The roles of TGFβ in the tumour microenvironment

Abstract

The influence of the microenvironment on tumour progression is becoming clearer. In this Review we address the role of an essential signalling pathway, that of transforming growth factor-β, in the regulation of components of the tumour microenvironment and how this contributes to tumour progression.

Transforming Growth Factor-β Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2–Dependent Bladder Cancer Cell Migration and Invasion

“…10 TGF-b isoforms signal through canonical signaling pathways that include activation of SMAD proteins or through noncanonical signaling pathways that include phosphatidylinositol 3-kinase, RhoA, or TAK1 pathways. 10,11 Procancer effects may be driven by either canonical or noncanonical activity, with noncanonical activity shown to promote cancer cell invasion through induction of epithelial-mesenchymal transition (EMT), modulation of miRNA levels, and stimulation of mTOR activity. 12e15 Recent work has also suggested a role for TGF-b in regulating cancer progression through effects on the tumor microenvironment, including immune modulation and effects on cancer-associated fibroblasts.…”

“…12e15 Recent work has also suggested a role for TGF-b in regulating cancer progression through effects on the tumor microenvironment, including immune modulation and effects on cancer-associated fibroblasts. 10,11 The role of TGF-b in bladder cancer has been studied in significantly less detail. It has been shown that several singlenucleotide polymorphisms in genes encoding TGF-b1 and the TGF-b receptor I (TGFbRI) appear to be involved in bladder cancer risk and prognosis.…”

Reprogramming during epithelial to mesenchymal transition under the control of TGFβ

“…67 Many tissue-specific knockout mouse models have also been generated that clearly demonstrate the tumor suppressor activity of TGFb in a variety of organs, including the breast. 64 Some of these models have made clear that the more sensitive cell type to the tumor-derived TGFb are the resident fibroblasts of the tumor stroma or immune cells, such as T lymphocytes that contribute to enhanced tumor growth and cancer progression when TGFb receptor or Smad signaling is lost in these cells. 68 The other face of TGFb in tumor progression is a protumorigenic that seems to be more universal and usually is linked to every tumor type studied so far.…”

“…7 b) However, the pro-EMT action of TGFb represents a pro-tumorigenic and pro-metastatic aspect of the biology of this growth factor in the context of cancer. 64 In the sequence of multi-stage events of cancer progression, the pro-tumorigenic TGFb actions are usually thought to follow the tumor suppressive effects that TGFb exhibits as a factor that maintains epithelial tissue homeostasis. 64 In other words, the pro-tumorigenic, pro-EMT effects of TGFb, at the cellular level correlate to one of the hallmarks of the tumor suppressive effects TGFb has.…”

“…64 In the sequence of multi-stage events of cancer progression, the pro-tumorigenic TGFb actions are usually thought to follow the tumor suppressive effects that TGFb exhibits as a factor that maintains epithelial tissue homeostasis. 64 In other words, the pro-tumorigenic, pro-EMT effects of TGFb, at the cellular level correlate to one of the hallmarks of the tumor suppressive effects TGFb has. This complicated concept is explained by the observation that longterm exposure to TGFb bypasses the initial growth arrest response of mammary epithelial cells in culture, and proceeds with sustained cell proliferation in the presence of a mesenchymal phenotype.…”