The Synergistic Cooperation between TGF-β and Hypoxia in Cancer and Fibrosis

Abstract

Transforming growth factor β (TGF-β) is a multifunctional cytokine regulating homeostasis and immune responses in adult animals and humans. Aberrant and overactive TGF-β signaling promotes cancer initiation and fibrosis through epithelial-mesenchymal transition (EMT), as well as the invasion and metastatic growth of cancer cells. TGF-β is a key factor that is active during hypoxic conditions in cancer and is thereby capable of contributing to angiogenesis in various types of cancer. Another potent role of TGF-β is suppressing immune responses in cancer patients. The strong tumor-promoting effects of TGF-β and its profibrotic effects make it a focus for the development of novel therapeutic strategies against cancer and fibrosis as well as an attractive drug target in combination with immune regulatory checkpoint inhibitors. TGF-β belongs to a family of cytokines that exert their function through signaling via serine/threonine kinase transmembrane receptors to intracellular Smad proteins via the canonical pathway and in combination with co-regulators such as the adaptor protein and E3 ubiquitin ligases TNF receptor-associated factor 4 (TRAF4) and TNF receptor-associated factor 6 (TRAF6) to promote non-canonical pathways. Finally, the outcome of gene transcription initiated by TGF-β is context-dependent and controlled by signals exerted by other growth factors such as EGF and Wnt. Here, we discuss the synergistic cooperation between TGF-β and hypoxia in development, fibrosis and cancer.

Keywords: HIF-1α/2α; Smad; TGF-β; TRAF6; cancer; fibrosis; hypoxia.

Figure 4

A graphical illustration of several organs where TGF-β and hypoxia contribute to tumor aggressiveness; included are references to studies that have investigated synergistic cooperation between TGF-β and hypoxia in respective cancer types. See also Table 1.

Figure 1

(A) A graphical illustration of canonical (left) and non-canonical (right) TGF-β signaling. In canonical TGF-β signaling, TGF-β ligand binds to TGFβRI (TβRI) and TGFβRII (TβRII) receptors, resulting in their activation in a hetero-tetrameric complex. The intracellular Smad2/3 are next activated by phosphorylation, initiated by TGFβRI; pSmad2/3 form a complex with Smad4 and, together with certain transcription factors (TF), activate specific targets genes that contain Smad-binding elements (SBEs), implicated in growth inhibition, apoptosis, ECM synthesis, and immune response. In the non-canonical signaling pathway, TGF-β induces the expression of TRAF6 and ubiquitinates it in a Lys63-dependent manner, promoting its catalytic activity. TRAF6 then activates TACE and PSEN1, resulting in the proteolytic cleavage of TGFβRI, generating the soluble TGFβRI intracellular domain (TGFβRI-ICD/ TβRI-ICD). The endosomal adaptor proteins APPL1/APPL2 and intact microtubules are required for the translocation of TGFβRI-ICD to the nucleus, where it contributes to activating specific target genes. Other modes of non-canonical TGF-β signaling pathways are also shown. Adapted from [43,44,46,47,48,49,50,51,54]. (B) TGF-β signaling can also induce EMT through the activation of non-Smad pathways such as Rho GTPase and via the phosphorylation of the polarity protein PAR6, leading to cytoskeletal rearrangements and the breakdown of epithelial cell junctions, respectively. Adapted from [52,53,54,55,56].

Figure 2

A graphical illustration of varied regions in solid tumors. The tumor region close to the blood vessel contains oxygenated cells, followed by a region of hypoxic cells and necrotic cells. Adapted from [72,73].

Figure 3

A graphical illustration of normoxia and hypoxia. HIF-α is degraded by VHL under normoxic conditions. Under hypoxic conditions, HIF-α is stabilized and induces the expression of target genes that are associated with tumor promotion. SSB (single-strand break), CSC (cancer stem cell). Adapted from [79].

Figure 5

A graphical illustration of crosstalk between TGF-β and hypoxia in renal cell carcinoma and solid tumors. TGF-β and hypoxia pathways promote tumor progression in renal cell carcinoma (A) and other solid tumors (B) through TGFβRI (TβRI) and HIF-1α/2α and enhances expression of VEGF, CA9 and GLUT1 [2,67,73,123,124]. Adapted from [67].