Abstract
Therapy resistance is responsible for tumour recurrence and represents one of the major challenges in present oncology. Significant advances have been made in the understanding of the mechanisms underlying resistance to conventional and targeted therapies improving the clinical management of relapsed patients. Unfortunately, in too many cases, resistance reappears leading to a fatal outcome. The recent introduction of immunotherapy regimes has provided an unprecedented success in the treatment of specific cancer types; however, a good percentage of patients do not respond to immune-based treatments or ultimately become resistant. Cellular plasticity, cancer cell stemness and tumour heterogeneity have emerged as important determinants of treatment resistance. Epithelial-to-mesenchymal transition (EMT) is associated with resistance in many different cellular and preclinical models, although little evidence derives directly from clinical samples. The recognition of the presence in tumours of intermediate hybrid epithelial/mesenchymal states as the most likely manifestation of epithelial plasticity and their potential link to stemness and tumour heterogeneity, provide new clues to understanding resistance and could be exploited in the search for anti-resistance strategies. Here, recent evidence linking EMT/epithelial plasticity to resistance against conventional, targeted and immune therapy are summarized. In addition, future perspectives for related clinical approaches are also discussed.
Highlights
The emergence of therapy resistance is one of the main unsolved issues in present oncology and represents a major hurdle to defeating cancer.Traditionally, two forms of tumour drug resistance, innate and acquired, have been considered responsible for tumour relapse either soon after initial treatment or even following several years of initial response and tumour shrinkage [1,2,3]
Since the beginning of the present century, a myriad of articles have described the acquisition of Epithelial-to-mesenchymal transition (EMT) by normal and malignant epithelial cells under different stimulus in culture, starting from the original identification of Snail transcription factor as an E-cadherin repressor and EMT-inducer [40,41] followed by the identification of additional EMT-transcription factors (EMT-TFs), such as Slug, zinc finger E-box binding homeobox 1 and 2 (ZEB1, ZEB2), Twist or the basic-loop-helix transcription factor 3 E47/TCF3, presently considered as classical or core EMT-TFs (Table 1)
The association between EMT and cancer stem cells (CSCs) during tumour progression and metastasis is not fully understood and, importantly, it might depend on particular tumour contexts [50], as exemplified by the non-classical EMT-TF paired related homeobox 1 (Prrx1) that represses CSC traits in triple-negative breast cancer (TNBC) cells while its silencing is required for metastatic colonization associated with the acquisition of stemness properties and an mesenchymal-to-epithelial transition (MET) phenotype [47]
Summary
The emergence of therapy resistance is one of the main unsolved issues in present oncology and represents a major hurdle to defeating cancer. The discovery of CSCs soon led to the exposure of their increased resistance to chemo- and radiotherapy compared to non-CSCs in the same tumour (reviewed in Reference [8]) This point has been confirmed in different experimental situations in which conventional therapies were able to eliminate non-CSCs while slowly proliferating CSCs were unaffected [9,10,11,12]. Original studies in tumour cell lines revealed that cells undergoing EMT achieve resistance to genotoxic stress mediated by conventional radio- and chemotherapy [17,18,19,20] This was later confirmed using different therapeutic drugs reinforcing the link between CSCs, EMT and resistance [8,16,21,22,23]. Future perspectives for refining predictive resistance biomarkers and novel clinical approaches will be discussed
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