A cytokine in turmoil: Transforming growth factor beta in cancer

Abstract

Cancer remains one of the debilitating health threats to mankind in view of its incurable nature. Many factors are complicit in the initiation, progression and establishment of cancers. Early detection of cancer is the only window of hope that allows for appreciable management and possible limited survival. However, understanding of cancer biology and knowledge of the key factors that interplay at multi-level in the initiation and progression of cancer may hold possible avenues for cancer treatment and management. In particular, dysregulation of growth factor signaling such as that of transforming growth factor beta (TGF-β) and its downstream mediators play key roles in various cancer subtypes. Expanded understanding of the context/cell type-dependent roles of TGF-β and its downstream signaling mediators in cancer may provide leads for cancer pharmacotherapy. Reliable information contained in original articles, reviews, mini-reviews and expert opinions on TGF-β, cancer and the specific roles of TGF-β signaling in various cancer subtypes were retrieved from major scientific data bases including PubMed, Scopus, Medline, Web of Science core collections just to mention but a sample by using the following search terms: TGF-β in cancer, TGF-β and colorectal cancer, TGF-β and brain cancer, TGF-β in cancer initiation, TGF-β and cell proliferation, TGF-β and cell invasion, and TGF-β-based cancer therapy. Retrieved information and reports were carefully examined, contextualized and synchronized into a coherent scientific content to highlight the multiple roles of TGF-β signaling in normal and cancerous cells. From a conceptual standpoint, development of pharmacologically active agents that exert non-specific inhibitory effects on TGF-β signaling on various cell types will undoubtedly lead to a plethora of serious side effects in view of the multi-functionality and pleiotropic nature of TGF-β. Such non-specific targeting of TGF-β could derail any beneficial therapeutic intention associated with TGF-β-based therapy. However, development of pharmacologically active agents designed specifically to target TGF-β signaling in cancer cells may improve cancer pharmacotherapy. Similarly, specific targeting of downstream mediators of TGF-β such as TGF-β type 1 and II receptors (TβRI and TβRII), receptor-mediated Smads, mitogen activated protein kinase (MAPK) and importing proteins in cancer cells may be crucial for cancer pharmacotherapy.

Keywords: Carcinogenesis; Cytokines; MAPK; Pharmacotherapy; Smad; TGF-β.