This study was supported by the David and Sarah Babish Fund, The Bircher Research Fund (Sackler Faculty of Medicine), and The Ernest and Tova Turnheim Clinical Research Fund in Dentistry, all of Tel Aviv University, Israel, and by the Academy of Finland, the Finnish Cancer Society, and KEVO grants of Oulu University Hospital, Oulu, Finland.
Molecular crosstalk between cancer cells and tumor microenvironment components suggests potential targets for new therapeutic approaches in mobile tongue cancer
Version of Record online: 16 AUG 2012
© 2012 The Authors. Cancer Medicine published by Blackwell Publishing Ltd.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Volume 1, Issue 2, pages 128–140, October 2012
How to Cite
Dayan, D., Salo, T., Salo, S., Nyberg, P., Nurmenniemi, S., Costea, D. E. and Vered, M. (2012), Molecular crosstalk between cancer cells and tumor microenvironment components suggests potential targets for new therapeutic approaches in mobile tongue cancer. CANCER MEDICINE, 1: 128–140. doi: 10.1002/cam4.24
- Issue online: 3 OCT 2012
- Version of Record online: 16 AUG 2012
- Manuscript Accepted: 2 JUL 2012
- Manuscript Revised: 29 JUN 2012
- Manuscript Received: 12 JUN 2012
- David and Sarah Babish Fund
- The Bircher Research Fund
- The Ernest and Tova Turnheim Clinical Research Fund
- Tel Aviv University
- Academy of Finland
- Finnish Cancer Society
- Oulu University Hospital
- Cancer-associated fibroblasts;
- mobile tongue cancer;
- molecular crosstalk;
- myoma model;
- protumorigenic inflammatory cells
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.