Abstract
Transforming growth factor (TGF)-β1 contributes to autocrine and paracrine functions in the tumor microenvironment (TME). The present study examined the effects of TGF-β1 crosstalk in TME and its role in mediating tumor formation and progression by targeted abrogation of TGF-β1 expression in metastatic cells in situ. Using species-specific primers, we found a significant increase in MMP-9 gene expression in the tumor-reactive stroma during late-stage metastasis in the lung. This effect was also confirmed in cancer-associated fibroblasts (CAFs) when co-cultured with the tumor cells. Knockdown of TGF-β1 expression in the tumor cells negatively affected matrix metalloproteinase (MMP)-9 gene expression. Fibroblasts, cultured in the presence of tumor cells with intact TGF-β1, showed a significant increase in proliferation rate, as well as expression of VEGF, bFGF, and SDF-1, which was not seen when TGF-β1 expression was abrogated in tumor cells. Absence of TGF-β1 in tumor cells also failed to result in myofibroblast differentiation. Co-implantation of CAFs and tumor cells with either intact TGF-β1 expression or devoid of TGF-β1 in vivo showed a significant increase in tumor growth kinetics in both cell types, suggesting a possible activation TGF-β receptor signaling in tumor cells in response to TGF-β from the TME.
Highlights
The concept of “seed and soil” suggests that by exerting regulatory functions and selective pressures, the tumor microenvironment (TME) determines and shapes the malignant phenotype of cancer cells and promotes metastasis[1]
In order to establish the significance of tumor-reactive stroma on tumor growth, and to determine if this influence is impacted by Transforming growth factor (TGF)-β1 in vivo, we first analyzed the expression of key molecules in both tumor and stromal compartments using species-specific primers
Using primers specific for human gene transcripts, the relative gene expression was determined in the tumor, and by using mouse-specific primers, contribution from the stromal cells was analyzed for TGF-β1, matrix metalloproteinase (MMP)-9 and MMP-2
Summary
The concept of “seed and soil” suggests that by exerting regulatory functions and selective pressures, the tumor microenvironment (TME) determines and shapes the malignant phenotype of cancer cells and promotes metastasis[1]. Previous studies from our laboratory and others have shown that TGF-β1 acts through autocrine signaling to promote epithelial-mesenchymal transition in the tumor cells, and increase migration and invasion[27,28,29]. Results of our studies indicated that silencing of TGF-β1 in tumor cells in situ exerted a significant effect on tumor fibroblast proliferation, differentiation and expression of protumorigenic growth factors, in particular, MMP9, as well as myofibroblast differentiation. Absence of TGF- β1 within tumor cells significantly decreased the growth of tumors in vivo, but co-transplantation of CAFs with tumor cells lacking TGF-β1 resulted in a significant increase in tumor growth These results indicate that development of TGF-β targeted therapies delivered to both tumor cells and cells in TME may offer better scope for minimizing the rate of organ metastasis
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