6.7. EMT and resistance to cancer treatment

Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)

Part II. Cancer stem cells

The acquisition of drug resistance by cancer cells subjected to chemotherapy, targeted therapies and radiotherapy leads to tumour recurrence and metastasis and is a formidable clinical challenge for effective treatment of cancer patients (Holohan et al., 2013). It is becoming increasingly clear that EMT plays an important role in such acquisition. In cancer cell lines exposed to cytotoxic chemotherapy, cells that emerge following treatment express increased levels of mesenchymal markers, indicating that they have undergone EMT (Tsai and Yang, 2013). In human patients with colorectal cancer or non-small-cell lung cancer (NSCLC), comparison of biopsied tumour tissue before and after chemotherapy has demonstrated an increase in mesenchymal markers subsequent to treatment (Tsai and Yang, 2013). Recurrent tumours in a subset of patients exhibit an EMT gene signature coupled with reduced disease-free survival (Tsai and Yang, 2013). Resistance to chemotherapy has also been linked to expression of EMT TFs, and TGF-β-induced EMT activation by chemotherapy may increase metastasis (Chang and Mani, 2013). Recent studies have also indicated a role of EMT in the acquisition of resistance to targeted therapies. Examination of NSCLC cell lines has revealed that those expressing markers of EMT are resistant to treatment with EGF-R inhibitors such as gefitinib and erlotinib (Holohan et al., 2013; Tsai and Yang, 2013). Furthermore, markers of EMT have been observed in tumour biopsies from patients who developed resistance to EGF-R inhibitors, demonstrating that EMT-associated resistance to drug therapy occurs clinically (Holohan et al., 2013). A further example of acquired drug resistance involving EMT is the failure of antiangiogenic therapy in the treatment of metastatic tumours. Recent studies have established that the use of antiangiogenic therapy results in the development of hypoxia and activation of the hypoxia cascade, leading to the activation of EMT.

There are several potential mechanisms that may account for the acquisition of drug resistance via EMT. One consequence of EMT is a reduction in cell proliferation, resulting in the resistance of cells to conventional chemotherapy, which primarily targets rapidly dividing cells (Tsai and Yang, 2013). Cells that have undergone EMT also exhibit increased resistance to apoptosis, providing a potential survival advantage during a therapeutic assault (Chang and Mani, 2013; Tsai and Yang, 2013). In addition, epithelial cancer cells that have undergone EMT and acquired CSC properties exhibit increased resistance to cancer therapy and the fraction of CSCs in tumours often increases after chemotherapy, suggesting a link between CSCs derived through EMT and resistance to treatment (Chang and Mani, 2013).

Since EMT is involved in the acquisition of drug and radiation resistance by cancer cells and plays a critical role in metastatic disease, targeted killing of cancer cells that have undergone EMT will be required if durable clinical responses are to be realized. However, because these dangerous cells are, by definition, resistant to therapy, current therapeutic modalities have been relatively ineffective in eliminating them. Several challenges exist in targeting cells that have undergone EMT. In addition to accounting for their inherent drug resistance, identification of appropriate targets is critical. EMT TFs are technically challenging to target (Tsai and Yang, 2013) and therapeutic strategies that interfere with the induction of EMT or the functional consequences of EMT may be more effective (Nieto, 2013; Tsai and Yang, 2013). The plasticity of EMT also requires the appropriate temporal window for effective treatment to be identified (Tsai and Yang, 2013). For example, inhibiting EMT prior to tumour cell dissemination may be beneficial in delaying or preventing metastasis, while doing so after cells have disseminated may result in reversion of EMT at distant sites, potentially promoting metastatic spread (Nieto, 2013; Tsai and Yang, 2013). Furthermore, the potential for differentiation of epithelial cells present in the bulk tumour cell population towards a CSC state requires that the bulk tumour cells be targeted together with novel agents against CSCs (Holohan et al., 2013). Therefore, the combination of cytotoxic chemotherapy and therapeutic agents targeting EMT may overcome drug resistance in disseminated tumour cells (Tsai and Yang, 2013).

Potential therapeutic strategies for targeting CSCs that arise via EMT include selectively killing mesenchymal cells by blocking EMT pathways and forcing epithelial differentiation to convert resistant mesenchymal cells into sensitive epithelial cells (Chang and Mani, 2013). Interestingly, restoration of E-cadherin expression and inhibition of Twist or Zeb1 have been shown to restore chemosensitivity in cancer cell lines, suggesting that shifting cells back towards the epithelial state can induce sensitivity (Chang and Mani, 2013). Resistance to EGF-R inhibitors resulting from EMT may be overcome through the use of inhibitors against the receptor tyrosine kinase AXL, suggesting that the use of multiple targeted therapies may be beneficial in eliminating cells with elevated metastatic potential (Holohan et al., 2013).


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