Semin Radiat Oncol. 2019 Jan;29(1):42-54. doi: 10.1016/j.semradonc.2018.10.003.

Targeting Cancer Stem Cell Redox Metabolism to Enhance Therapy Responses.

Luo M1, Wicha MS2.

1 University of Michigan Rogel Cancer Center and Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan. Electronic address: mingluo@med.umich.edu.
2 University of Michigan Rogel Cancer Center and Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan. Electronic address: mwicha@med.umich.edu.

 

Abstract

Cancer has long been viewed as a disease of altered metabolism. Although it has long been recognized that the majority of cancer cells display increased dependence on glycolysis, the metabolism of “cancer stem-like cells” (CSCs) that drive tumor growth and metastasis is less well characterized. In this chapter, we review the current state of knowledge of CSC metabolism with an emphasis on the development of therapeutic strategies to exploit the metabolic vulnerabilities of these cells. We outline emerging evidence indicating distinct metabolic pathways active in the proliferative, epithelial- (E) and quiescent, mesenchymal-like (M) CSC states in triple negative breast cancer. These CSC states are characterized by their different redox potentials and divergent sensitivities to inhibitors of glycolysis and redox metabolism. We highlight the roles of two redox-regulated signaling pathways, hypoxia-inducible factor 1α and nuclear factor erythroid 2-related factor 2, in regulating CSC epithelial-mesenchymal plasticity during metabolic and/or oxidative stress, and discuss clinical strategies using combinations of pro-oxidant-based therapeutics simultaneously targeting E- and M-like CSCs. By specifically targeting CSCs of both states, these strategies have the potential to increase the therapeutic efficacy of traditional chemotherapy and radiation therapy. Copyright © 2018. Published by Elsevier Inc.

PMID: 30573183

 

Summary 

Breast cancer (BC) is increasingly recognized as a complex disease, in which six different subtypes of cancer have been characterized based on distinct gene expression signatures and histological characteristics [1-4]. While therapeutics targeting the estrogen receptor (ER) and the epidermal growth factor receptor family member HER2/ErbB2 have provided substantial clinical benefits for subtypes of BC patients expressing these molecular markers, treatment of patients with triple-negative breast cancer (TNBC) has been especially challenging due to the heterogeneity of the disease and the absence of well-defined molecular targets. One of the reasons for the lack of efficacy of current therapies in TNBC may be their inability to effectively target “cancer stem cells”. These cells, residing at the apex of tumor heterogeneity and virtually resistant to ionizing radiation and chemotherapy, largely contribute to treatment failure as well as metastasis [5-11].

Previous studies in our lab demonstrated that breast cancer stem cells (BCSCs) maintain the plasticity to transition between proliferative epithelial (E) and quiescent mesenchymal-like (M) states [12]. This plasticity of BCSCs suggests that CSCs are not a fixed population but rather a dynamic, metaplastic phenotypic state acquired due to dynamic tumor microenvironment changes (i.e., growth factor/inflammatory signaling, stromal-tumor interactions and metabolic reprograming, etc.)[13-15]. For example, HER2 overexpression drives the self-renewal of ALDH+ E-BCSCs that are sensitive to the HER2 antibody trastuzumab [16]. In contrast, resistance to HER2 blockade is associated with an increase in CD24CD44+ M-BCSCs resulting from the activation of an IL6 driven inflammatory loop [17]. Moreover, in trastuzumab-resistant HER2+ breast cancer, a combinatory approach targeting IL6 receptor by tocilizumab and HER2 by trastuzumab synergistically abrogates tumor growth and metastases by eliminating both M- and E-BCSCs [17]. These studies suggest that therapeutic strategies collectively targeting distinct BCSC states offer great advantage and potential to eliminate metastatic and drug-resistant breast cancer including TNBC. However, such combinatory strategies to collectively target distinct BCSC states in TNBC have not been identified.

Our current research centers on the understanding of how metabolic/oxidative stress modulates the epithelial-mesenchymal plasticity of BCSCs, and to identify the metabolic vulnerabilities of distinct BCSC states. We have demonstrated that metabolic stressors including 2-deoxyglucose (2DG, a well-known glycolysis inhibitor), hydrogen peroxide (H2O2), and hypoxia promote the transition of ROSlo M-BCSCs to their ROShi E-state, and this transition is reversed by the thiol antioxidant N-acetyl-cysteine, and facilitated by the activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibited robust NRF2-mediated antioxidant responses, rendering them vulnerable to ROS-induced differentiation and cytotoxicity following inhibition of thioredoxin (TXN) and glutathione (GSH) antioxidant pathways[18]. These studies also indicated that E- and M-like BCSCs significantly differ in their metabolic pathways, redox potential, and sensitivities to inhibitors of glycolysis and NRF2-mediated redox metabolism. By exploiting these metabolic differences, we have developed a conceptual framework to simultaneously abrogate BCSCs of distinct states in advanced/aggressive cancer including TNBC. Indeed, we demonstrated that co-inhibition of glycolysis (which induces the transition of BCSCs from the M- to E-state) and thioredoxin and glutathione antioxidant pathways (which induce differentiation and subsequent apoptosis of E-BCSCs) synergistically suppressed tumor growth, tumor-initiating potential and metastasis by eliminating both M- and E-BCSCs in patient-derived xenograft (PDX) and systemic metastasis models of TNBC[18].

These findings have enormous clinical implications for cancer treatment. We were recently invited to write a review article to discuss a potential novel cancer treatment strategy by targeting CSC redox metabolism to enhance therapeutic responses. In this review article[19], we highlight the emerging knowledge regarding redox-regulated CSC plasticity, the underlying signaling mechanisms governing redox regulation of CSC state dynamics, and the different metabolic pathways contributing to their differential redox potentials as well as divergent responses to inhibitors of glycolysis and redox metabolism. We emphasize the implications of our recent findings for the development of novel combinatory therapeutic strategies to effectively target CSCs of distinct phenotypic states, and discuss how these strategies may enhance tumor responses to the conventional treatment approaches including chemo- and radiation therapies.

 

Schematic diagram illustrating a pro-oxidant based therapeutic approach with potential to increase treatment responses for traditional cancer therapies.

 

 

Figure 1. Combination strategies utilizing traditional cancer therapies (i.e., standard radio-chemotherapies or anti-angiogenic therapies) in combination with inhibitors of NRF2-mediated antioxidant responses (i.e., NRF2 inhibitor Trig or inhibitors of TXN/GSH antioxidant pathways including AUR/BSO) enhance treatment responses by simultaneously targeting CSCs of distinct states.

 

Funding Support: This research was supported by R01 CA101860 and R35 CA197585 from the NIH and from the BCRF to Max S. Wicha.; by R01 CA182804 and P30 CA086862 to Douglas R. Spitz.; and by R01 CA196018 and U01 CA210152 to Gary. D. Luker.

 

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