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Review
. 2020 Mar 17;10:319.
doi: 10.3389/fonc.2020.00319. eCollection 2020.

Novel Therapeutic Strategies for Ovarian Cancer Stem Cells

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Free PMC article
Review

Novel Therapeutic Strategies for Ovarian Cancer Stem Cells

Nastassja Terraneo et al. Front Oncol. .
Free PMC article

Abstract

Ovarian cancer (OC) is one of the most lethal gynecologic malignancies. Due to the lack of specific symptoms and screening methods, this disease is usually diagnosed only at an advanced and metastatic stage. The gold-standard treatment for OC patients consists of debulking surgery followed by taxane combined with platinum-based chemotherapy. Most patients show complete clinical remission after first-line therapy, but the majority of them ultimately relapse, developing radio- and chemoresistant tumors. It is now proposed that the cause of recurrence and reduced therapy efficacy is the presence of small populations of cancer stem cells (CSCs). These cells are usually resistant against conventional cancer therapies and for this reason, effective targeted therapies for the complete eradication of CSCs are urgently needed. In this review article, we highlight the mechanisms of CSC therapy resistance, epithelial-to-mesenchymal transition, stemness, and novel therapeutic strategies for ovarian CSCs.

Keywords: Auger electron and alpha particle emitters; L1CAM; cancer stem cells; epithelial-to-mesenchymal transition; ovarian cancer; radioimmunotherapy; therapeutic strategies.

Figures

Figure 1
Figure 1
Models of tumor development and heterogeneity. (A) The cancer stem cell (CSC) model of tumor development. Genetic or epigenetic mutations activate stem-like programs in a single cell, generating a CSC. This CSC is able to indefinite self-renewal and/or differentiation and all derived tumor cells have a hierarchical inheritance pattern. (B) The clonal evolution (CE) model of tumor development. Due to the acquisition of epigenetic and genetic mutations through time, any cell might have tumorigenic potential. Tumor heterogeneity is due to the propagation of cells carrying genetic mutations. (C) The plasticity model highlights the plastic state of cancer stemness. Based on the model, differentiated non-tumorigenic cancer cells can potentially revert back to CSCs.
Figure 2
Figure 2
The role of cancer stem cells in drug resistance. Standard chemotherapeutics are not able to kill cancer stem cells (CSCs), which can promote tumor regrowth and eventually result in disease relapse. Different mechanisms, including increased.
Figure 3
Figure 3
Mechanisms of cancer stem cell resistance toward conventional therapy. Therapy resistance mechanisms include drug efflux by ABC transporters, increased detoxification by ALDH activity, efficient ROS scavenging, and activation of developmental pathways mediating survival. Signals released by cancer stem cell (CSC) niche are also important to support survival, proliferation and therapy resistance.
Figure 4
Figure 4
Cancer stem cells are sustained by biological processes within the cancer stem cell niche. Different biological processes like EMT, hypoxia, inflammation, and angiogenesis maintain cancer stem cells (CSCs). Cytokines and growth factors produced by tumor cells and tumor-associated cells increase proliferation and survival of CSCs, promoting tumor invasion and metastasis formation.
Figure 5
Figure 5
EMT contributes to invasiveness, stemness, and drug resistance. Activation of EMT results in migration and fast tissue invasion. Furthermore, EMT activation affects tumor-initiating properties of cancer cells, with the greatest properties found at the intermediate level of EMT. Drug resistance of cancer cells also seems to be highest in cells with intermediate EMT phenotype.
Figure 6
Figure 6
Cellular damages induced by different LET radiations. (A) Low-LET radiations produced by beta-particles induce individual DNA lesions that can be easily repaired by the DNA repair machinery. (B) Auger electrons are released as a cascade close to cell membrane or DNA, producing clusters of lethal DNA lesions. (C) Alpha radiations have high-LET and produce multiple damages along a linear track that are difficult to repair. Blue dots: ionizations/excitations.
Figure 7
Figure 7
Therapeutic relevance of cancer stem cells. Conventional cancer therapies mostly kill the tumor bulk population, while therapy-resistant cancer stem cells (CSCs) survive and continue to proliferate, leading to tumor recurrence. CSC-specific therapies need to be designed in order to precisely eradicate CSCs. Without self-renewing CSCs to drive tumor progression, the tumor shrinks, and regresses.

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References

    1. Ring KL, Pakish J, Jazaeri AA. Immune checkpoint inhibitors in the treatment of gynecologic malignancies. Cancer J. (2016) 22:101–7. 10.1097/PPO.0000000000000179 - DOI - PubMed
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. (2019) 69:7–34. 10.3322/caac.21551 - DOI - PubMed
    1. Zhang XY, Zhang PY. Recent perspectives of epithelial ovarian carcinoma. Oncol Lett. (2016) 12:3055–58. 10.3892/ol.2016.5107 - DOI - PMC - PubMed
    1. Klotz DM, Wimberger P. Cells of origin of ovarian cancer: ovarian surface epithelium or fallopian tube? Arch Gynecol Obstet. (2017) 296:1055–62. 10.1007/s00404-017-4529-z - DOI - PubMed
    1. Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. . Ovarian cancer statistics, 2018. CA Cancer J Clin. (2018) 68:284–96. 10.3322/caac.21456 - DOI - PMC - PubMed

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