Abstract
Fibroblasts become cancer-associated fibroblasts (CAFs) in the tumor microenvironment after activation by transforming growth factor-β (TGF-β) and are critically involved in cancer progression. However, it is unknown whether the TGF superfamily member Nodal, which is expressed in various tumors but not expressed in normal adult tissue, influences the fibroblast to CAF conversion. Here, we report that Nodal has a positive correlation with α-smooth muscle actin (α-SMA) in clinical melanoma and colorectal cancer (CRC) tissues. We show the Nodal converts normal fibroblasts to CAFs, together with Snail and TGF-β signaling pathway activation in fibroblasts. Activated CAFs promote cancer growth in vitro and tumor-bearing mouse models in vivo. These results demonstrate that intercellular crosstalk between cancer cells and fibroblasts is mediated by Nodal, which controls tumor growth, providing potential targets for the prevention and treatment of tumors.
Highlights
Melanoma and colorectal cancer (CRC) are extremely malignant tumors due to their rapid development [1,2]
We show that Nodal contributes to the conversion of fibroblasts to cancer-associated fibroblasts (CAFs) in vitro through α-smooth muscle actin (α-SMA) detection compared to normal fibroblasts and those treated with self-derived Nodal protein, exogenous recombinant Nodal protein, or tumor cell-derived Nodal protein in a process that involves
Fibroblasts were activated by growth factors such as transforming growth factor-β (TGF-β), chemokines, and cytokines [21]
Summary
Melanoma and colorectal cancer (CRC) are extremely malignant tumors due to their rapid development [1,2]. Cancer-associated fibroblasts (CAFs), the most abundant stromal cells in the tumor microenvironment, have been consistently researched over the decades regarding their interaction with cancer cells [5,6,7]. Normal fibroblasts are quiescent and are activated during wound healing and by tumors, leading to identification by various markers such as α-smooth muscle actin (α-SMA, encoded by the ACTA2 gene) [8]. Activated fibroblasts play a critical role in the proliferation and metastasis of tumors and the key factor in the formation and development of metastasis lesions [9].
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