Molecular crosstalk between cancer cells and tumor microenvironment components suggests potential targets for new therapeutic approaches in mobile tongue cancer

Abstract

We characterized tumor microenvironment (TME) components of mobile tongue (MT) cancer patients in terms of overall inflammatory infiltrate, focusing on the protumorigenic/anti-inflammatory phenotypes and on cancer-associated fibroblasts (CAFs) in order to determine their interrelations and associations with clinical outcomes. In addition, by culturing tongue carcinoma cells (HSC-3) on a three-dimensional myoma organotypic model that mimics TME, we attempted to investigate the possible existence of a molecular crosstalk between cancer cells and TME components. Analysis of 64 cases of MT cancer patients revealed that the overall density of the inflammatory infiltrate was inversely correlated to the density of CAFs (P = 0.01), but that the cumulative density of the protumorigenic/anti-inflammatory phenotypes, including regulatory T cells (Tregs, Foxp3+), tumor-associated macrophages (TAM2, CD163+), and potentially Tregs-inducing immune cells (CD80+), was directly correlated with the density of CAFs (P = 0.01). The hazard ratio (HR) for recurrence in a TME rich in CD163+ Foxp3+ CD80+ was 2.9 (95% CI 1.03–8.6, P = 0.043 compared with low in CD163+ Foxp3+ CD80+). The HR for recurrence in a TME rich in CAFs was 4.1 (95% confidence interval [CI] 1.3–12.8, P = 0.012 compared with low in CAFs). In vitro studies showed cancer-derived exosomes, epithelial–mesenchymal transition process, fibroblast-to-CAF-like cell transdifferentiation, and reciprocal interrelations between different cytokines suggesting the presence of molecular crosstalk between cancer cells and TME components. Collectively, these results highlighted the emerging need of new therapies targeting this crosstalk between the cancer cells and TME components in MT cancer.

Human Bone Marrow Mesenchymal Stem Cells Induce Collagen Production and Tongue Cancer Invasion

“…However, the expression of CCL5 was not associated with the clinical outcome of the OTSCC patients (not shown). The expression of CCL5 was further studied in normal primary oral fibroblasts (NOF, [28]) and CaDEC12 cells [11]. Immunoassay detecting secreted CCL5 in cell culture media showed very low or no CCL5 expression in normal fibroblasts, but considerable higher expression in CaDEC12 cells (Figure 4C).…”

“…Human gingival fibroblasts (GF) used in this study were obtained from biopsies of healthy gingiva as described earlier [27]. Carcinoma-associated fibroblasts (CaDEC12) [11]derived from a specimen of tongue SCC as well as normal oral fibroblasts (NOFs) [28] were cultured in the same media as GFs [27]. All cells were cultured in a humidified atmosphere of 5% CO 2 at 37°C.…”

“…Our recent study profiled the molecular cross-talk between oral cancer cells and TME and presented that the examination of known pro-tumorigenic components of the inflammatory infiltrate, such as regulatory T cells, TAM2 (i.e. TAM subtype supporting invasion and metastasis) cells, and regulatory T-cell inducing immune cells, revealed negative impact for patients similar to CAFs [11]. …”

Hepatic Stellate Cells Secreted Hepatocyte Growth Factor Contributes to the Chemoresistance of Hepatocellular Carcinoma

“…Therefore, a thorough understanding of the mechanisms by which the residual tumor cells survive chemotherapy treatment is essential to find out more effective chemotherapeutic strategies. Recent studies have proposed that both genetic alterations of cancer cells and their surrounding microenvironment could be associated with chemoresistance [16]. Stromal cells could potentially induce chemoresistance acquisition in tumor cells, including cell-cell and cell-matrix interactions, local release of soluble factors and so on [17].…”

Endostatin induces proliferation of oral carcinoma cells but its effect on invasion is modified by the tumor microenvironment

“…Primary human gingival fibroblasts (GFs) were obtained from biopsies of healthy gingiva [25]. Cancer associated fibroblasts (CAFs) were derived from tongue squamous cell carcinoma [26]. GFs and CAFs were cultured in DMEM supplemented with 100 U/ml penicillin, 100 mg/ml streptomycin, 50 mg/ml ascorbic acid, 250 ng/ml fungizone, 1 mM sodium pyruvate (Sigma-Aldrich) and 10% FBS (Perbio Science).…”