Abstract
Tumor microenvironment (TME) is an active player in carcinogenesis and changes in its composition modify cancer growth. Carcinoma-associated fibroblasts, bone marrow-derived multipotent mesenchymal stem cells (BMMSCs), and inflammatory cells can all affect the composition of TME leading to changes in proliferation, invasion and metastasis formation of carcinoma cells. In this study, we confirmed an interaction between BMMSCs and oral tongue squamous cell carcinoma (OTSCC) cells by analyzing the invasion progression and gene expression pattern. In a 3-dimensional myoma organotypic invasion model the presence of BMMSCs inhibited the proliferation but increased the invasion of OTSCC cells. Furthermore, the signals originating from OTSCC cells up-regulated the expression of inflammatory chemokines by BMMSCs, whereas BMMSC products induced the expression of known invasion linked molecules by carcinoma cells. Particularly, after the cell-cell interactions, the chemokine CCL5 was abundantly secreted from BMMSCs and a function blocking antibody against CCL5 inhibited BMMSC enhanced cancer invasion area. However, CCL5 blocking antibody did not inhibit the depth of invasion. Additionally, after exposure to BMMSCs, the expression of type I collagen mRNA in OTSCC cells was markedly up-regulated. Interestingly, also high expression of type I collagen N-terminal propeptide (PINP) in vivo correlated with the cancer-specific mortality of OTSCC patients, whereas there was no association between cancer tissue CCL5 levels and the clinical parameters. In conclusion, our results suggest that the interaction between BMMSC and carcinoma cells induce cytokine and matrix molecule expression, of which high level of type I collagen production correlates with the prognosis of OTSCC patients.
Highlights
The tumor microenvironment (TME) undergoes extensive changes during tumor growth [1] and the progression of a tumor is dependent on stromal elements [2]
Cells in the microenvironment, including carcinoma-associated fibroblasts (CAFs), bone marrow-derived multipotent mesenchymal stromal cells (BMMSCs), tumor associated macrophages (TAMs) and other inflammatory cells as well as vascular cells all contribute to varying degrees to the hallmarks of cancer and cancer ecosystem [3] [4]
The effect of BMMSCs on tongue cancer cell invasion was examined in the myoma organotypic model [29] that is more faithful to the human TME than previous animal tissue derived models
Summary
The tumor microenvironment (TME) undergoes extensive changes during tumor growth [1] and the progression of a tumor is dependent on stromal elements [2]. Cells in the microenvironment, including carcinoma-associated fibroblasts (CAFs), bone marrow-derived multipotent mesenchymal stromal cells (BMMSCs), tumor associated macrophages (TAMs) and other inflammatory cells as well as vascular cells all contribute to varying degrees to the hallmarks of cancer and cancer ecosystem [3] [4]. They produce extracellular matrix, growth factors, cytokines, proteases and their regulators, and provide a microenvironment supporting cancer cell proliferation and immortality, inducing angiogenesis, reprogramming energy metabolism, evading immune destruction, and favoring invasion and metastasis [5],[1,3,6], [4]. 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]
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