TGF-β in radiotherapy: mechanisms of tumor resistance and normal tissues injury

Emerging evidences show that changes in tumor stroma can adapt cancer cells to radiotherapy, thereby leading to a reduction in tumor response to treatment. On the other hand, radiotherapy is associated with severe reactions in normal tissues which limit the amount radiation dose received by tumor. These challenges open a window in radiobiology and radiation oncology to explore mechanisms for improving tumor response and also alleviate side effects of radiotherapy. Transforming growth factor beta (TGF-beta) is a well-known and multitasking cytokine that regulates a wide range of reactions and interactions within tumor and normal tissues. Within tumor microenvironment (TME), TGF-beta is the most potent suppressor of immune system activity against cancer cells. This effect is mediated through stimulation of CD4+ which differentiates to T regulatory cells (Tregs), infiltration of fibroblasts and differentiation into cancer associated fibroblasts (CAFs), and also polarization of macrophages to M2 cells. These changes lead to suppression of cytotoxic CD8 + T lymphocytes (CTLs) and natural killer (NK) cells to kill cancer cells. TGF-beta also plays a key role in the angiogenesis, invasion and DNA damage responses (DDR) in cancer cells. In normal tissues, TGF-beta triggers the expression of a wide range of pro-oxidant and pro-fibrosis genes, leading to fibrosis, genomic instability and some other side effects. These properties of TGF-beta make it a potential target to preserve normal tissues and sensitize tumor via its inhibition. In the current review, we aim to explain the mechanisms of upregulation of TGF-beta and its consequences in both tumor and normal tissues.