New advances in cancer therapy targeting TGF-β signaling pathways.
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ABSTRACT:
SUBMITTER: Shou M
PROVIDER: S-EPMC10746361 | biostudies-literature | 2023 Dec
REPOSITORIES: biostudies-literature
Publications
New advances in cancer therapy targeting TGF-β signaling pathways.
Shou Minyue M Zhou Hanyu H Ma Ling L
Molecular therapy oncolytics 20231203
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Project description:IntroductionThe transforming growth factor-β (TGF-β) signaling pathway has a pivotal role in tumor suppression and yet, paradoxically, in tumor promotion. Functional context dependent insights into the TGF-β pathway are crucial in developing TGF-β-based therapeutics for cancer.Areas coveredThis review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression by TGF-β. It is then explained how tumors can evade these effects and how TGF-β contributes to further growing and spreading of some of the tumors. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. This review focuses on anti-TGF-β based treatment and other options targeting activated pathways in tumors where the TGF-β tumor suppressor pathway is lost. Pre-clinical as well up to date results of the most recent clinical trials are given.Expert opinionTargeting the TGF-β pathway can be a promising direction in cancer treatment. However, several challenges still exist, the most important are differentiating between the carcinogenic effects of TGF-β and its other physiological roles, and delineating the tumor suppressive versus the tumor promoting roles of TGF-β in each specific tumor. Future studies are needed in order to find safer and more effective TGF-β-based drugs.
| S-EPMC3745214 | biostudies-literature
Project description:TGF-β is a multifunctional cytokine that plays an important role in both physiologic and pathologic processes, including cancer. Importantly, TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor or a tumor promoter, depending on the stage of tumor development. The aberrantly upregulated production of TGF-β has been strongly implicated in tumor progression, angiogenesis, and metastasis, as well as immune evasion. Therefore, hyperactivated TGF-β signaling is considered a potential therapeutic target for cancer therapy. Numerous inhibitors of overactivated TGF-β signaling have been developed, and some of them are currently in clinical trials. This review focuses on the TGF-β signaling that contributes to tumor progression and immune evasion in the tumor microenvironment and presents recent achievements on TGF-β signaling inhibition as a single or combined therapeutic approach in cancer therapy.
| S-EPMC7783242 | biostudies-literature
Project description:The transforming growth factor β (TGF-β) pathway, which is well studied for its ability to inhibit cell proliferation in early stages of tumorigenesis while promoting epithelial-mesenchymal transition and invasion in advanced cancer, is considered to act as a double-edged sword in cancer. Multiple inhibitors have been developed to target TGF-β signaling, but results from clinical trials were inconsistent, suggesting that the functions of TGF-β in human cancers are not yet fully explored. Multiple drug resistance is a major challenge in cancer therapy; emerging evidence indicates that TGF-β signaling may be a key factor in cancer resistance to chemotherapy, targeted therapy and immunotherapy. Finally, combining anti-TGF-β therapy with other cancer therapy is an attractive venue to be explored for the treatment of therapy-resistant cancer.
| S-EPMC8669610 | biostudies-literature
Project description:Transforming growth factor β (TGF-β) has long been identified with its intensive involvement in early embryonic development and organogenesis, immune supervision, tissue repair, and adult homeostasis. The role of TGF-β in fibrosis and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, overexpressed TGF-β causes epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, cancer-associated fibroblast (CAF) formation, which leads to fibrotic disease, and cancer. Given the critical role of TGF-β and its downstream molecules in the progression of fibrosis and cancers, therapeutics targeting TGF-β signaling appears to be a promising strategy. However, due to potential systemic cytotoxicity, the development of TGF-β therapeutics has lagged. In this review, we summarized the biological process of TGF-β, with its dual role in fibrosis and tumorigenesis, and the clinical application of TGF-β-targeting therapies.
| S-EPMC9033932 | biostudies-literature
Project description:BackgroundGastric cancer (GC) ranks as the fifth most prevalent cancer globally, and its pronounced invasiveness and propensity to spread provide significant challenges for therapy. At present, there are no efficacious medications available for the treatment of patients with GC. Isoliensinine (ISO), a bisbenzylisoquinoline alkaloid, was isolated from Nelumbo nucifera Gaertn. It possesses anti-tumor, antioxidant, and other physiological effects. Nevertheless, there is currently no available study on the impact of ISO on GC, and further investigation is needed to understand its molecular mechanism.MethodsISO target points and GC-related genes were identified, and the cross-target points of ISO and GC were obtained. We then examined cross-targeting and found genes that were differentially expressed in GCs. Kaplan-Meier survival curves were used to screen target genes, and the STRING database and Cytoscape 3.9.1 were used to construct protein-protein interactions and drug-target networks. In addition, molecular docking studies confirmed the interactions between ISO screen targets. Finally, in vitro tests were used to establish the impact of ISO on GC cells.ResultsThrough bioinformatics research, we have identified TGFBR1 as the target of ISO in GC. In addition, we noticed a substantial inhibition in GC cell proliferation, migration, and invasion activities following ISO treatment. Moreover, we noticed that ISO treatment effectively suppressed TGF-β-induced epithelial-mesenchymal transition (EMT) and activation of the TGF-β-Smad pathway. Furthermore, we discovered that siTGFBR1 nullified the impact of ISO on TGF-β-triggered migration, invasion, and activation of the TGF-β-Smad pathway.ConclusionOur research suggests that ISO specifically targets TGFBR1 and regulates the TGF-β-Smad signaling pathway to suppress the proliferation and migration of GC cells.
| S-EPMC11446791 | biostudies-literature
Project description:Transforming growth factor (TGF)-beta plays a pivotal role in regulation of progression of cancer through effects on tumor microenvironment as well as on cancer cells. TGF-beta inhibitors have recently been shown to prevent the growth and metastasis of certain cancers. However, there may be adverse effects caused by TGF-beta signaling inhibition, including the induction of cancers by the repression of TGF-beta-mediated growth inhibition. Here, we present an application of a short-acting, small-molecule TGF-beta type I receptor (TbetaR-I) inhibitor at a low dose in treating several experimental intractable solid tumors, including pancreatic adenocarcinoma and diffuse-type gastric cancer, characterized by hypovascularity and thick fibrosis in tumor microenvironments. Low-dose TbetaR-I inhibitor altered neither TGF-beta signaling in cancer cells nor the amount of fibrotic components. However, it decreased pericyte coverage of the endothelium without reducing endothelial area specifically in tumor neovasculature and promoted accumulation of macromolecules, including anticancer nanocarriers, in the tumors. Compared with the absence of TbetaR-I inhibitor, anticancer nanocarriers exhibited potent growth-inhibitory effects on these cancers in the presence of TbetaR-I inhibitor. The use of TbetaR-I inhibitor combined with nanocarriers may thus be of significant clinical and practical importance in treating intractable solid cancers.
| S-EPMC1800736 | biostudies-literature
Project description:Transforming growth factor βs (TGF-βs) are closely related ligands that have pleiotropic activity on most cell types of the body. They act through common heterotetrameric TGF-β type II and type I transmembrane dual specificity kinase receptor complexes, and the outcome of signaling is context-dependent. In normal tissue, they serve a role in maintaining homeostasis. In many diseased states, particularly fibrosis and cancer, TGF-β ligands are overexpressed and the outcome of signaling is diverted toward disease progression. There has therefore been a concerted effort to develop drugs that block TGF-β signaling for therapeutic benefit. This review will cover the basics of TGF-β signaling and its biological activities relevant to oncology, present a summary of pharmacological TGF-β blockade strategies, and give an update on preclinical and clinical trials for TGF-β blockade in a variety of solid tumor types.
| S-EPMC5630004 | biostudies-literature
Project description:Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide. In Egypt, CRC constitutes 4.2% of all cancers with median age is 50 years old.
| 2268489 | ecrin-mdr-crc
Project description:Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.
| S-EPMC9805914 | biostudies-literature
Project description:The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the "guardian of the genome". Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an "undruggable" target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.
| S-EPMC9977964 | biostudies-literature