Sheikh Khansa Ali, Amjad Momna, Irfan Mahnoor Tabassum, Anjum Sumaira, Majeed Tanveer, Riaz Muhammad Usman, Jassim Amar Yasser, Sharif Elham Abdullatif M, Ibrahim Wisam Nabeel
Department of Biotechnology, Kinnaird College for Women, Lahore, Pakistan.
School of Computer Science, University College Dublin, Belfield, Dublin 4, Ireland.
Onco Targets Ther. 2025 Feb 18;18:233-262. doi: 10.2147/OTT.S493643. eCollection 2025.
Cancer persists as a ubiquitous global challenge despite the remarkable advances. It is caused by uncontrolled cell growth and metastasis. The Transforming Growth Factor-beta (TGF-β) signaling pathway is considered a primary regulator of various normal physiological processes in the human body. Recently, factors determining the nature of TGF-β response have received attention, specifically its signaling pathway which can be an attractive therapeutic target for various cancer treatments. The TGF-β receptor is activated by its ligands and undergoes transduction of signals via canonical (SMAD dependent) or non-canonical (SMAD independent) signaling pathways regulating several cellular functions. Furthermore, the cross talk of the TGF-β signaling pathway cross with other signaling pathways has shown the controlled regulation of cellular functions. This review highlights the cross talk between various major signaling pathways and TGF-β. These signaling pathways include Wnt, NF-κB, PI3K/Akt, and Hedgehog (Hh). TGF-β signaling pathway has a dual role at different stages. It can suppress tumor formation at early stages and promote progression at advanced stages. This complex behaviour of TGF-β has made it a promising target for therapeutic interventions. Moreover, many strategies have been designed to control TGF-β signaling pathways at different levels, inhibiting tumor-promoting while enhancing tumor-suppressive effects, each with unique molecular mechanisms and clinical implications. This review also discusses various therapeutic inhibitors including ligand traps, small molecule inhibitors (SMIs), monoclonal antibodies (mAbs), and antisense oligonucleotides which target specific components of TGF-β signaling pathway to inhibit TGF-β signaling and are studied in both preclinical and clinical trials for different types of cancer. The review also highlights the prospect of TGF-β signaling in normal physiology and in the case of dysregulation, TGF-β inhibitors, and different therapeutic effects in cancer therapy along with the perspective of combinational therapies to treat cancer.
尽管取得了显著进展，但癌症仍然是一个普遍存在的全球性挑战。它是由不受控制的细胞生长和转移引起的。转化生长因子-β（TGF-β）信号通路被认为是人体各种正常生理过程的主要调节因子。最近，决定TGF-β反应性质的因素受到了关注，特别是其信号通路，它可能是各种癌症治疗中一个有吸引力的治疗靶点。TGF-β受体被其配体激活，并通过调节几种细胞功能的经典（依赖SMAD）或非经典（不依赖SMAD）信号通路进行信号转导。此外，TGF-β信号通路与其他信号通路的相互作用显示了对细胞功能的可控调节。本综述重点介绍了各种主要信号通路与TGF-β之间的相互作用。这些信号通路包括Wnt、NF-κB、PI3K/Akt和Hedgehog（Hh）。TGF-β信号通路在不同阶段具有双重作用。它可以在早期抑制肿瘤形成，在晚期促进肿瘤进展。TGF-β的这种复杂行为使其成为治疗干预的一个有前景的靶点。此外，已经设计了许多策略来在不同水平上控制TGF-β信号通路，抑制肿瘤促进作用同时增强肿瘤抑制作用，每种策略都有独特的分子机制和临床意义。本综述还讨论了各种治疗抑制剂，包括配体陷阱、小分子抑制剂（SMIs）、单克隆抗体（mAbs）和反义寡核苷酸，它们靶向TGF-β信号通路的特定成分以抑制TGF-β信号，并在针对不同类型癌症的临床前和临床试验中进行了研究。该综述还强调了TGF-β信号在正常生理学中的前景，以及在失调情况下、TGF-β抑制剂以及癌症治疗中的不同治疗效果，以及联合治疗癌症的前景。
