Targeting TGFβ signal transduction for cancer therapy

Abstract

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 cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGFβ are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial–mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGFβ 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 TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGFβ in maintaining tissue homeostasis makes targeting TGFβ a challenge. Here, we review the pleiotropic functions of TGFβ in cancer initiation and progression, summarize the recent clinical advancements regarding TGFβ 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-TGFβ therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.

TRIM37 orchestrates renal cell carcinoma progression via histone H2A ubiquitination-dependent manner

“…Based on TCGA datasets and our RCC cohort, the dominant mRNA-high alteration across TRIM37 and TGF-β1 signaling still dictated the clinical. However, we should notice that TGF-β1 signaling has a dichotomous role in tumorigenesis, acting as a tumor suppressor in early stages and tumor promoter in late stages [ 47 ]. In late tumor stages, TGF-β1 signaling activation induces Smad2/3 phosphorylation and translocation to nucleus, thus exerting tumor EMT process, invasiveness and metastasis.…”

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

“…Both fresolimumab, a pan-TGF-β neutralizing antibody, and LY3022859, an anti-TβRII IgG1 monoclonal antibody, exhibited anti-tumor activity in a phase 1 clinical trial for various cancers (Colak and ten Dijke, 2017). TβR inhibitors, including LY2157299 and PF06952229, have being tested in clinical trials for patients with advanced or drug-resistant cancers (NCT03685591) (Liu et al, 2021).…”

Two Complementarity Immunotherapeutics in Non-Small-Cell Lung Cancer Patients—Mechanism of Action and Future Concepts

“…Bempegaldesleukin and ALT-803 have been used in combination with nivolumab and atezolizumab in patients with various types of cancer (including hematologic) in phase I clinical trials with promising results and satisfactory safety [ 79 , 80 ]. In turn, therapies in which anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies were combined with therapies aimed at reducing the activity of immunosuppressive cytokines such as TGF-β (tumour growth factor beta), M-CSF (macrophage-colony stimulating factor), and IL-10 seem to be less effective [ 81 , 82 ]. Addition of drugs blocking IL-10 or TGF-β function to classical immunotherapy increased the risk of adverse effects in the form of autoimmune reactions [ 83 , 84 , 85 , 86 ].…”