Transforming growth factor-β and the hallmarks of cancer

Abstract

Tumorigenesis is in many respects a process of dysregulated cellular evolution that drives malignant cells to acquire six phenotypic hallmarks of cancer, including their ability to proliferate and replicate autonomously, to resist cytostatic and apoptotic signals, and to induce tissue invasion, metastasis, and angiogenesis. Transforming growth factor-β (TGF-β) is a potent pleiotropic cytokine that functions as a formidable barrier to the development of cancer hallmarks in normal cells and tissues. Paradoxically, tumorigenesis counteracts the tumor suppressing activities of TGF-β, thus enabling TGF-β to stimulate cancer invasion and metastasis. Fundamental gaps exist in our knowledge of how malignant cells overcome the cytostatic actions of TGF-β, and of how TGF-β stimulates the acquisition of cancer hallmarks by developing and progressing human cancers. Here we review the molecular and cellular mechanisms that underlie the ability of TGF-β to mediate tumor suppression in normal cells, and conversely, to facilitate cancer progression and disease dissemination in malignant cells.

Fig. 1

TGF-β and the hallmarks of cancer. Tumorigenesis converts TGF-β from a powerful tumor suppressor to a lethal tumor promoter that enables evolving cancer cells to acquire the 6 phenotypic traits or hallmarks of cancer. In normal epithelial, endothelial, and hematopoietic cells, TGF-β suppresses the formation of cancer hallmarks (red wheel). However, genetic or epigenetic events conspire to inactivate the tumor suppressing functions of TGF-β, thereby conferring oncogenic behaviors upon this multifunctional cytokine and its ability to stimulate the development of cancer hallmarks (green wheel). Bracketed numbers correspond to individual chapter subheadings that describe the indicated functions of TGF-β.

Fig. 2

Canonical and noncanonical TGF-β signaling. TGF-β stimulates responsive cells by binding and activating two transmembrane Ser/Thr protein kinase receptors termed, TGF-β type I (TβR-I) and type II (TβR-II). Activation of these ligand:receptor ternary complexes requires TβR-II to transphosphorylate TβR-I, which phosphorylates and activates Smad2/3. Once activated, Smad2/3 form heterocomplexes with Smad4, which collectively translocate to the nucleus to mediate canonical signaling events by TGF-β (left panel). Noncanonical TGF-β signaling takes place through the ability of TGF-β to stimulate MAP kinases, small GTPases, and PI3K/AKT, and to inhibit NF-κB. Altered coupling of TGF-β to its canonical and noncanonical effector pathways contributes to the development of oncogenic signaling by TGF-β. See text for specific details of TGF-β signaling in normal and malignant cells.