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.

Tenascin-C: Exploitation and collateral damage in cancer management

“…94 In early stages TGFb may play a role in suppression of malignancy but at later stages may promote tumor progression. 95,96 Since TGFb induces tenascin-C expression, 97 it is intriguing to speculate that this pathway may contribute to tenascin-C induction by radiotherapy. In addition, irradiation induced hypoxia or inflammation might also trigger tenascin-C expression by other pathways.…”

Radiation-induced Epstein–Barr virus reactivation in gastric cancer cells with latent EBV infection

“…Low-dose radiation (50 mGy gamma-rays) exposure of normal cells showed some bystander effects on transformed cells leading to their apoptosis in a TGF-beta-dependent manner. 22 Although TGF-beta typically represses NF-kappaB signaling in normal cells, recent in vitro and in vivo evidence suggests an aberrant ability of TGF-beta signaling to activate NF-kappaB signaling in several different cancers as a means of promoting malignant tumor cell phenotypes. 32,33 Aspirin was also shown to have such a dual nature in NF-kappaB regulation.…”

“…31 Another study revealed that the TGF-beta overexpression after the radiation exposure induced TGF-beta signaling through the induction of Smad7 and TGF-beta type II receptor. 22 It is also involved in the activation of p53 and ataxia telangiectasia mutated (ATM) signaling pathways thereby increasing apoptosis in irradiated cells. Low-dose radiation (50 mGy gamma-rays) exposure of normal cells showed some bystander effects on transformed cells leading to their apoptosis in a TGF-beta-dependent manner.…”

“…21 In lymphoblastoid cell lines with latent EBV infection, ionizing radiation also induced lytic EBV infection. 10,19 Irradiation can activate TGF-beta signaling, 22 which is known to induce EBV reactivation in EBV-infected B cells. 23 In this study, we examined the effect of ionizing radiation on EBV genome expression in the SNU-719 cell line, a human gastric epithelial carcinoma cell line with natural EBV infection.…”

The transforming growth factor beta-1 in the oncogenesis of human lung adenocarcinoma

“…Имеющиеся данные свидетельствуют о том, что активация TGF-β1-пути является одной из основных причин неблагоприятно-го прогноза [9]. Показано, что у больных РЛ повыше-ны уровни TGF-β1 в плазме крови как исходные, так и после лучевой терапии [10].…”