Keywords
How to Cite
Abstract
The development of cancer resistance to radio- chemo- and immunotherapy seriously compromises treatment outcomes. The present review of publications related to the phenotypic plasticity of malignant cells leads, with account of the principal characteristics of the stem-cell, epithelial, mesenchymal and senescent phenotypes, to the conclusion that the key factor of the therapeutic resistance of cancer is the reversibility of malignant cell transitions between these phenotypes. Such transitions depend on cells environment including host age and metabolic and endocrine conditions. Modulating the metabolic parameters of tumor host may significantly influence the efficacy of anticancer therapy without affecting the viability and/or proliferation of cancer cells in any of their particular phenotypic states. This stance is illustrated with data on the anticancer effects of antidiabetic biguanides. Analyzing in terms of reversibility of phenotypic states the effects of interventions having nonobvious cytostatic and/or cytotoxic consequences may help to understand the mechanisms of such interventions and to expand the scope of criteria useful in searching for novel anticancer therapies.
References
Nowell PC. The clonal evolution of tumor cell populations // Science. 1976;194:23–8.
Nussinov R, Tsai C-J, Jang H. Anticancer drug resistance: An update and perspective // Drug Resist Updates. 2021;59:100796. doi:10.1016/j.drup.2021.100796
Aleksakhina SN, Kashyap A, Imyanitov EN. Mechanisms of acquired tumor drug resistance // Biochim Biophys Acta Rev Cancer. 2019;1872:188310. doi:10.1016/j.bbcan.2019.188310
Welch DR, Hurst DR. Defining the hallmarks of metastasis // Cancer Res. 2019;79:3011–27.
Settleman J, Neto JMF, Bernards R. Thinking differently about cancer treatment regimens // Cancer Discov. 2021;11:1016–23.
Viossat Y, Noble R. A theoretical analysis of tumour containment // Nat Ecol Evolut. 2021;5:826–35.
Karabicici M, Alptekin S, Fırtına Karagonlar Z, Erdal E. Doxorubicin-induced senescence promotes stemness and tumorigenicity in EpCAM-/CD133- nonstem cell population in hepatocellular carcinoma cell line, HuH-7 // Mol Oncol. 2021;15:2185–202.
Welte Y, Adjaye J, Lehrach HR, Regenbrecht CRA. Cancer stem cells in solid tumors: elusive or illusive? // Cell Communicat Signal. 2010;8:6. doi:10.1186/1478-811X-8-6
Quintana E, Shackleton M, Foster HR et al. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized // Cancer Cell. 2010;18:510–23.
Rumman M, Dhawan J, Kassem M. Concise review: Quiescence in adult stem cells: Biological significance and relevance to tissue regeneration // Stem Cells. 2015;33:2903–12.
Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial-mesenchymal transitions in development and disease // Cell. 2009;139:871–90.
Sheng G. Defining epithelial-mesenchymal transitions in animal development // Development. 2021;148(8). doi:10.1242/dev.198036
Pastushenko I, Brisebarre A, Sifrim A et al. Identification of the tumour transition states occurring during EMT // Nature. 2018;556:463–8.
Emert BL, Cote CJ, Torre EA et al. Variability within rare cell states enables multiple paths toward drug resistance // Nat Biotechnol. 2021;39:865–76.
Sahoo S, Ashraf B, Duddu AS et al. Interconnected high-dimensional landscapes of epithelial–mesenchymal plasticity and stemness in cancer // Clin Exper Metastasis. 2022. doi:10.1007/s10585-021-10139-2
Willet SG, Lewis MA, Miao Z-F et al. Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis // EMBO J. 2018;37:e98311. doi:10.15252/embj.201798311
Mills JC, Stanger BZ, Sander M. Nomenclature for cellular plasticity: are the terms as plastic as the cells themselves? // EMBO J. 2019;38:e103148. doi:10.15252/embj.2019103148
Nami B, Ghanaeian A, Black C, Wang Z. Epigenetic silencing of HER2 expression during epithelial-mesenchymal transition leads to trastuzumab resistance in breast cancer // Life. 2021;11:868. doi:10.3390/life11090868
Nami B, Ghanaeian A, Black C, Wang Z. Epigenetic silencing of HER2 expression during epithelial-mesenchymal transition leads to trastuzumab resistance in breast cancer // Life. 2021;11:868. doi:10.3390/life11090868
Shay JW, Wright WE. Senescence and immortalization: role of telomeres and telomerase // Carcinogenesis. 2004;26:867–74.
Krishnamurthy J, Torrice C, Ramsey MR et al. Ink4a/Arf expression is a biomarker of aging // J Clin Invest. 2004;114:1299–307.
Wolf AM. The tumor suppression theory of aging // Mech Ageing Develop. 2021;200:111583. doi:10.1016/j.mad.2021.111583
Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of Cellular Senescence // Trends Cell Biol. 2018;28:436–53.
Sharpless NE, Sherr CJ. Forging a signature of in vivo senescence // Nat Rev Cancer. 2015;15:397–408.
Prokhorova EA, Egorshina AY, Zhivotovsky B, Kopeina GS. The DNA-damage response and nuclear events as regulators of nonapoptotic forms of cell death // Oncogene. 2020;39:1–16.
Inomata K, Aoto T, Binh NT et al. Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation // Cell. 2009;137:1088–99.
Schneider L, Pellegatta S, Favaro R et al. DNA damage in mammalian neural stem cells leads to astrocytic differentiation mediated by BMP2 signaling through JAK-STAT // Stem Cell Rep. 2013;1:123–38.
Golomb L, Sagiv A, Pateras IS et al. Age-associated inflammation connects RAS-induced senescence to stem cell dysfunction and epidermal malignancy // Cell Death Differ. 2015;22:1764–74.
Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer // Nat Rev Cancer. 2022. doi:10.1038/s41568-022-00450-9
Demaria M, Ohtani N, Youssef Sameh A et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA // Develop Cell. 2014;31:722–33.
Storer M, Mas A, Robert-Moreno A et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning // Cell. 2013;155:1119–30.
Li Y, Zhao H, Huang X et al. Embryonic senescent cells re-enter cell cycle and contribute to tissues after birth // Cell Res. 2018;28:775–8.
Tripathi U, Misra A, Tchkonia T, Kirkland JL. Impact of senescent cell subtypes on tissue dysfunction and repair: Importance and research questions // Mech Ageing Develop. 2021;198:111548. doi:10.1016/j.mad.2021.111548
Sikora E, Bielak-Zmijewska A, Mosieniak G. A common signature of cellular senescence; does it exist? // Ageing Res Rev. 2021;71:101458. doi:10.1016/j.arr.2021.101458
Golubev AG, Khrustalev S, Butov AA. An in silico investigation into the causes of telomere length heterogeneity and its implications for the Hayflick limit // J Theor Biol. 2003;225:153–70.
Adler FR, Amend SR, Whelan CJ, Baratchart E. From Ecology to Cancer Biology and Back Again // Frontiers Media SA. 2022.
Голубев АГ. Общие принципы взаимоотношений живых организмов с экосистемой и злокачественных клеток с живым организмом // Биосфера. 2022;14:61–74 [Golubev AG. Common principles of interelationships between living organbisms and an ecosystem and between malignant cells and a living organism // Biosfera. 2022;14:61–74 (In Russ.)].
Denmeade S, Antonarakis ES, Markowski MC. Bipolar androgen therapy (BAT): A patient's guide // Prostate. 2022;82:753–62.
Zhang J, Cunningham J, Brown J, Gatenby R. Evolution-based mathematical models significantly prolong response to abiraterone in metastatic castrate-resistant prostate cancer and identify strategies to further improve outcomes // Life. 2022;11:e76284.
Gunnarsson EB, De S, Leder K, Foo J. Understanding the role of phenotypic switching in cancer drug resistance // J Theor Biol. 2020;490:110162. doi:10.1016/j.jtbi.2020.110162
Fane M, Weeraratna AT. How the ageing microenvironment influences tumour progression // Nat Rev Cancer. 2020;20:89–106.
Bouleftour W, Magne N. Aging preclinical models in oncology field: from cells to aging // Aging Clin Exper Res. 2021. doi 10.1007/s40520-021-01981-1:
Habr D, McRoy L, Papadimitrakopoulou VA. Age is just a number: Considerations for older adults in cancer clinical trials // J Natl Cancer Inst. 2021;113:1460–4.
Golubev AG, Anisimov VN. Aging and cancer: Is glucose a mediator between them? // Oncotarget. 2019;10:6758–67.
Li S, Zhu H, Chen H et al. Glucose promotes epithelial-mesenchymal transitions in bladder cancer by regulating the functions of YAP1 and TAZ // J Cell Mol Med. 2020;24:10391–401.
Li W, Zhang L, Chen X et al. Hyperglycemia promotes the epithelial-mesenchymal transition of pancreatic cancer via hydrogen peroxide // Oxid Med Cell Longev. 2016. doi:10.1155/2016/5190314
Wu J, Chen J, Xi Y et al. High glucose induces epithelial‑mesenchymal transition and results in the migration and invasion of colorectal cancer cells // Exper Therap Med. 2018;16:222–30.
Anisimov VN. Metformin for cancer and aging prevention: is it a time to make the long story short? // Oncotarget. 2015;6:39398–407.
Dilman VM, Anisimov VN. Potentiation of antitumor effect of cyclophosphamide and hydrazine sulfate by treatment with the antidiabetic agent, 1-phenylethylbiguanide (phenformin) // Cancer Lett. 1979;7:357–61.
Alexandrov VA, Anisimov VN, Belous NM et al. The inhibition of the transplacental blastomogenic effect of nitrosomethylurea by postnatal administration of buformin to rats // Carcinogenesis. 1980;1:975–8.
Dilman VM, Revskoy SY, Golubev AG. Neuroendocrine-ontogenetic mechanism of aging: toward an integrated theory of aging // Int Rev Neurobiol. 1986;28:89–156.
Samuel SM, Varghese E, Koklesová L et al. Counteracting chemoresistance with metformin in breast cancers: Targeting cancer stem cells // Cancers. 2020;12. doi:10.3390/cancers12092482
Di Matteo S, Nevi L, Overi D et al. Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells // Sci Rep. 2021;11:2557. doi:10.1038/s41598-021-81172-0
Patil S. Metformin treatment decreases the expression of cancer stem cell marker CD44 and stemness related gene expression in primary oral cancer cells // Arch Oral Biol. 2020;113:104710. doi:10.1016/j.archoralbio.2020.104710
Yin W, Liu Y, Liu X et al. Metformin inhibits epithelial-mesenchymal transition of oral squamous cell carcinoma via the mTOR/HIF-1α/PKM2/STAT3 pathway // Oncol Lett. 2021;21:31. doi:10.3892/ol.2020.12292
Seo Y, Kim J, Park SJ et al. Metformin suppresses cancer stem cells through AMPK activation and inhibition of protein prenylation of the mevalonate pathway in colorectal cancer // Cancers. 2020;12. doi 10.3390/cancers12092554:
Zhang C, Wang Y. Metformin attenuates cells stemness and epithelial‑mesenchymal transition in colorectal cancer cells by inhibiting the Wnt3a/β‑catenin pathway // Mol Med Rep. 2019;19:1203–9.
Deschênes-Simard X, Parisotto M, Rowell M-C et al. Circumventing senescence is associated with stem cell properties and metformin sensitivity // Aging Cell. 2019;18:e12889. doi:10.1111/acel.12889
Zahra MH, Afify SM, Hassan G et al. Metformin suppresses self-renewal and stemness of cancer stem cell models derived from pluripotent stem cells // Cell Biochem Funct 2021;39:896–907.
Park JH, Kim YH, Park EH et al. Effects of metformin and phenformin on apoptosis and epithelial-mesenchymal transition in chemoresistant rectal cancer // Cancer Sci. 2019;110:2834–45.
Zhao H, Swanson KD, Zheng B. Therapeutic repurposing of biguanides in cancer // Trends Cancer. 2021;7:714–30.
Kuo CL, Hsieh Li SM, Liang SY et al. The antitumor properties of metformin and phenformin reflect their ability to inhibit the actions of differentiated embryo chondrocyte 1 // Cancer Manag Res. 2019;11:6567–79.
García Rubiño ME, Carrillo E, Ruiz Alcalá G et al. Phenformin as an anticancer agent: Challenges and prospects // Int J Mol Sci. 2019;20. doi:10.3390/ijms20133316
Vara-Ciruelos D, Dandapani M, Russell FM et al. Phenformin, but not metformin, delays development of T cell acute lymphoblastic leukemia/lymphoma via cell-autonomous AMPK activation // Cell Rep. 2019;27:690–8.e4. doi:10.1016/j.celrep.2019.03.067
Дильман ВМ, Берштейн ЛМ, Цырлина ЕВ и др. Коррекция эндокринно-метаболических нарушений у онкологических больных. Эффекты бигуанидов (фенформин и адебита), мисклерона и дифенина // Вопросы онкологии. 1975;21(11):33–9 [Dilman VM, Bershtein LM, Tsyrlina YeV et al. Correction of endorine-metabolic disorders in cancer patients. The effects of biguanides (phenformin and adebit), miscleron and diphenin // Voprosy onkologii. 1975;21(11):33–9 (In Russ.)].
Vidoni C, Ferraresi A, Esposito A et al. Calorie restriction for cancer prevention and therapy: Mechanisms, expectations, and efficacy // J Cancer Prevent. 2021;26:224–36.
Golubev AG. Commentary: Is life extension today a Faustian bargain? // Front Med. 2018;5. doi:10.3389/fmed.2018.00073
Golubev AG. COVID-19: A challenge to physiology of aging // Front Physiol. 2020;11. doi:10.3389/fphys.2020.584248
Голубев АГ, Семиглазова ТЮ, Клюге ВА и др. Три пандемии сразу: неинфекционная (онкологическая), инфекционная (CoVID-19) и поведенческая (гипокинезия) // Вопросы онкологии. 2021;67(2):163–80 [Golubev AG, Semiglazova TY, Klyuge VA et al. Three pandemics at once: noninfectious (cancer), infectious (COVID-19), and behavioral (hypokinesia) // Voprosy onkologii. 2021;67(2):163–80 (In Russ.)].
Yang H, Liu Y, Kong J. Effect of aerobic exercise on acquired gefitinib resistance in lung adenocarcinoma // Translat Oncol. 2021;14:101204. doi:10.1016/j.tranon.2021.101204
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
© АННМО «Вопросы онкологии», Copyright (c) 2022