Year: 2014
Type: editorial
Abstract: Growth factors and cytokines perform an important role in the etiology and progression of a number of different types of cancer ( 1 , 2 ). These peptides can function either as cis/autocrine or as trans/paracrine effectors for tumor cells and/or for different types of surrounding host cells that can influence tumor initiation, progression, and metastasis. The transforming growth factor β (TGF-β) superfamily, which is found in all metazoans, consists of 30 distinct ligands that include TGF-βs, activins, Nodal, bone morphogenetic proteins, and growth and differentiation factors ( 3 ). In mammals there are three different, highly homologous TGF-β isoforms, TGF-β1, TGF-β2, and TGF-β3, that are initially synthesized from a large inactive/latent precursor bound to other proteins and that need to be proteolytically processed by proprotein convertases to produce biologically active dimeric ligands. Activation of canonical (Smad-dependent) and noncanonical (Smad-independent) pathways by all members of this superfamily requires ligand binding to one of five distinct members of the type 2 serine/threonine kinase receptors and subsequent heterodimerization and serine/threonine transphosphorylation of one of seven different type 1 serine/threonine kinase receptors ( 3 , 4 ). For some ligands, additional coreceptors (eg, Cripto-1/Cryptic, endoglin, betaglycan, and Dragon) are needed for optimal ligand binding to and activation of the type 2–-type 1 receptor heterodimeric receptor complex. Reciprocally, there are inhibitory proteins (eg, Lefty, CD-109, BAMBI, COCO, Chordin, and Cerberus) that can bind to either ligands and/or the receptors and effectively antagonize signaling through this pathway ( 5 , 6 ). After phosphorylation of the type 1 receptor, the type 1 receptor becomes activated and can then bind to and phosphorylate several distinct R-SMAD proteins (Smads 2 or 3 for TGF-β, Activin, and Nodal signaling or Smads 1, 5, or 8 for growth and differentiation factors and bone morphogenetic protein signaling). The R-Smads can then form heteromeric complexes with Smad 4. These later events probably occur in early endosomes through a clathrin-dependent internalization pathway that requires accessory proteins such as SARA ( 7 , 8 ). The activated/phosphorylated R-Smad/Smad 4 complexes can then translocate to the nucleus where they directly regulate in a positive or negative fashion gene transcription. This occurs by the binding of the Smad 2 or 3 and Smad 4 complexes or the Smad 1, 5, or 8 and Smad 4 complexes to site-specific recognition sequences within the promoter regions of target genes that contain specific Smad binding elements. Various other DNA-binding cofactors such p300, CBP, and FOXH1 can synergistically amplify Smad-dependent gene transcription. Alternatively, activated type 1–type 2 receptor complexes can be internalized by cholesterol-enriched lipid rafts/caveolae, which can then result in the dampening of the canonical Smad-dependent signaling pathways by facilitating the inhibitory Smads, Smad 6 or Smad 7,in the activation of proteosome E3 ubiquitin ligases such as Smurfs (1 and 2), thereby leading to receptor degradation. Alternatively, activated type 1 and type 2 receptor complexes may be degraded through a caveolin/lysosomal pathway. Internalization through either of these two raft-dependent pathways may simultaneously engage noncanonical Smad-independent signaling pathways such as activation of c-src, ras, PI3K/Akt, p44 ERK, TRAF6, TAK1, p38 MAPK, JNK, or small GTPases such as RhoA. Finally, interaction between the Smad-dependent and Smad-independent signaling pathways with the Wnt/β-catenin, Notch, and Hedgehog pathways can amplify TGF-β signaling, especially during tumor progression, and can interact with different members of the TGF-β superfamily to regulate various phases of early embryonic development and to control the normal maintenance of adult tissue stem cells or their surrounding niche ( 9 , 10 ). TGF-βs are important regulators in a number of pathophysiological conditions, including wound healing, fibrosis, inflammation, immune suppression, and cancer. In particular, TGF-β1 has been shown to have a paradoxical or Jekyll-and-Hyde role in cancer ( 11 , 12 ). During the early stages of carcinoma development, TGF-β1 functions as a potent tumor suppressor by inhibiting cell proliferation and by promoting apoptosis and autophagy. Later, TGF-β1 can flip and actually promote tumor progression by facilitating cell invasion and metastasis. These latter responses to elevated TGF-β signaling may be due to the enhancement of epithelial mesenchymal transition by TGF-β1 and the association of the mesenchymal state with the expansion and maintenance of cancer stem cell populations ( 13 , 14 ). Likewise, TGF-β1 promotes tumor angiogenesis, functions as a potent immune suppressor, and assists in the recruitment of immune inhibitory components to the tumor and metastatic microenvironments ( 15 ). The mechanistic role of TGF-β in cancer development and tumor promotion as highlighted by Principe et al. ( 16 ) in this issue of the Journal has important implications in the design and use of different TGF-β pathway inhibitors, especially in the context of when these inhibitors are chronologically used to therapeutically treat different types and stages of cancer. The authors correctly note that the possible combinatorial use of inhibitors to other oncogenic signaling pathways may be particularly efficacious in the treatment of cancer with TGF-β pathway inhibitors, especially as common intracellular/effector nexus points between these different pathways are deciphered. As noted ( 16 ), the expression of TGF-β in early cancers has a favorable prognosis, whereas in more advanced tumors elevated TGF-β levels are associated with tumor size, aggressiveness, and metastatic spread. This advocates for the judicious and individualized use of TGF-β inhibitors in an oncogenic setting.
DOI: 10.1093/jnci/djt441
Author: D. Salomon
Language: English
Topic: TGF-β signaling in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,436
OpenAlex ID: W2129484112