Transforming Growth Factor‐β and Cancer

Abstract

Members of the TGF‐β super‐family regulate differentiation, proliferation, growth arrest, and apoptosis. TGF‐β mediated signalling proceeds via binding of the ligand to membrane receptor kinases, phosphorylation of TβRII receptor to the TβRI receptor kinase, and subsequently Smad activation, resulting in gene transcription. Dysfunctional TGF‐β signalling is associated with cancer development and progression, while TGF‐β ligand secretion and activation enhances tumour aggressiveness and correlates with metastatic behaviour in human tumours. Molecular exploitation of defective signalling effectors of this pathway is of major significance in detection and therapeutic targeting of human cancers. The present chapter summarizes the current knowledge on the contribution of dysfunctional TGF‐β1 signalling in tumour development and progression and its relevance in cancer prognosis and therapy.

TGF‐β receptor I inhibitor enhances response to enzalutamide in a pre‐clinical model of advanced prostate cancer

“…Transforming growth factor‐β (TGF‐β) has tumor‐inhibitory activity in the early stages of prostate tumorigenesis, but it promotes migration and invasion in late stages toward metastasis . TGF‐β1 signaling impairs growth by inhibiting proliferation and inducing apoptosis, and advances invasion and metastatic progression through two transmembrane serine/threonine kinase receptors, type I and type II receptors (TβRI and TβRII) . The TGF‐β intracellular signaling network centers around the receptor‐activated Smads and Smad4 (primarily in cytoplasm) that upon nuclear import induce transcriptional regulation .…”

“…The TGF‐β intracellular signaling network centers around the receptor‐activated Smads and Smad4 (primarily in cytoplasm) that upon nuclear import induce transcriptional regulation . The role of TGF‐β as an inhibitor of epithelial cell proliferation in normal homeostasis and a potent inducer of EMT is well‐established . Conditional abrogation of the essential signaling effector for TGF‐β, TβRII receptor leads to tumorigenic growth and metastatic spread of epithelial tissues in several human cancers, including prostate tumors .…”

Prostate tumor neuroendocrine differentiation via EMT: The road less traveled

“…Transforming growth factor-β (TGF-β) is a primary inducer of EMT [13] . TGF-β signaling controls prostate growth by inhibiting proliferation, inducing apoptosis, and promoting migration and invasion through two transmembrane serine/threonine kinases, type I and type II receptors (TβRI and TβRII) [26] . By the stimulation of these receptors, the intracellular effectors Smad2/3 form a complex with Smad4 allowing its nuclear translocation and transcriptional activation of target genes in response to TGF-β [27] .…”

“…By the stimulation of these receptors, the intracellular effectors Smad2/3 form a complex with Smad4 allowing its nuclear translocation and transcriptional activation of target genes in response to TGF-β [27] . In the early stages of tumorigenesis TGF-β has tumor-suppressor function via apoptosis induction, but it promotes tumor migration and invasion in late stages towards metastasis via effects on the actin cytoskeleton [26] , [28] . The biological and clinical impact of the dual functions of TGF-β as a cytokine with apoptosis-inducing, as well as EMT-promoting and invasive properties on human cancer development and metastatic progression has been intimately linked with several malignancies, including urothelial carcinoma [29] , [30] , breast cancer [31] and prostate cancer [26] .…”

Genetic Variation in the Transforming Growth Factor-β-Signaling Pathway, Lifestyle Factors, and Risk of Colon or Rectal Cancer

“…1 A functional TGF-β-signaling pathway can restrict cell growth by inhibiting cell proliferation, mediating differentiation, and inducing apoptosis; a dysfunctional TGF-β-signaling pathway is associated with cancer development, progression, and metastasis. 2 The TGF-β cytokine family includes bone morphogenetic proteins (BMP), which have been independently associated with colon and rectal cancer. 3 Regulation of TGF-β signaling involves interaction with Smad proteins and runt-related transcription factors (RUNX), including RUNX1, RUNX2 , and RUNX3 .…”