR activities in normal keratinocytes. (Top) In the absence of inflammatory cytokines TLR2 ligands stimulate a stronger barrier—reduced permeability and production of antimicrobial peptides (AMP), and may also induce chemokine CXCL8. (Bottom) In the presence of inflammatory mediators IFN-gamma or IL-17, TLR expression increases, and TLR ligands stimulate keratinocyte participation in inflammation with production of IL-1beta and TNF-alpha. TNF-alpha and possibly other inflammatory mediators contribute to increased permeability. References: Beklen et al. [92], Beklen et al., [93], Guo et al. [94], McClure and Massari [95], Mullin and Snock [86], Sugawara et al. [97], and Uehara et al. [99].

Figure 3

Outcomes of interactions between OSCC cells, monocytes and a TLR4 ligand E. coli LPS. OSCC cells selectively inhibit LPS-induced TNF-alpha production in monocytes-macrophages without disrupting IL-6. OSCC and monocyte-macrophage-derived IL-6 activates STAT3 in most cells. LPS-induced CCL2 and CXCL8 recruit monocytes and neutrophils IL-6-induced STAT3 activation upregulates VEGF-A and VEGF-C production, stimulating vasculogenesis and lymphangiogenesis, respectively. References: Kurago et al. [109], Lam-ubol et al. [179], Palani et al. [96], Rajarathnam et al. [180], and Shinriki et al. [181].

Figure 4

Carcinoma cell-intrinsic pro-tumor effects of TLR activities. TLR ligands activate NF-kB and ERK1/2 MAPK pathways leading to increased proliferation, improved survival, and resistance to drugs. The induction of STAT3-activating factors (such as IL-6) can also contribute to CSC expansion and survival. So far the role of p-gp has been demonstrated in normal stem cells. References: Frank et al. [219], Kurago et al. [109], Palani et al. [96], Shinriki et al. [181], Szczepanski et al. [110], and Yeh et al. [162].