SUMMARY. In recent decades, the efforts of specialists in different fields of medicine have been aimed at determining the role of stress in the onset of cancer and subsequent tumor progression due to the invasive migration of malignancy transformed cells and the formation of metastasis. Merely subjective assertions about the existence of a connection between the malignant process development and the action of the factors, capable of triggering malignant transformation of cells, are insufficient. At present, the results obtained in the in vitro and in vivo studies or confirmed by numerous clinical observations ex vivo are considered to be evidential. The review raises questions about the manifestations of stress on the cellular level, which is deemed to be a trigger of tumor progression. It was demonstrated that cellular stress covers a wide range of intracellular structural and functional changes and molecular transformations that occur in cells in response to stressful environmental factors, including mechanical damage, extreme temperatures, impact of trauma, hypoxia, oxidative stress, and some viral infections. The mechanisms by which intracellular impairments promote malignant growth and progression of neoplasms with different histogenesis were characterized. In particular, these include DNA damage, the formation of disordered proteins, mitochondrial signaling stress, the stress of the endoplasmic reticulum, and the proliferation or elimination of damaged cells. It was shown that cells may react to stress in different ways, from the activation of survival modes to the initiation of cellular death. Therefore, the structural, functional, and molecular biological changes on the cellular and subcellular levels that occur due to the cellular stress should be considered as possible targets in the elaboration of the methods of target chemotherapy, on the one hand, and in planning the means of preventing the occurrence of malignant neoplasms, on the other hand.
Keywords: cellular stress, stressors, intracellular organelles, structural and functional impairments, carcinogenesis, proliferation, invasion, metastases, apoptosis
Full text and supplemented materials
Free full text: PDFReferences
Abrisch, R.G., Gumbin, S.C., Wisniewski, B.T., Lackner, L.L., and Voeltz, G.K., Fission and fusion machineries converge at ER contact sites to regulate mitochondrial morphology, J. Cell Biol., 2020, vol. 219. https://doi.org/10.1083/jcb.201911122
Almanza, A., Carlesso, A., Chintha C., et al., Endoplasmic reticulum stress signalling—From basic mechanisms to clinical applications, FEBS J., 2018. https://doi.org/10.1111/febs.14608
An, G., Park, J., Song, J., et al., Relevance of the endoplasmic reticulum-mitochondria axis in cancer diagnosis and therapy, Exp. Mol. Med., 2024, vol. 56, pp. 40–50. https://doi.org/10.1038/s12276-023-01137-3
Antonangeli, F., Grimsholm, O., Rossi, M.N., and Velotti, F., Editorial: Cellular stress and inflammation: how the immune system drives tissue homeostasis, Front. Immunol., 2021, vol. 12, p. 668876. https://doi.org/10.3389/fimmu.2021.668876
Bottone, M.G., Santin, G., Aredia, F., et al., Morphological features of organelles during apoptosis: An overview, Cells, 2013, vol. 2, pp. 294–305. https://doi.org/10.3390/cells2020294
Cai, W., Sun, X., Jin, F., Xiao, D., Li, H., Sun, H., et al., PERK-eIF2α-ERK1/2 axis drives mesenchymal-endothelial transition of cancer-associated fibroblasts in pancreatic cancer, Cancer Lett., 2021, vol. 515, pp. 86–95. https://doi.org/10.1016/j.canlet.2021.05.021
Chen, X. and Cubillos-Ruiz, J.R., Endoplasmic reticulum stress signals in the tumour and its microenvironment, Nat. Rev. Cancer, 2021, vol. 21, pp. 71–88. https://doi.org/10.1038/s41568-020-00312-2
Cortesi, M., Rossino, G., Chakrabarty, A., and Rossi, D., Tumor adaptation to cellular stresses: Mechanisms, biomarkers and therapeutic opportunities, Front. Med., 2023, vol. 10, p. 1268976. https://doi.org/10.3389/fmed.2023.1268976
Denais, C.M., Gilbert, R.M., Isermann, P., et al., Nuclear envelope rupture and repair during cancer cell migration, Science, 2016, vol. 352, pp. 353–358. https://doi.org/10.1126/science.aad7297
DuFort, Ch.,C., Paszek, M.J., and Weaver, V.M., Balancing forces: architectural control of mechanotransduction, Nat. Rev. Mol. Cell. Biol., 2011, vol. 12, pp. 308–319. https://doi.org/10.1038/nrm3112
Fan, F., Liu, F., Shen, P., Tao, L., Zhang, H., and Wu., H., Salvianolic acid B, a new type I IRE1 kinase inhibitor, abrogates AngII-induced angiogenesis by interacting with IRE1 in its active conformation, Clin. Exp. Pharmacol. Physiol., 2023, vol. 50, pp. 82–95. https://doi.org/10.1111/1440-1681.13726
Farhad, H.A., An overview of Stress in cellular and molecular levels and the importance of studying responses to stresses in biology, Res. J. Biotechnol., 2021, vol. 16, pp. 258–282.
Fernandez, M.K., Sinha, M., Zidan, M., and Renz, M., Nuclear actin filaments – A historical perspective, Nucleus, 2024, vol. 15, p. 2320656. https://doi.org/10.1080/19491034.2024.2320656
Fu, Y., Zou, T., and Shen, X., Lipid metabolism in cancer progression and therapeutic strategies, MedComm, 2020, vol. 2, pp. 27–59. https://doi.org/10.1002/mco2.27
Fulda, S., Gorman, A.M., Hori, O., and Samali, A., Cellular stress responses: Cell survival and cell death, Cell Bio-l., 2010. https://doi.org/10.1155/2010/214074
Gao, Z.W., Wang, H.P., Lin, F., Wang, X., Long, M., Zhang, H.Z. and Dong, K., CD73 promotes proliferation and migration of human cervical cancer cells independent of its enzyme activity, BMC Cancer, 2017, vol. 17, pp. 1–8. https://doi.org/10.1186/s12885-017-3128-5
Gruber, L., Jobst, M., Kiss, E., et al., Intracellular remodeling associated with endoplasmic reticulum stress modifies biomechanical compliance of bladder cells, Cell Commun. Signal., 2023, vol. 21, p. 307. https://doi.org/10.1186/s12964-023-01295-x
Halász, H., Szatmári, Z., Kovács, K., et al., Changes of ex vivo cervical epithelial cells due to electroporation with JMY, Int. J. Mol. Sci., 2023, vol. 24, p. 16863. https://doi.org/10.3390/ijms242316863
Harry, J.A. and Ormiston, M.L., Novel pathways for targeting tumor angiogenesis in metastatic breast cancer, Front. Oncol., 2021, vol. 11, p. 772305. https://doi.org/10.3389/fonc.2021.772305
Heo, S.-J., Driscoll, T.P., Thorpe, S.D., et al., Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity, Elife, 2016, vol. 30, p. e18207. https://doi.org/10.7554/eLife.18207
Hochberg-Laufer, H., Schwed-Gross, A., Neugebauer, K.M., and Shav-Tal, Ya., Uncoupling of nucleo-cytoplasmic RNA export and localization during stress, Nucleic Acids Res., 2019, vol. 47, pp. 4778–4797. https://doi.org/10.1093/nar/gkz168
Iqbal, M.J., Kabeer, A., Abbas, Z., et al., Interplay of oxidative stress, cellular communication and signaling pathways in cancer, Cell Commun. Signal., 2024, vol. 22, pp. 1–16. https://doi.org/10.1186/s12964-023-01398-5
Isah, T., Stress and defense responses in plant secondary metabolites production, Biol. Res., 2019, vol. 52, p. 39. https://doi.org/10.1186/s40659-019-0246-3
Jaecker, F.F., Almeida, J.A., Krull, C.M., et al., Nucleoli in epithelial cell collectives respond to tumorigenic, spatial, and mechanical cues, Mol. Biol. Cell, 2022, vol. 33. https://doi.org/10.1091/mbc.E22-02-0070
Jin, Y., Tan, Y., Wu, J., and Ren, Z., Lipid droplets: A cellular organelle vital in cancer cells, Cell Death Discovery, 2023, vol. 9, p. 254.
Katona, M., Bartók, Á., Nichtova, Z., et al., Capture at the ER-mitochondrial contacts licenses IP(3) receptors to stimulate local Ca2+ transfer and oxidative metabolism, Nat. Commun., 2022, vol. 13, p. 6779. https://doi.org/10.1038/s41467-022-34365-8
Kim, K.H. and Lee, Ch.B., Socialized mitochondria: mitonuclear crosstalk in stress, Exp. Mol. Med., 2024, vol. 56, pp. 1033–1042. https://doi.org/10.1038/s12276-024-01211-4
Kim, T., Han, S., Chun, Y., Yang, H., Min, H., Jeon, S.Y., Kim, J., Moon, H.-G., and Lee, D., Comparative characterization of 3D chromatin organization in triple-negative breast cancers, Exp. Mol. Med., 2022, vol. 54, pp. 585–600. https://doi.org/10.1038/s12276-022-00768-2
Lafontaine, D.L.J., Riback, J.A., Bascetin, R., and Brangwynne, C.P., The nucleolus as a multiphase liquid condensate, Nat. Rev. Mol. Cell. Biol., 2021, vol. 22, pp. 165–182. https://doi.org/10.1038/s41580-020-0272-6
Latonen, L., Phase-to-phase with nucleoli - stress responses, protein aggregation and novel roles of RNA, Front. Cell. Neurosci., 2019, vol. 26, p. 151. https://doi.org/10.3389/fncel.2019.00151
Lechuga, S. and Ivanov, A.I., Actin cytoskeleton dynamics during mucosal inflammation: A view from broken epithelial barriers, Curr. Opin. Physiol., 2021, vol. 19, pp. 10–16. https://doi.org/10.1016/j.cophys.2020.06.012
Lewinska, A., Bednarz, D., Adamczyk-Grochala J., and Wnuk, M., Phytochemical-induced nucleolar stress results in the inhibition of breast cancer cell proliferation, Redox Biol., 2017, vol. 12, pp. 469–482. https://doi.org/10.1016/j.redox.2017.03.014
Limia, C.M., Sauzay, C., Urra, H., et al., Emerging roles of the endoplasmic reticulum associated unfolded protein response in cancer cell migration and invasion, Cancers, 2019, vol. 11, p. 631. https://doi.org/10.3390/cancers11050631
Lindström, M.S., Jurada, D., Bursac, S., Orsolic, I., Bartek, J., and Volarevic, S., Nucleolus as an emerging hub in maintenance of genome stability and cancer pathogenesis, Oncogene, 2018, vol. 37, pp. 2351–2366. https://doi.org/10.1038/s41388-017-0121-z
Liu, J. and Add, Y.A., Tools to dissect lipid droplet regulation, players, and mechanisms, ACS Chem. Biol., 2025, vol. 20, pp. 539–552. https://doi.org/10.1021/acschembio.4c00835
Liu, X., Zhang X., Zhao, L., Long, J., Feng, Z., Su, J., Gao, F., and Liu, J., Mitochondria as a sensor, a central hub and a biological clock in psychological stress-accelerated aging, Ageing. Res. Rev., 2024, vol. 93, p. 102145. https://doi.org/10.1016/j.arr.2023.102145
Lu, H., Wang, X., Li, M., Ji, D., Liang, D., Liang, C., Liu, Y., Zhang, Z., Cao, Y., and Zou, W., Mitochondrial unfolded protein response and integrated stress response as promising therapeutic targets for mitochondrial diseases, Cells, 2022, vol. 12, p. 20. https://doi.org/10.3390/cells12010020
Maeshima, K., Iida, S., and Tamura, S., Physical Nature of Chromatin in the Nucleus, Cold Spring Harbor Perspect. Med., 2021, vol. 13, p. a040675. https://doi.org/10.1101/cshperspect.a040675
Miller, B., Kim, S.J., Kumagai, H., Yen, K., and Cohen, P., Mitochondria-derived peptides in aging and healthspan, J. Clin. Invest., 2022, vol. 132, p. e158449. https://doi.org/10.1172/JCI158449
Molines, A.T., Lemiere, J., Goshima, G., and Chang, F., Effect of cytoplasm concentration on cytoskeleton dynamics, Biophys. J., 2010, vol. 118, p. 351a. https://doi.org/10.1016/j.bpj.2019.11.2022
Nakagawa, K., Lokugamage, G., and Makino, S., Viral and cellular mRNA translation in coronavirus-infected cells, Adv. Virus Res. Coronaviruses, 2016, vol. 96, pp. 165–192. https://doi.org/10.1016/bs.aivir.2016.08.001
Nie, Zh., Chen, M., Wen, X., et al., Endoplasmic reticulum stress and tumor microenvironment in bladder cancer: the missing link, Front. Cell Dev. Biol., 2021, vol. 9. https://doi.org/10.3389/fcell.2021.683940
Northcott, J.M., Dean, I.S., Mouw, J.K., and Weaver, V.M., Feeling stress: the mechanics of cancer progression and aggression, Front. Cell Dev. Biol., 2018, vol. 6. https://doi.org/10.3389/fcell.2018.00017
Obr, A.E., Kumar, S., Chang, Y-J., Bulatowicz, J.J., Barnes, B.J., Birge, R.B., Lazzarino, D.A., Gallagher, E., LeRoith, D., and Wood, T.L., Insulin-like growth factor receptor signaling in breast tumor epithelium protects cells from endoplasmic reticulum stress and regulates the tumor microenvironment, Breast Cancer Res., 2018, vol. 20, p. 138. https://breast-cancer-research.biomedcentral.com/articles/10.1186/ s13058-018-1063-2.
Orsolic, I., Jurada, D., Pullen, N., et al., The relationship between the nucleolus and cancer: Current evidence and emerging paradigms, Semin. Cancer Biol., 2016, vol. 37, pp. 36–50. https://doi.org/10.1016/j.semcancer.2015.12.004
Palumbieri, M.D., Merigliano, C., Gonzalez-Acosta, D., et al., Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity, Nat. Commun., 2023, vol. 14, p. 7819. https://doi.org/10.1038/s41467-023-43183-5
Panas, M.D., Ivanov, P., and Anderson, P., Mechanistic insights into mammalian stress granule dynamics, J. Cell. Biol., 2016, vol. 215, pp. 313–323. https://doi.org/10.1083/jcb.201609081
Pérez-Domínguez, S., Kulkarni, S.G., Pabijan, J., et al., Reliable, standardized measurements for cell mechanical properties, Nanoscale, 2023, vol. 15, pp. 16371–16380. https://doi.org/10.1039/d3nr02034g
Pianese, G., Beitrag zur Histologie und Aetiologie des Carcinoms, Jena: G. Fischer, 1896. https://wellcomecollection.org/works/wb835qxp.
Poljšak, B. and Milisav, I., Clinical implications of cellular stress responses, Bosnian J. Basic Med. Sci., 2012, vol. 12, pp. 122–126. https://doi.org/10.17305/bjbms.2012.2510
Prasad, M., Walker, A.N., Kaur, J., et al., Endoplasmic reticulum stress enhances mitochondrial metabolic activity in mammalian adrenals and gonads, Mol. Cell Biol., 2016, vol. 36, pp. 3058–3074. https://doi.org/10.1128/MCB.00411-16
Pundel, O.J., Blowes, L.M., and Connelly, J.T., Extracellular adhesive cues physically define nucleolar structure and function, Adv. Sci., 2022, vol. 9, p. e2105545. https://doi.org/10.1002/advs.202105545
Reineke, L.C., Cheema, S.A., Dubrulle, J., and Neilson, J.R., Chronic starvation induces noncanonical pro-death stress granules, J. Cell Sci., 2018, vol. 131, p. jcs220244. https://doi.org/10.1242/jcs.220244
Sakaguchi, M., Kitaguchi, D., Morinami, S., Kurashiki, Y., Hashida, H., Miyata, S., Yamaguchi, M., Sakai, M., Murata, N., and Tanaka, S., Berberine-induced nucleolar stress response in a human breast cancer cell line, Biochem. Biophys. Res. Commun., 2020, vol. 528, pp. 227–233. https://doi.org/10.1016/j.bbrc.2020.05.020
Schneider, E., Rissiek, A., Winzer, R., Puig, B., Rissiek, B., Haag, F., Mittrücker, H.W., Magnus, T., and Tolosa, E., Generation and function of non-cell-bound CD73 in inflammation, Front. Immunol., 2019, vol. 10, p. 1729. https://doi.org/10.3389/fimmu.2019.01729
Sehgal, P. and Chaturvedi, P., Chromatin and cancer: implications of disrupted chromatin organization in tumorigenesis and its diversification, Cancers, 2023, vol. 15, p. 466. https://doi.org/10.3390/cancers15020466
Sekine, Y., Houston, R., and Sekine, S., Cellular metabolic stress responses via organelles, Exp. Cell Res., 2021, vol. 400, p. 112515. https://doi.org/10.1016/j.yexcr.2021.112515
Siklos, M. and Kubicek, S., Therapeutic targeting of chromatin: status and opportunities, FEBS J., 2022, vol. 289, pp. 1276–1301. https://doi.org/10.1111/febs.15966
Stephens, P.J., Greenman, C.D., Fu, B., et al., Massive genomic rearrangement acquired in a single catastrophic event during cancer development, Cell, 2011, vol. 144, pp. 27–40. https://doi.org/10.1016/j.cell.2010.11.055
Stephens A.D., Liu, P.Z., Kandula, W., et al., Physicochemical mechanotransduction alters nuclear shape and mechanics via heterochromatin formation, Mol. Biol. Cell, 2019, vol. 30, pp. 2320–2330. https://doi.org/10.1091/mbc.E19-05-0286
Strom, A.R., Biggs, R.J., Banigan, E.J., Wang, X., Chiu, K., Herman, C., Collado, J., Yue, F., Politz, J.C.R., Tait, L.J., et al., Hp1α is a chromatin crosslinker that controls nuclear and mitotic chromosome mechanics, Elife, 2021, vol. 10, pp. 1–30. https://doi.org/10.7554/eLife.63972
Terzoudi, G.I., Karakosta, M., Pantelias, A., et al., Stress induced by premature chromatin condensation triggers chromosome shattering and chromothripsis at DNA sites still replicating in micronuclei or multinucleate cells when primary nuclei enter mitosis, Mutat. Res., Genet. Toxicol. Environ. Mutagen., 2015, vol. 793, pp. 185–198. https://doi.org/10.1016/j.mrgentox.2015.07.014
Vilarrasa-Blasi, R., Soler-Vila, P., Verdaguer-Dot, N., Russiñol N., Di Stefano, M., Chapaprieta, V., Clot, G., Farabella, I., Cuscó, P., Kulis, M., et al., Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation, Nat. Commun., 2021, vol. 12, p. 651. https://doi.org/10.1038/s41467-020-20849-y
Wang, A., Kolhe, J.A., Gioacchini, N., et al., Mechanism of long-range chromosome motion triggered by gene activation, Dev. Cell, 2020, vol. 52, pp. 309–320. https://doi.org/10.1016/j.devcel.2019.12.007
Wang, F., Zhang, D., Zhang, D., Li, P., and Gao, Y., Mitochondrial protein translation: emerging roles and clinical significance in disease, Front. Cell. Dev. Biol., 2021, vol. 9, p. 675465. https://doi.org/10.3389/fcell.2021.675465
Wang, Z.-H., Chen, L., Li, W., et al., Mitochondria transfer and transplantation in human health and diseases, Mitochondrion, 2022, vol. 65, pp. 80–87. https://doi.org/10.1016/j.mito.2022.05.002
Weeks, S.E., Metge, B.J., and Samant, R.S., The nucleolus: a central response hub for the stressors that drive cancer progression, Cell. Mol. Life Sci., 2019, vol. 76, pp. 4511–4524. https://doi.org/10.1007/s00018-019-03231-0
Wei, M., Fan, X., Ding, M., et al., Nuclear actin regulates inducible transcription by enhancing RNA polymerase II clustering, Sci. Adv., 2020, vol. 6, p. eaay6515. https://doi.org/10.1126/sciadv.aay6515
Welch, W.I. and Suhan, J.P., Morphological study of the mammalian stress response: characterization of changes in cytoplasmic organelles, cytoskeleton, and nucleoli, and appearance of intranuclear actin filaments in rat fibroblasts after heat-shock treatment, J. Cell Biol., 1985, vol. 101, pp. 1198–1211. https://doi.org/10.1083/jcb.101.4.1198
Wu, H., Chen, W., Chen, Z., Li, X., and Wang, M., Novel tumor therapy strategies targeting endoplasmic reticulum-mitochondria signal pathways, Ageing Res. Rev., 2023, vol. 88, p. 101951. https://doi.org/10.1016/j.arr.2023.101951
Zarrella, S., Miranda, M.R., Covelli, V., Restivo, I., Novi, S., Pepe, G., Tesoriere, L., Rodriquez, M., Bertamino, A., Campiglia, P., Tecce, M.F., and Vestuto, V., Endoplasmic reticulum stress and its role in metabolic reprogramming of cancer, Metabolites, 2025, vol. 15, p. 221. https://doi.org/10.3390/metabo15040221
Zhang, Y.-G., Niu, J.-T., Wu, H.-W., et al., Actin-binding proteins as potential biomarkers for chronic inflammation-induced cancer diagnosis and therapy, Anal. Cell. Pathol., 2021 vol. 2021, p. 6692811. https://doi.org/10.1155/2021/6692811
Zhang, Y., Yao, J., Zhang, M., Wang, Y. and Shi, X., Mitochondria-associated endoplasmic reticulum membranes (MAMs): Possible therapeutic targets in heart failure, Front. Cardiovasc. Med., 2023, vol. 10. https://doi.org/10.3389/fcvm.2023.1083935
Zhang, W., Shi, Yi., Oyang, L., et al., Endoplasmic reticulum stress-a key guardian in cancer, Cell Death Discovery, 2024, vol. 10, p. 343. https://doi.org/10.1038/s41420-024-02110-3