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 Table of Contents  
EDITORIAL
Year : 2016  |  Volume : 7  |  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 Publication1-Feb-2017

Correspondence Address:
Amit Kumar
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_13_17

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How to cite this article:
Kumar A. Cancer metastasis: Epithelial-to-mesenchymal transition in cancer radiotherapy. J Radiat Cancer Res 2016;7:97-8

How to cite this URL:
Kumar A. Cancer metastasis: Epithelial-to-mesenchymal transition in cancer radiotherapy. J Radiat Cancer Res [serial online] 2016 [cited 2020 Aug 10];7:97-8. Available from: http://www.journalrcr.org/text.asp?2016/7/4/97/199307

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.[1] 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.[2] EMT is a morphogenetic program of normal embryonic development, by which nonmotile epithelial cells acquire mesenchymal phenotype (fibroblast-like) and adhesion/invasive abilities.[3] 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.[2] 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.[4] 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.[5] 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.[6] Recent studies, including ours, showed that gamma-irradiated human lung epithelial carcinoma,[7],[8] breast carcinoma,[9] and esophageal carcinoma [10] 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.[11] 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.[12] 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.

 
  References Top

1.
Steeg PS. Targeting metastasis. Nat Rev Cancer 2016;16:201-18.  Back to cited text no. 1
    
2.
Meng F, Wu G. The rejuvenated scenario of epithelial-mesenchymal transition (EMT) and cancer metastasis. Cancer Metastasis Rev 2012;31:455-67.  Back to cited text no. 2
    
3.
Yang J, Weinberg RA. Epithelial-mesenchymal transition: At the crossroads of development and tumor metastasis. Cell 2008;14:818-29.  Back to cited text no. 3
    
4.
Baumann M, Krause M, Overgaard J, Debus J, Bentzen SM, Daartz J, et al. Radiation oncology in the era of precision medicine. Nat Rev Cancer 2016;16:234-49.  Back to cited text no. 4
    
5.
Shiozawa Y, Nie B, Pienta KJ, Morgan TM, Taichman RS. Cancer stem cells and their role in metastasis. Pharmacol Ther 2013;138:285-93.  Back to cited text no. 5
    
6.
Camphausen K, Moses MA, Beecken WD, Khan MK, Folkman J, O'Reilly MS. Radiation therapy to a primary tumor accelerates metastatic growth in mice. Cancer Res 2001;61:2207-11.  Back to cited text no. 6
    
7.
Gomez-Casal R, Bhattacharya C, Ganesh N, Bailey L, Basse P, Gibson M, et al. Non-small cell lung cancer cells survived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymal transition phenotypes. Mol Cancer 2013;12:94.  Back to cited text no. 7
    
8.
Narang H, Kumar A, Bhat N, Pandey BN, Ghosh A. Effect of proton and gamma irradiation on human lung carcinoma cells: Gene expression, cell cycle, cell death, epithelial-mesenchymal transition and cancer-stem cell trait as biological end points. Mutat Res 2015;780:35-46.  Back to cited text no. 8
    
9.
Kumar A, Ali A, Pandey BN. Ionizing Radiation Induces Migratory and Invasive Phenotypes Via E-Cadherin-Catenin-Small Rho-GTPases Axis in MCF7 Human Breast Carcinoma Cells, Proceedings of International Congress of Radiation Research, Warsaw, Poland; 2011.  Back to cited text no. 9
    
10.
He E, Pan F, Li G, Li J. Correction: Fractionated ionizing radiation promotes epithelial-mesenchymal transition in human esophageal cancer cells through PTEN deficiency-mediated Akt activation. PLoS One 2015;10:e0133097.  Back to cited text no. 10
    
11.
Marcucci F, Stassi G, De Maria R. Epithelial-mesenchymal transition: A new target in anticancer drug discovery. Nat Rev Drug Discov 2016;15:311-25.  Back to cited text no. 11
    
12.
Broustas CG, Lieberman HB. DNA damage response genes and the development of cancer metastasis. Radiat Res 2014;181:111-30.  Back to cited text no. 12
    




 

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