Molecular crosstalk between cancer cells and tumor microenvironment components suggests potential targets for new therapeutic approaches in mobile tongue cancer.
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.
Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel.
Dan
D
Dayan
Tuula
T
Salo
Sirpa
S
Salo
Pia
P
Nyberg
Sini
S
Nurmenniemi
Daniela Elena
DE
Costea
Marilena
M
Vered
D000368:Aged; D054338:Cell Transdifferentiation; D058750:Epithelial-Mesenchymal Transition; D055354:Exosomes; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018655:Lymphocyte Count; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014062:Tongue Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
Cancer-associated fibroblasts; mobile tongue cancer; molecular crosstalk; myoma model; protumorigenic inflammatory cells