ASTROnews: The epithelial–mesenchymal transition: Implications for radiotherapy

The concept of the epithelial–mesenchymal transition (EMT) was developed in the field of embryology but has more recently been extended to cancer progression and metastasis. In embryology, EMT is a program of development of cells characterized by loss of cell adhesion, repression of E-cadherin expression and increased cell mobility. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. It has become apparent that several oncogenic-associated pathways induce EMT including Src, Ras, Ets, integrin, TGF-ß, Wnt/ß-catenin and Notch. In particular, Ras-MAPK has been shown to activate two related transcription factors known as Snail and Slug. Both of these proteins are transcriptional repressors of E-cadherin, and their expression induces EMT. Recently, activation of the phosphatidylinositol 3’ kinase (PI3K)/AKT axis is emerging as a central feature of EMT1. Cells undergoing EMT typically show a less well-differentiated morphology, express vimentin rather than cytokeratin and become more motile. In general, tumors with these characteristics have a poor prognosis due to their propensity to develop metastases, increased drug resistance and acquire some properties of stem cells.

Several lines of evidence have emerged that connect radiation and EMT in normal cells. In 2007, the group of Mary Helen Barcellos-Hoff showed that ionizing radiation sensitized non-malignant human mammary epithelial cells to undergo TGF-ß-mediated EMT, suggesting radiation-induced signaling pathways elicit heritable phenotypes that could contribute to neoplastic progression2. Another area of research that has yet to develop is linking the well-documented induction of TGF-ß in pulmonary tissue after radiotherapy with the observation that TGF-ß also induces alveolar epithelial cells to undergo EMT leading to the progression of fibrosis3. The development of strategies to prevent the development of EMT may prevent unwanted side effects of radiation.

The implication of EMT for tumor response to radiation also has several lines of developing evidence. In the past few years, reports have shown that irradiation enhanced the migration and invasiveness of human cancer cells4-6. More recently, Tsukamoto and colleagues confirmed that irradiation not only enhanced the invasive potential of endometrial cancer cells but that the irradiation-enhanced invasiveness was associated with morphologic and molecular alternations consistent with a change to a mesenchymal-like phenotype 7. To complete a vicious cycle, studies have suggested that the acquisition of EMT phenotype is associated with chemo- and radioresistance. This is exemplified by a recent study from Kurrey and colleagues who demonstrated that the transcriptional factors Snail and Slug orchestrate a program of gene repression and concurrent derepression that leads to tumor cells with three critical capabilities, namely EMT, resistance to p53-mediated apoptosis and a “stem-like” self-renewal program8. This leads to resistance to radiotherapy or chemotherapy mediated cellular stress and speculation that this may be a determinative aspect of aggressive cancer metastases.

The subject of cancer stem cells (CSCs) and treatment radioresistance is also receiving attention, and it has been proposed that EMT may provide a link between cancer metastasis and stem cell properties9. This is supported by observations that the induction of EMT in transformed mammary epithelial cells creates populations of cells that are highly enriched for cancer stem cells, as demonstrated by tumor-seeding ability, mammosphere formation and cell-surface marker expression10. One more factor to throw into the mix is hypoxia. In a recent study, a number of different cancer cells were exposed to carefully controlled hypoxic conditions and investigated for EMT changes11. All the cancer cells were found to respond to the hypoxic exposure within 72 hours by classic EMT changes including development of a fibroblastoid phenotype, Snail and ß-catenin nuclear translocation, and changes in E-cadherin; they also showed increased migration and invasiveness. The widespread existence of hypoxia in tumors and its known role in resistance to both radiation and drug treatment might be partially explained by its dual effects of promoting EMT and the self-renewal of CSCs12. The emerging picture is that EMT provides a mechanism of escape to a new, less adverse niche where resistance to apoptosis ensures cell survival in conditions of stress in the primary tumor and the acquisition of ‘‘stemness’’ ensures generation of the critical tumor mass required for progression of micrometastases to macrometastases.

The implications for radiotherapy are that we need to find strategies to prevent radiation-induced TGF-ß signaling pathways in normal cells to circumvent carcinogenesis and prevent fibrosis. Whereas we need to find strategies for tumor treatment that combine agents that specifically target the EMT process in combination with radiation.

Dr. Wilson is chief of radiation biology at William Beaumont Hospital in Royal Oak, Mich. Comments are welcome at communications@astro.org.

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