Therapeutic targeting of replicative immortality
One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolve...
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| Format: | Online |
| Language: | English |
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Academic Press
2015
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600408/ |
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pubmed-4600408 |
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pubmed-46004082016-03-22 Therapeutic targeting of replicative immortality Yaswen, Paul MacKenzie, Karen L. Keith, W. Nicol Hentosh, Patricia Rodier, Francis Zhu, Jiyue Firestone, Gary L. Matheu, Ander Carnero, Amancio Bilsland, Alan Sundin, Tabetha Honoki, Kanya Fujii, Hiromasa Georgakilas, Alexandros G. Amedei, Amedeo Amin, Amr Helferich, Bill Boosani, Chandra S. Guha, Gunjan Ciriolo, Maria Rosa Chen, Sophie Mohammed, Sulma I. Azmi, Asfar S. Bhakta, Dipita Halicka, Dorota Niccolai, Elena Aquilano, Katia Ashraf, S. Salman Nowsheen, Somaira Yang, Xujuan Review One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed “senescence,” can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells’ heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy. Academic Press 2015-12 /pmc/articles/PMC4600408/ /pubmed/25869441 http://dx.doi.org/10.1016/j.semcancer.2015.03.007 Text en © 2015 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Yaswen, Paul MacKenzie, Karen L. Keith, W. Nicol Hentosh, Patricia Rodier, Francis Zhu, Jiyue Firestone, Gary L. Matheu, Ander Carnero, Amancio Bilsland, Alan Sundin, Tabetha Honoki, Kanya Fujii, Hiromasa Georgakilas, Alexandros G. Amedei, Amedeo Amin, Amr Helferich, Bill Boosani, Chandra S. Guha, Gunjan Ciriolo, Maria Rosa Chen, Sophie Mohammed, Sulma I. Azmi, Asfar S. Bhakta, Dipita Halicka, Dorota Niccolai, Elena Aquilano, Katia Ashraf, S. Salman Nowsheen, Somaira Yang, Xujuan |
| spellingShingle |
Yaswen, Paul MacKenzie, Karen L. Keith, W. Nicol Hentosh, Patricia Rodier, Francis Zhu, Jiyue Firestone, Gary L. Matheu, Ander Carnero, Amancio Bilsland, Alan Sundin, Tabetha Honoki, Kanya Fujii, Hiromasa Georgakilas, Alexandros G. Amedei, Amedeo Amin, Amr Helferich, Bill Boosani, Chandra S. Guha, Gunjan Ciriolo, Maria Rosa Chen, Sophie Mohammed, Sulma I. Azmi, Asfar S. Bhakta, Dipita Halicka, Dorota Niccolai, Elena Aquilano, Katia Ashraf, S. Salman Nowsheen, Somaira Yang, Xujuan Therapeutic targeting of replicative immortality |
| author_facet |
Yaswen, Paul MacKenzie, Karen L. Keith, W. Nicol Hentosh, Patricia Rodier, Francis Zhu, Jiyue Firestone, Gary L. Matheu, Ander Carnero, Amancio Bilsland, Alan Sundin, Tabetha Honoki, Kanya Fujii, Hiromasa Georgakilas, Alexandros G. Amedei, Amedeo Amin, Amr Helferich, Bill Boosani, Chandra S. Guha, Gunjan Ciriolo, Maria Rosa Chen, Sophie Mohammed, Sulma I. Azmi, Asfar S. Bhakta, Dipita Halicka, Dorota Niccolai, Elena Aquilano, Katia Ashraf, S. Salman Nowsheen, Somaira Yang, Xujuan |
| author_sort |
Yaswen, Paul |
| title |
Therapeutic targeting of replicative immortality |
| title_short |
Therapeutic targeting of replicative immortality |
| title_full |
Therapeutic targeting of replicative immortality |
| title_fullStr |
Therapeutic targeting of replicative immortality |
| title_full_unstemmed |
Therapeutic targeting of replicative immortality |
| title_sort |
therapeutic targeting of replicative immortality |
| description |
One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed “senescence,” can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells’ heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy. |
| publisher |
Academic Press |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600408/ |
| _version_ |
1613486178450800640 |