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Targeting TGF? signal transduction for cancer therapy.

ABSTRACT: Transforming growth factor-? (TGF?) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGF? family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGF?, a well-characterized family member that has a dichotomous role in cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGF? are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial-mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGF? to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition, promotion of angiogenesis, and suppression of the anti-tumor immune reaction. The pro-oncogenic roles of TGF? have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGF? in maintaining tissue homeostasis makes targeting TGF? a challenge. Here, we review the pleiotropic functions of TGF? in cancer initiation and progression, summarize the recent clinical advancements regarding TGF? signaling interventions for cancer treatment, and discuss the remaining challenges and opportunities related to targeting this pathway. We provide a perspective on synergistic therapies that combine anti-TGF? therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.

SUBMITTER: Liu S

PROVIDER: S-EPMC7791126 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Targeting TGFβ signal transduction for cancer therapy.

Liu Sijia S Ren Jiang J Ten Dijke Peter P

Signal transduction and targeted therapy 20210108 1

Transforming growth factor-β (TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGFβ, a well-characterized family member that has a dichotomous role in canc ...[more]

PMID: 33414388

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Project description:Networks of fixed topology are used to summarize the collective understanding of the flow of signaling information within a cell (i.e., canonical signaling networks). Moreover, these canonical signaling networks are used to interpret how observed oncogenic changes in protein activity or expression alter information flow in cancer cells. However, creating a novel branch within a signaling network (i.e., a noncanonical edge) provides a mechanism for a cell to acquire the hallmark characteristics of cancer. The objective of this study was to assess the existence of a noncanonical edge within a receptor tyrosine kinase (RTK) signaling network based upon variation in protein expression alone, using a mathematical model of the early signaling events associated with epidermal growth factor receptor 1 (ErbB1) signaling network as an illustrative example. The abundance of canonical protein-RTK complexes (e.g., growth factor receptor bound protein 2-ErbB1 and Src homology 2 domain containing transforming protein 1-ErbB1) were used to establish a threshold that was correlated with ligand-dependent changes in cell proliferation. Given the available data, the uncertainty associated with this threshold was estimated using an empirical Bayesian approach. Using the variability in protein expression observed among a collection of breast cancer cell lines, this model was used to assess whether a noncanonical edge (e.g., Irs1-ErbB1) exceeds the threshold and to identify cell lines where this noncanonical edge is likely to be observed. Taken together, the simulations suggest that the topology of signal transduction networks within cells is influenced by quantitative parameters, such as protein expression and binding affinity. Moreover, forming this noncanonical pathway was not due solely to overexpression of the cell surface receptor but was influenced by overexpression of all members of the multiprotein complex. Multivariate alterations in expression of signaling proteins in cancer cells may activate noncanonical pathways and may rewire the signaling network within a cell.

Dataset Information

Targeting TGF? signal transduction for cancer therapy.

Publications

Targeting TGFβ signal transduction for cancer therapy.

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