Abstract
It is well recognized that cancer cells subvert the phenotype of stromal naïve fibroblasts and instruct the neighboring cells to sustain their growth agenda. The mechanisms underpinning the switch of fibroblasts to cancer-associated fibroblasts (CAFs) are the focus of intense investigation. One of the most significant hallmarks of the biological identity of CAFs is that their tumor-promoting phenotype is stably maintained during in vitro and ex vivo propagation without the continual interaction with the adjacent cancer cells. In this review, we discuss robust evidence showing that the master cytokine Transforming Growth Factor-β1 (TGFβ-1) is a prime mover in reshaping, via epigenetic switches, the phenotype of stromal fibroblasts to a durable state. We also examine, in detail, the pervasive involvement of TGFβ-1 signaling from both cancer cells and CAFs in fostering cancer development, taking colorectal cancer (CRC) as a paradigm of human neoplasia. Finally, we review the stroma-centric anticancer therapeutic approach focused on CAFs—the most abundant cell population of the tumor microenvironment (TME)—as target cells.
Highlights
The reductionist viewpoint of neoplasia based on the autonomous behavior of tumor cells has been superseded by the mounting evidence that cancer is a complex micro-ecosystem comprising the transformed cells and heterotypic non-cancer cell populations resident in the tumor microenvironment (TME), [1,2]
In detail, the experimental evidence supporting the involvement of TGF-β1 in re-programming the epigenetic signature of stromal fibroblasts, we provide a brief description of the master cytokine as a busy purveyor of key biological information to target cells
We have focused our attention on the epigenetic instructions of TGF-β1 in the shaping of the cancer-associated fibroblasts (CAFs) phenotype
Summary
The reductionist viewpoint of neoplasia based on the autonomous behavior of tumor cells has been superseded by the mounting evidence that cancer is a complex micro-ecosystem comprising the transformed cells and heterotypic non-cancer cell populations resident in the tumor microenvironment (TME), [1,2]. Tumor stroma does not invariably act as a partner in crime but may restrain cancer growth, an inhibitory role shown in murine pancreatic cancer [11,12] In this context, the secretion by CAFs of pro-collagen fibrils into the extracellular matrix (ECM)—referred to as desmoplasia—serves as a barrier impeding the growth of cancer cells instead of enhancing their biological aggressiveness. One of the most significant hallmarks of the biological identity of CAFs is that their tumor-promoting phenotype remains stable during in vitro and ex vivo propagation without the continual interaction with neighboring cancer cells This intriguing finding, discussed in detail below, has been reported in a large number of studies [20,21,22,23]; see citations of this review. CAF phenotype? How the biological changes imposed on stromal fibroblasts by tumor cells and sustained by TGF-β1 affect cancer medicine?
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