Role of Radiation-induced TGF-beta Signaling in Cancer Therapy

Abstract

TGF-β signaling regulates several different biological processes involving cell-growth, differentiation, apoptosis, motility, angiogenesis, epithelial mesenchymal transition and extracellular matrix production that affects embryonic development and pathogenesis of various diseases, including cancer, its effects depending on the cellular context and physiological environment. Growth suppression mediated by TGF-β signaling often associated with inhibition of c-myc, cdks and induction of p15, p27, Bax and p21. Despite its growth inhibitory effect, in certain conditions TGF-β may act as a promoter of cell proliferation and invasion. Loss of responsiveness to growth suppression by TGF-β due to mutation or loss of TGF-beta type II receptor (TβRII) and Smad4 in several different cancer cells are reported. In addition, TGF-β binding to its receptor activates many non-canonical signaling pathways. Radiation induced TGF-β is primarily involved in normal tissue injury and fibrosis. Seminal studies from our group have used radio-adjuvant therapies, involving classical components of the pathway such as TβRII and SMAD4 to overcome the growth promoting effects of TGF-β. The main impediment in the radiation-induced TGF-β signaling is the induction of SMAD7 that blocks TGF-β signaling in a negative feedback manner. It is well demonstrated from our studies that the use of neutralizing antibodies against TGF- β can render a robust radio-resistant effect. Thus, understanding the functional interactions of TGF-β signaling components of the pathway with other molecules may help tailor appropriate adjuvant radio-therapeutic strategies for treatment of solid tumors.

Figure 1. Dual effects of TGF-β signaling on the growth of cells and impact of radiation

Classical canonical TGF-β signaling pathway showing the dual effects of this signaling on the cell growth. Normally this pathway induces cell growth suppressive effects, however, during the process of tumorigenesis due to several factors TGF-β signaling pathway induces proliferation, invasiveness, angiogenesis, metastasis and immune suppression. In this figure, based on the findings from our group, radiation can potently induce TGF-β and this TGF-β can be activated to exert negative growth effects by inducing the expression of cdk inhibitors such as p21 and p16. It is also shown here that the inhibitory Smad7 can be induced by Smad4 that can in turn inhibit the TGF-β signaling.

Figure 2. A schematic representation of genetic lesions at different stages of TGF-β that lead to tumorigenesis in pancreatic cancer model

In a normal condition, TGF-β signaling leads to growth suppression. However due to mutations or loss of several key genes involved in this signaling pathways, the growth suppressive effects are transformed to growth proliferative effects. SMAD4 and TβRII genes are often mutated in pancreatic carcinoma. Alteration in any of these components can lead to abnormal cell proliferation and render radio-resistance phenotype.

Figure 3. Radiation induced SMAD7, a bottleneck in radiotherapy

As a negative feedback mechanism, radiation-induced TGF-β, elevates the expression of SMAD7, which blocks the activity of this pathway. TIEG2 (also known as KLF11) is a tumor suppressor gene that causes repression of SMAD7 expression and can be a useful target for adjuvant radiotherapy to harness the negative growth effects of TGF-β signaling pathway. Thus, over expression of TIEG2 will drive the TGF-β pathway towards the growth suppressive functions and enhance the radiation response.