TGF-beta signaling can have either tumor-suppressing or tumor-promoting effects in a cell- and context-dependent manner. The tumor suppressive effects of TGF-beta signaling arise from its ability to induce the expression of genes that inhibit cell proliferation, induce apoptosis, activate autophagy, inhibit growth factor signaling by stromal fibroblasts, suppress inflammation, and inhibit angiogenesis. These effects maintain homeostasis in normal tissues and prevent the early stages of tumor formation. As a result of mutations or epigenetic modifications that are introduced during cancer progression, cancer cells can become resistant to the suppressive effects of TGF-beta signaling. Loss of the tumor suppressive arm of the TGF-beta signaling pathway allows cancer cells to utilize this pathway to specifically promote processes that support tumor progression, including the stimulation of cell proliferation, immunosuppression, angiogenesis, cancer stem cell self-renewal, the epithelial to mesenchymal transition, and metastasis. Understanding the mechanisms by which the tumor-suppressing or tumor-promoting effects of TGF-beta signaling can be regulated may have therapeutic potential for inhibiting the progression of several different types of human cancer.
TGF-beta Signaling Regulates the Expression of Multiple Target Genes with Tumor-Suppressing & Tumor-Promoting Effects
Transforming growth factor (TGF)-beta is a multifunctional cytokine that can have either tumor-suppressing or tumor-promoting effects in a cell- and context-dependent manner. TGF-beta signals through a heterotetrameric receptor complex composed of two type I and two type II transmembrane serine/threonine kinase receptors. Following ligand binding, the type II receptor (TGF-beta RII) phosphorylates the type I receptor (TGF-beta RI), leading to the recruitment and phosphorylation of Smad2 and Smad3 in most cell types, or Smad1 and Smad5 in some cells depending on the type I receptor that is expressed. Activated Smad proteins associate with Smad4 and translocate to the nucleus, where they recruit additional transcriptional regulators, including DNA-binding transcription factors, co-activators, co-repressors, and chromatin remodeling factors, that control the expression of numerous target genes. Differential expression of these factors may be responsible for cell type-specific responses to TGF-beta. While many of the tumor-suppressing and tumor-promoting effects of TGF-beta have been shown to be directly dependent on Smad signaling, TGF-beta can also activate a number of other signaling pathways, including Ras/MAPK, Par6, RhoA/ROCK1, PI 3-K/Akt, p38, and JNK, which may contribute to the cancer-related effects of TGF-beta signaling in a Smad-dependent or Smad-independent manner. Activation of these signaling pathways is both cell type-specific and context-dependent. This BIObrief highlights genes that are regulated by TGF-beta signaling and the mechanisms by which these genes suppress or promote tumor formation and progression.