The tale of transforming growth factor-beta (TGFbeta) signaling: a soigné enigma

Abstract

Transforming growth factor-beta (TGFbeta) is a secreted cytokine, which intricately controls a plethora of physiological and pathological processes during development and carcinogenesis. TGFbeta exerts antiproliferative effects and functions as a tumor suppressor during early stages of tumorigenesis, whereas at later stages it functions as a tumor promoter aiding in metastatic progression through an autocrine TGFbeta loop. Intricate knowledge of TGFbeta signaling and its regulation are still evolving. In this review, we make an attempt to showcase the associated enigma of TGFbeta signaling in its dual functional role as tumor suppressor and metastatic promoter during early and late stages of carcinogenesis, respectively.

Figure 1. Schematic Representation of Canonical and Non-canonical TGFβ Signaling Pathway

Binding of TGFβ to its cognate receptor initiates the signaling pathway. In the canonical pathway, activated type I receptors phosphorylates R-Smads, which subsequently form a complex with the Co-Smad, Smad4. The resulting R-Smads/Co-Smad complex translocates to the nucleus and interacts with distinct transcription factors to turn on or off transcription of many TGFβ-responsive genes that regulate cell proliferation and differentiation. Additionally, TGFβ activates different non-Smad pathways, including PI3K, Ras, Par6, Jnk/p38/MAPK pathways, which cumulatively regulate TGFβ-mediated functions.

Figure 2. Paradoxical Effects of TGFβ Signaling

In normal epithelium TGFβ functions as a tumor suppressor through its antiproliferative and pro-apoptotic effects. But with tumor progression, autocrine loops of TGFβ are activated and tumor cells become resistant to the antiproliferative effects of TGFβ. This change of sensitivity of tumor cells to TGFβ is accompanied by EMT with concomitant loss of adherens and tight junctions, downregulation of E-Cadherin expression, and increase in mesenchymal cell markers such as Dab2, N-Cadherin, and ILEI. EMT renders mobility to the tumor cells, which is a critical pre-requisite for metastatic progression of the tumor. Evidences exist for a role of both Smad-independent and Smad-dependent pathways in TGFβ-mediated EMT. It is important to note that both transcriptional and posttranscriptional regulatory pathways are involved in this process.