Crosstalk between cancer stem cells and the tumor microenvironment drives progression of premalignant oral epithelium

Abstract

Cancer stem cells (CSC) are a subpopulation of cancer cells that exhibit properties of self-renewal and differentiation and have been implicated in metastasis and treatment failures. There is mounting evidence that carcinogen-initiated mucosal epithelial stem cells acquire the CSC phenotype following exposure to environmental or infectious mutagens and are responsible for promoting the malignant transformation of premalignant (dysplastic) epithelium. CSC further contribute to the progression of dysplasia by activating signaling pathways through crosstalk with various cell populations in the tumor microenvironment. Two cell types, tumor-associated macrophages (TAM) and vascular endothelial cells (EC) nurture CSC development, support CSC stemness, and contribute to tumor progression. Despite mounting evidence implicating CSC in the initiation and progression of dysplastic oral epithelium to squamous cell carcinoma (SCC), the molecular mechanisms underlying these synergistic biological processes remain unclear. This review will examine the mechanisms that underlie the transformation of normal epithelial stem cells into CSC and the mechanistic link between CSC, TAM, and EC in the growth and the malignant conversation of dysplastic oral epithelium.

Keywords: angiogenesis; cancer stem cells; carcinogenesis; endothelial cells; epithelial dysplasia; macrophages; premalignant; tumor progression.

Figure 1

Key genetic and molecular events during the progression of premalignant oral epithelium to oral squamous cell carcinoma are depicted in this multistep model of histologic progression. The histological sequence of events seen in the progression of premalignant epithelium is initiated in the basal cell layer following exposure of stem cells to carcinogens. This results in irreversible damage and or epigenetic modification of DNA resulting in the emergence of a population of cancer stem cells. The subsequent exposure to promoting agents contribute to the clonal expansion of initiated cancer stem cells. With the continued exposure to promoting agents, a subset of initiated stem cells undergoes malignant conversion (i.e., carcinoma in situ). Over time cancer stem cells and bulk tumor cells acquire additional mutations many which involve loss or inactivation of tumor suppressor genes (TP53, PTEN, LOH) and overexpression of molecular mediators (Il-6, IL-8, VEGFR, PDGF). The bidirectional exchange of information between cancer and host cells contribute to acquisition of more aggressive phenotypes by the invading cancer cells (100X magnification, inset, white boarder, 400X).

Figure 2

Reciprocal exchange of cytokine mediators between cancer stem cells (CSC), endothelial cells (EC), and macrophages (M1 and M2). CSC located in the basal layer of dysplastic epithelium produce, among others, the angiogenic mediators VEGF and IL-8. EC in turn produce IL-6 which plays an important role in maintaining the CSC stemness. EC also play a role in transitioning proinflammatory M1 macrophages to protumor M2 macrophages via production of IL-6, colony stimulating factor 1 (CSF-1), TGF-β1, macrophage inhibitory cytokine 1 (MIC-1). Lastly, M2 macrophages promote angiogenesis via production of VEGF and IL-8 and help maintain CSC stemness through IL-8 production.