Cellular context-dependent "colors" of transforming growth factor-beta signaling

Abstract

Transforming growth factor (TGF)-beta signaling has interesting characteristics in the context of cancer. Although perturbations of TGF-beta signaling are strongly implicated in cancer progression, TGF-beta signaling has both tumor-suppressive and tumor-promoting effects. For example, TGF-beta inhibits cancer cell proliferation in some cellular contexts, but promotes it in others. Although several approaches to treating cancer have been considered using TGF-beta-based therapeutic strategies, the contradictory behaviors of TGF-beta have made these approaches complex. To put them to practical use, either the tumor-suppressive or tumor-promoting arm needs to be specifically manipulated. However, there is virtually no method to specifically regulate a certain cell response induced by TGF-beta. In this review, we first consider the basic machinery of TGF-beta signaling, and describe several cell responses induced by TGF-beta stimulation in specific contexts. Mechanisms by which TGF-beta can induce several responses in a cellular context-dependent fashion are discussed with established paradigms and models. We also address perspectives on the specific control of only a subset of numerous cell responses induced by TGF-beta stimulation. Such methods will aid specific regulation of either the tumor-suppressive or tumor-promoting arm of the TGF-beta pathway and in realization of TGF-beta-based treatment of malignant tumors.

Figure 1

Intracellular transforming growth factor‐β (TGF‐β) signal transduction through Smad proteins. TGF‐β signals are transduced by type II receptor (TβRII) and type I receptor (ALK5), and their downstream Smad proteins. Activated Smad complex interacts with DNA‐binding transcription factors and binds to the promoter regions of TGF‐β target genes. co‐Smad, common‐partner Smad; P, phosphate; R‐Smad, receptor‐regulated Smad.

Figure 2

Cell responses induced by transforming growth factor‐β (TGF‐β). TGF‐β suppresses tumorigenesis and tumor progression through some mechanisms (indicated as blue circles), but cancer cells also take advantage of its several pro‐tumorigenic properties (red circles).

Figure 3

Several mechanisms of cellular context‐specific diversity of transforming growth factor‐β (TGF‐β)‐induced cell responses. (a) “Signal cross‐talk” model. In “context 1”, but not “context 2”, signal X is transduced in cells to modify downstream transducers of TGF‐β signaling and induce a certain “context 1”‐specific cell response. (b) “Genetic alterations” model. In “context 1”, expression of a certain target gene is induced by TGF‐β signaling. In “context 2”, the gene is deleted at the chromosomal level and TGF‐β stimulation fails to induce its expression. (c) “Epigenetics” model. In “context 1”, promoter regions of certain TGF‐β target genes adopt an “open conformation” and are exposed to the Smad complex. Conversely, in “context 2”, promoter regions of the same target genes adopt a “closed conformation” and the Smad complex fails to access the Smad‐binding elements. This difference results in differential responses to TGF‐β stimulation. (d) “Non‐coding RNA” model. In “context 2”, transcribed mRNAs of TGF‐β target genes are negatively regulated by non‐coding RNA (ncRNA). In “context 1”, such ncRNA is not expressed, resulting in translation of the mRNAs. (e) “Cofactors” model. Almost all TGF‐β target genes (A–I) are regulated by Smad proteins. Expression profiles of cofactors of Smad proteins differ between “context 1” and “context 2”, resulting in different responses to TGF‐β stimulation.

Figure 4

Development of a synexpression‐specific inhibitor of transforming growth factor‐β (TGF‐β) signaling. One of many TGF‐β‐induced cellular responses, human homolog of maternal Id‐like molecule (HHM) inhibits a subset of synexpression groups. An HHM‐like low molecular weight compound, which abrogates only one type of Smad–cofactor complex, inhibits only one TGF‐β‐induced cellular response.