Stem Cell Plasticity and Dormancy in the Development of Cancer Therapy Resistance.

Maria Laura De Angelis,Ann Zeuner,Filippo La Torre,Federica Francescangeli

doi:10.3389/fonc.2019.00626

Maria Laura De Angelis, Ann Zeuner + Show 2 more

Open Access

https://doi.org/10.3389/fonc.2019.00626

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Abstract

Cancer treatment with either standard chemotherapy or targeted agents often results in the emergence of drug-refractory cell populations, ultimately leading to therapy failure. The biological features of drug resistant cells are largely overlapping with those of cancer stem cells and include heterogeneity, plasticity, self-renewal ability, and tumor-initiating capacity. Moreover, drug resistance is usually characterized by a suppression of proliferation that can manifest as quiescence, dormancy, senescence, or proliferative slowdown. Alterations in key cellular pathways such as autophagy, unfolded protein response or redox signaling, as well as metabolic adaptations also contribute to the establishment of drug resistance, thus representing attractive therapeutic targets. Moreover, a complex interplay of drug resistant cells with the micro/macroenvironment and with the immune system plays a key role in dictating and maintaining the resistant phenotype. Recent studies have challenged traditional views of cancer drug resistance providing innovative perspectives, establishing new connections between drug resistant cells and their environment and indicating unexpected therapeutic strategies. In this review we discuss recent advancements in understanding the mechanisms underlying drug resistance and we report novel targeting agents able to overcome the drug resistant status, with particular focus on strategies directed against dormant cells. Research on drug resistant cancer cells will take us one step forward toward the development of novel treatment approaches and the improvement of relapse-free survival in solid and hematological cancer patients.

Highlights

Resistance to chemotherapy and molecularly targeted therapies is a major problem that limits the effectiveness of cancer treatments
Senescence has been proposed as a process adopted by tumor cells to escape from therapy [11], suggesting that drug resistance is a composite picture of heterogeneous cell states
The link between stemness and drug resistance derives mainly from three observations: [1] cancer stem cells (CSCs) populations are more resistant to therapy [28], [2] cancers with a stemness-related gene expression have a worse prognosis [29,30,31,32,33], and [3] cells with combined features of stemness, drug resistance, and dormancy have been identified in several tumors including pancreatic carcinoma [34, 35], ovarian cancer [36], melanoma [37], lung cancer [38], and chronic myeloid leukemia (CML) [39]

Summary

Introduction

Resistance to chemotherapy and molecularly targeted therapies is a major problem that limits the effectiveness of cancer treatments. The link between stemness and drug resistance derives mainly from three observations: [1] CSCs populations are more resistant to therapy [28], [2] cancers with a stemness-related gene expression have a worse prognosis [29,30,31,32,33], and [3] cells with combined features of stemness, drug resistance, and dormancy have been identified in several tumors including pancreatic carcinoma [34, 35], ovarian cancer [36], melanoma [37], lung cancer [38], and CML [39].

Results

Conclusion