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A perspective analysis: microRNAs, glucose metabolism, and drug resistance in colon cancer stem cells

Cancer Gene Therapy volume 29, pages 4–9 (2022)Cite this article

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Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide [1]. It develops from stem cells of the intestinal crypt due to metabolic, genetic, epigenetic, and micro-environmental alterations [2,3,4]. The stemness behavior of a subpopulation of cancer cells (cancer stems cells, CSCs), also known as tumor-initiating cells, has been related to drug resistance, metastatic potential, and source of tumor heterogeneity [5]. CSCs were identified for the first time in hereditary tumors, human acute myeloid leukemia, and subsequently in various solid tumors, including colon, breast, brain, lung, and prostate cancers. Several studies suggest that in cancer stem cells, the aberrant metabolism is a driving force of epigenetic and genetic changes, affecting, in turn, tumor onset, development, heterogeneity, and recurrence [6,7,8]. Indeed, emerging evidence showed that CSCs exhibit a metabolic phenotype similar to normal stem cells, suggesting the importance of metabolic reprogramming in supporting stemness properties [7, 8]. Therefore, the CSCs’ metabolic phenotype is the subject of an intense investigation to identify new metabolic targets as therapeutic usage. Glucose is a fundamental nutrient in cellular stemness; in fact, the CSCs population is related to high glucose levels in the tumor microenvironment [9]. Although most data suggest that CSCs are primarily glycolytic, mounting evidence indicates their ability to exploit the mitochondrial oxidative metabolism. They underline the metabolic plasticity of CSCs to switch between Oxidative Phosphorylation System (OXPHOS) and glycolysis in an environment-dependent manner [10].

Standard chemotherapeutic agents target proliferating cancer cells unaffecting quiescent CSCs [11]. Therefore, several fields of research try to differentiated therapeutic strategies to target normal cells, cancer cells, and CSCs to reinforce the physiologic antitumor activity, reduce tumor bulk, and decrease the percentage of recurrence in cancer patients. As CSCs serve as a major contributor to metastatic spreading, they represent a profitable targeting option. It was shown that the bone morphogenetic protein 4 (BMP4) induces differentiation of colon CSCs (CCSCs) and sensitizes them to 5-fluorouracil (5-FU) and oxaliplatin in vivo [12]. A variant of BMP7 (BMP7v) suppresses the Wnt pathway and reduces mesenchymal traits and survival of CCSCs. Moreover, it exerts an antiangiogenic effect in vivo, sensitizing tumor cells to chemotherapy regardless of their mutational profile [13]. Immunotherapies could be a promising approach to target CCSCs, e.g., by using monoclonal antibodies to target specific CSCCs surface markers such as CD44 or LGR5 [14, 15]. Alternatively, the ASB4 gene is a tumor-associated antigen of CCSCs that can induce specific cytotoxic T cells (CTLs) responses to CSCs. Therefore, the selective targeting of CCSCs by exploiting CTLs specific for the ASB4 antigen could be beneficial to prevent tumor relapse [16]. In the end, a multimodal therapeutic approach that involves all the targets described in a contest of precision medicine, using three-dimensional (3D) CRC organoid models from patient-derived cells or engineering tissue chips, in combination with nanomedicine and drug delivery technologies, has to be considered. Critical stemness-associated pathways in CCSCs are regulated by microRNAs [17] and microRNA-targeted therapy seems to be a promising tool to inhibit the tumorigenic program of CCSCs by inhibition of oncogenic microRNAs or by restoring of tumor suppressor microRNAs [17].

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Fig. 1: In vitro effect of 2-DG and 5-FU treatment on miR-483-3p expression and apoptosis in CCSC cell lines.
Fig. 2: In vivo effect of 2-DG treatment on tumor growth and miR-483-3p expression in CCSC cell lines.

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Acknowledgements

This work was financed by the Italian Ministry of Health funds (Ricerca Finalizzata GR-2011-02350699).

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Author notes

  1. These authors contributed equally: Sara Pagotto, Maria Luisa Colorito

Authors and Affiliations

  1. Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy

    Sara Pagotto, Maria Luisa Colorito, Nicola Tinari & Rosa Visone

  2. Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy

    Sara Pagotto, Nicola Tinari, Feliciano Protasi, Rosa Visone & Angelo Veronese

  3. Cellular and Molecular Pathophysiology Laboratory, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy

    Annalisa Nicotra, Tiziana Apuzzo, Giorgio Stassi & Simone Di Franco

  4. Department of Medicine and Aging Science, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy

    Feliciano Protasi

  5. Department of Neuroscience, Imaging, and Clinical Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy

    Angelo Veronese

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Contributions

A.V. designed the study. G.S. provided CCSCs from CRC patients. M.L.C., S.P., A.N., and S.D.F. performed in vivo experiments, and cellular and genetic characterization. M.L.C., T.A., and S.D.F. performed cytofluorimetric analysis. A.V., S.P., R.V., A.N., S.D.F., M.L.C., N.T., F.P., and G.S. analyzed and interpreted the results. A.V., S.D.F., S.P., R.V., and M.L.C. wrote the manuscript. All the authors critically reviewed and revised the paper.

Corresponding authors

Correspondence to Simone Di Franco or Angelo Veronese.

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Animal work was undertaken in accordance with the Italian Ministry of Health authorization n. 461/2015-PR.

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Pagotto, S., Colorito, M.L., Nicotra, A. et al. A perspective analysis: microRNAs, glucose metabolism, and drug resistance in colon cancer stem cells. Cancer Gene Ther 29, 4–9 (2022). https://doi.org/10.1038/s41417-021-00298-5

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