|Year : 2016 | Volume
| Issue : 4 | Page : 97-98
Cancer metastasis: Epithelial-to-mesenchymal transition in cancer radiotherapy
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India
|Date of Web Publication||1-Feb-2017|
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Kumar A. Cancer metastasis: Epithelial-to-mesenchymal transition in cancer radiotherapy. J Radiat Cancer Res 2016;7:97-8
Cancer metastasis, a phenomenon of the spread of cancer cells in blood circulation and their growth in distant vital organs/tissues, is responsible for more than 90% of cancer-related deaths. The molecular mechanism of metastasis is not yet fully understood. However, an expanding body of research in animal tumor models and patient samples suggests epithelial-to-mesenchymal transition (EMT) as one of the most possible mechanisms of metastasis. EMT is a morphogenetic program of normal embryonic development, by which nonmotile epithelial cells acquire mesenchymal phenotype (fibroblast-like) and adhesion/invasive abilities. Cancer cells utilize this EMT program to adapt to various sequential steps of metastasis, for example, (i) to detach from the primary tumor site, (ii) to breach the basement membrane by proteolysis, (iii) to enter and survive in the blood circulation, and (iv) finally developing new secondary tumor growth sites in vital organs. Radiation therapy has been considered as one of the most effective treatment modalities to control the growth of primary tumor in a wide variety of cancer patients. However, even after several years of treatment, tumor recurrences and metastases have been observed. Therefore, it suggests that a comprehensive research is required to examine the molecular phenotype of surviving tumor cells, which are left at the primary site and continue circulating in the blood after radiotherapy. To explain the tumor recurrences, preexistence of cancer stem-like cells and their poor response to radiotherapy has been well documented, which is now gaining acceptance also. However, radiotherapy-induced acquisition of mesenchymal phenotype, which showed characteristics of stem-like cells, needs to be considered. Camphausen et al. reported that radiation treatment to a primary tumor accelerates metastatic growth in mice. Recent studies, including ours, showed that gamma-irradiated human lung epithelial carcinoma,, breast carcinoma, and esophageal carcinoma  exhibit EMT markers, cytoskeletal reorganization, and higher adhesion/migration and invasion abilities compared to unirradiated cells. Hence, these and other emerging evidence indicate the potential role of EMT-derived mesenchymal cells in local tumor recurrence and its acquired resistance to radiation and other DNA-damaging therapies. Recent review has causally linked DNA damage response (DDR) proteins (acting as co-transcriptional factors) to tumorigenesis and metastasis. For example, RAD9, PARP1, BRCA1, ATM, and TP53 have been found to be associated with metastasis in both experimental and human tumor samples. Therefore, it is likely that irradiated tumor cells with elevated DNA damage response would exhibit higher proclivity to disseminate and metastasize. It is also possible that EMT mediators (due to their role in survival) can help tumor cells to escape from cytotoxic therapies. Therefore, future research is needed to identify the signaling node of radiation-induced EMT in cancer cells and to validate them in tumor biopsy of patients treated with radiotherapy. Poorly radioresponsive human tumor could be a better model to discover the role of DDR proteins as regulators of metastasis. Since a significant number of highly effective DDR inhibitors are already available, these can be rationally combined with radiotherapy to test their efficacy to suppress the invasive and metastatic potential of tumor, in addition to primary tumor growth control. Targeting EMT mediators having a role in radiation survival would lead to the development of a new class of radiosensitizers, which would not only enhance the antitumor effect of radiation but may also prevent tumor recurrences and its metastasis.
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