Apoptosis and Cancer Progression: Balancing Tumor Suppression and Disease Advancement
Keywords:
Apoptosis, Cancer progression, Programmed cell death, Metastasis, Chemoresistance, Targeted therapyAbstract
Background:
Apoptosis is a tightly regulated form of programmed cell death that is essential for tissue homeostasis, normal development, and tumour suppression. Although defective apoptotic signalling is a hallmark of cancer, accumulating evidence indicates that apoptosis may also paradoxically promote tumour progression through its effects on the tumour microenvironment (TME), giving rise to the concept of the "apoptosis paradox."
Objectives:
To critically review the dual role of apoptosis in cancer progression, with particular emphasis on its immunomodulatory, regenerative, and pro-tumorigenic functions within the TME, and to discuss the therapeutic implications of targeting apoptosis-associated pathways.
Methods:
A comprehensive narrative review of the contemporary literature was conducted using peer-reviewed studies addressing the molecular mechanisms of apoptosis, apoptosis-mediated remodelling of the TME, immune regulation, autophagy, angiogenesis, metastasis, therapeutic resistance, and emerging apoptosis-targeted cancer therapies.
Results:
Current evidence demonstrates that, beyond eliminating damaged or transformed cells, apoptotic tumour cells actively influence the TME by releasing bioactive mediators that regulate immune responses, promote pro-tumorigenic macrophage polarization, stimulate angiogenesis and tissue regeneration, and facilitate tumour growth, metastatic dissemination, and resistance to therapy. Furthermore, the intricate interplay between apoptosis, autophagy, and immune signalling highlights the context-dependent nature of programmed cell death in cancer biology, challenging the traditional view of apoptosis as solely tumour suppressive.
Conclusions:
Apoptosis exhibits a dualistic role in cancer, functioning as both a tumour-suppressive and tumour-promoting process depending on the biological context. A deeper understanding of apoptosis-mediated interactions within the TME may uncover novel therapeutic targets and support the development of precision-based strategies that improve treatment efficacy and clinical outcomes in patients with cancer.
References
Parthita Das, Deeti Das, Suranjana Sarkar, Subhasis Sarkar and Bidisha Ghosh. Apoptotic genes which are involved in stem cell division: Their mutation and effects. Int. J. Clin. Biol. Biochem. 2024;6(1):37-40.
Wyllie, A.H. The biology of cell death in tumours. Anticancer Res. 1985, 5, 131–136.
Iversen, U.; Iversen, O.H.; Bluming, A.Z.; Ziegler, J.L.; Kyalwasi, S. Cell kinetics of African cases of Burkitt lymphoma. A preliminary report. Eur. J. Cancer 1972, 8, 305–308.
Langley, R.R.; Fidler, I.J. The seed and soil hypothesis revisited—the role of tumor-stroma interactions in metastasis to different organs. Int. J. Cancer 2011, 128, 2527–2535.
Elia, I.; Haigis, M.C. Metabolites and the tumour microenvironment: From cellular mechanisms to systemic metabolism. Nat. Metab. 2021, 3, 21–32.
Wang Q, Shao X, Zhang Y, Zhu M, Wang FXC, Mu J, et al. Role of tumor microenvironment in cancer progression and therapeutic strategy. Cancer Medicine. 2023 Feb 21;12(10).
Hinshaw DC, Shevde LA. The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Research. 2019 Jul 26;79(18):4557–66.
Wang,M.;Zhao,J.; Zhang, L.; Wei, F.; Lian, Y.; Wu, Y.; Gong, Z.; Zhang, S.; Zhou, J.; Cao, K.; et al. Role of tumor microenvironment in tumorigenesis. J. Cancer 2017, 8, 761–773.
Bairey, O.; Zimra, Y.; Shaklai, M.; Okon, E.; Rabizadeh, E. Bcl-2, Bcl-X, Bax, and Bak expression in short- and long-lived patients with diffuse large B-cell lymphomas. Clin. Cancer Res. 1999, 5, 2860–2866.
Hu,Q.;Peng, J.; Liu, W.; He, X.; Cui, L.; Chen, X.; Yang, M.; Liu, H.; Liu, S.; Wang, H. Elevated cleaved caspase-3 is associated with shortened overall survival in several cancer types. Int. J. Clin. Exp. Pathol. 2014, 7, 5057–5070.
Berardo, M.D.; Elledge, R.M.; de Moor, C.; Clark, G.M.; Osborne, C.K.; Allred, D.C. bcl-2 and apoptosis in lymph node positive breast carcinoma. Cancer 1998, 82, 1296–1302.
Labi, V.; Erlacher, M. How cell death shapes cancer. Cell Death Dis. 2015, 6, e1675.
Kim, R.; Kin, T.; Beck, W.T. Impact of Complex Apoptotic Signaling Pathways on Cancer Cell Sensitivity to Therapy. Cancers 2024, 16, 984. https://doi.org/10.3390/ cancers16050984
Gregory, C.D.; Ford, C.A.; Voss, J.J. Microenvironmental Effects of Cell Death in Malignant Disease. Adv. Exp. Med. Biol. 2016, 930, 51–88.
Holmgren, L.; O’Reilly, M.S.; Folkman, J. Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat. Med. 1995, 1, 149–153.
Perez-Garijo, A.; Fuchs, Y.; Steller, H. Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway. eLife 2013, 2, e01004
Wong, R.S. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30, 87 (2011). https://doi.org/10.1186/1756-9966-30-87
Fond, A.M.; Ravichandran, K.S. Clearance of Dying Cells by Phagocytes: Mechanisms and Implications for Disease Pathogenesis. Adv. Exp. Med. Biol. 2016, 930, 25–49.
Gregory, C.D.; Paterson, M. An apoptosis-driven ‘onco-regenerative niche’: Roles of tumour-associated macrophages and extracellular vesicles. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2017, 373, 1737.
Boada-Romero, E.; Martinez, J.; Heckmann, B.L.; Green, D.R. The clearance of dead cells by efferocytosis. Nat. Rev. Mol. Cell Biol. 2020, 21, 398–414.
Koren, E.; Fuchs, Y. Modes of Regulated Cell Death in Cancer. Cancer Discov. 2021, 11, 245–265.
Obenauf, A.C.; Zou, Y.; Ji, A.L.; Vanharanta, S.; Shu, W.; Shi, H.; Kong, X.; Bosenberg, M.C.; Wiesner, T.; Rosen, N.; et al. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature 2015, 520, 368–372.
Truman, L.A.; Ford, C.A.; Pasikowska, M.; Pound, J.D.; Wilkinson, S.J.; Dumitriu, I.E.; Melville, L.; Melrose, L.A.; Ogden, C.A.; Nibbs, R.; et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 2008, 112, 5026–5036.
Weigert, A.; Mora, J.; Sekar, D.; Syed, S.; Brune, B. Killing Is Not Enough: How Apoptosis Hijacks Tumor-Associated Macrophages to Promote Cancer Progression. Adv. Exp. Med. Biol. 2016, 930, 205–239.
Weichand, B.; Popp, R.; Dziumbla, S.; Mora, J.; Strack, E.; Elwakeel, E.; Frank, A.C.; Scholich, K.; Pierre, S.; Syed, S.N.; et al. S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1beta. J. Exp. Med. 2017, 214, 2695–2713.
Miksa, M.; Amin, D.; Wu, R.; Ravikumar, T.S.; Wang, P. Fractalkine-induced MFG-E8 leads to enhanced apoptotic cell clearance by macrophages. Mol. Med. 2007, 13, 553–560.
Bournazou, I.; Pound, J.D.; Duffin, R.; Bournazos, S.; Melville, L.A.; Brown, S.B.; Rossi, A.G.; Gregory, C.D. Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin. J. Clin. Investig. 2009, 119, 20–32.
Bournazou, I.; Mackenzie, K.J.; Duffin, R.; Rossi, A.G.; Gregory, C.D. Inhibition of eosinophil migration by lactoferrin. Immunol. Cell Biol. 2010, 88, 220–223.
Nagata, S.; Suzuki, J.; Segawa, K.; Fujii, T. Exposure of phosphatidylserine on the cell surface. Cell Death Differ. 2016, 23, 952–961.
Dransfield, I.; Farnworth, S. Axl and Mer Receptor Tyrosine Kinases: Distinct and Nonoverlapping Roles in Inflammation and Cancer? Adv. Exp. Med. Biol. 2016, 930, 113–132.
Stanford, J.C.; Young, C.; Hicks, D.; Owens, P.; Williams, A.; Vaught, D.B.; Morrison, M.M.; Lim, J.; Williams, M.; Brantley-Sieders, D.M.; et al. Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. J. Clin. Investig. 2014, 124, 4737–4752.
Bock, F.J.; Sedov, E.; Koren, E.; Koessinger, A.L.; Cloix, C.; Zerbst, D.; Athineos, D.; Anand, J.; Campbell, K.J.; Blyth, K.; et al. Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death. Nat. Commun. 2021, 12, 6572.
Cvetanovic, M.; Mitchell, J.E.; Patel, V.; Avner, B.S.; Su, Y.; van der Saag, P.T.; Witte, P.L.; Fiore, S.; Levine, J.S.; Ucker, D.S. Specific recognition of apoptotic cells reveals a ubiquitous and unconventional innate immunity. J. Biol. Chem. 2006, 281, 20055–20067.
Medina, C.B.; Mehrotra, P.; Arandjelovic, S.; Perry, J.S.A.; Guo, Y.; Morioka, S.; Barron, B.; Walk, S.F.; Ghesquiere, B.; Krupnick, A.S.; et al. Metabolites released from apoptotic cells act as tissue messengers. Nature 2020, 580, 130–135.
Ford, C.A.; Petrova, S.; Pound, J.D.; Voss, J.J.; Melville, L.; Paterson, M.; Farnworth, S.L.; Gallimore, A.M.; Cuff, S.; Wheadon, H.; et al. Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma. Curr. Biol. 2015, 25, 577–588.
Li, F.; Huang, Q.; Chen, J.; Peng, Y.; Roop, D.R.; Bedford, J.S.; Li, C.Y. Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration. Sci. Signal. 2010, 3, ra13.
Lauber, K.; Herrmann, M. Tumor biology: With a little help from my dying friends. Curr. Biol. 2015, 25, R198–R201.
Ichim, G.; Lopez, J.; Ahmed, S.U.; Muthalagu, N.; Giampazolias, E.; Delgado, M.E.; Haller, M.; Riley, J.S.; Mason, S.M.; Athineos, D.; et al. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol. Cell 2015, 57, 860–872.
Perez-Garijo, A.; Steller, H. Spreading the word: Non-autonomous effects of apoptosis during development, regeneration and disease. Development 2015, 142, 3253–3262.
Mantovani, A.; Sozzani, S.; Locati, M.; Allavena, P.; Sica, A. Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002, 23, 549–555
Sica, A.; Larghi, P.; Mancino, A.; Rubino, L.; Porta, C.; Totaro, M.G.; Rimoldi, M.; Biswas, S.K.; Allavena, P.; Mantovani, A. Macrophage polarization in tumour progression. Semin. Cancer Biol. 2008, 18, 349–355.
Gordon, S.; Mantovani, A. Diversity and plasticity of mononuclear phagocytes. Eur. J. Immunol. 2011, 41, 2470–2472.
Balkwill, F.R.; Mantovani, A. Cancer-related inflammation: Common themes and therapeutic opportunities. Semin. Cancer Biol. 2012, 22, 33–40.
Reiter, I.; Krammer, B.; Schwamberger, G. Cutting edge: Differential effect of apoptotic versus necrotic tumor cells on macrophage antitumor activities. J. Immunol. 1999, 163, 1730–1732.
Voss, J.J.L.P.; Ford, C.A.; Petrova, S.; Melville, L.; Paterson, M.; Pound, J.D.; Holland, P.; Giotti, B.; Freeman, T.C.; Gregory, C.D. Modulation of macrophage antitumor potential by apoptotic lymphoma cells. Cell Death Differ. 2017, 24, 971–983.
Degenhardt, K.; Mathew, R.; Beaudoin, B.; Bray, K.; Anderson, D.; Chen, G.; Mukherjee, C.; Shi, Y.; Gelinas, C.; Fan, Y.; et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 2006, 10, 51–64.
Ge, J.; Chen, Z.; Huang, J.; Chen, J.; Yuan, W.; Deng, Z.; Chen, Z. Upregulation of autophagy-related gene-5 (ATG-5) is associated with chemoresistance in human gastric cancer. PLoS ONE 2014, 9, e110293.
Fulda, S. Autophagy in Cancer Therapy. Front. Oncol. 2017, 7, 128.
Tilija Pun, N.; Jang, W.J.; Jeong, C.H. Role of autophagy in regulation of cancer cell death/apoptosis during anti-cancer therapy: Focus on autophagy flux blockade. Arch. Pharmacal Res. 2020, 43, 475–488.
Panda,P.K.; Mukhopadhyay,S.; Das, D.N.; Sinha, N.; Naik, P.P.; Bhutia, S.K. Mechanismofautophagicregulationin carcinogenesis and cancer therapeutics. Semin. Cell Dev. Biol. 2015, 39, 43–55.
Celesia, A.; Morana, O.; Fiore, T.; Pellerito, C.; D’Anneo, A.; Lauricella, M.; Carlisi, D.; De Blasio, A.; Calvaruso, G.; Giuliano, M.; et al. ROS-Dependent ER Stress and Autophagy Mediate the Anti-Tumor Effects of Tributyltin (IV) Ferulate in Colon Cancer Cells. Int. J. Mol. Sci. 2020, 21, 8135.
Das, G.; Shravage, B.V.; Baehrecke, E.H. Regulation and function of autophagy during cell survival and cell death. Cold Spring Harb. Perspect. Biol. 2012, 4, a008813.
Eskelinen, E.L. The dual role of autophagy in cancer. Curr. Opin. Pharmacol. 2011, 11, 294–300.
Towers, C.G.; Wodetzki, D.; Thorburn, A. Autophagy and cancer: Modulation of cell death pathways and cancer cell adaptations. J. Cell Biol. 2020, 219, e201909033.
Verma, A.K.; Bharti, P.S.; Rafat, S.; Bhatt, D.; Goyal, Y.; Pandey, K.K.; Ranjan, S.; Almatroodi, S.A.; Alsahli, M.A.; Rahmani, A.H.; et al. Autophagy Paradox of Cancer: Role, Regulation, and Duality. Oxidative Med. Cell. Longev. 2021, 2021, 8832541.
