It’s now been over two decades since the Hallmarks of Cancer proposed by Douglas Hanahan and Robert Weinberg were first published (1), during which time the landscape of cancer research has changed considerably. In addition to the original six biological capabilities put forward as being acquired during the multistep development of human tumors, which included enabling replicative immortality, the “next generation” of hallmarks introduced two emerging hallmarks and two enabling characteristics (2). The “new dimensions” of the Hallmarks of Cancer proposed most recently incorporates additional emerging hallmarks and enabling characteristics, including senescent cells (3).
Telomeres, protective structures that “cap” the ends of linear chromosomes and preserve genome stability (4, 5), are major players in enabling replicative immortality. Due to the end-replication problem and a variety of lifestyle factors and stresses, telomere length erodes with cell division and aging, causing telomeres to shorten until reaching a critically shortened length, at which point they become dysfunctional and a permanent cell cycle arrest known as replicative senescence is entered (6–8).
Telomere shortening-induced senescence serves as an effective barrier to unlimited cell growth, and therefore represents an important tumor suppressor mechanism 9). However, senescence also underlies important phenotypes associated with aging and cancer; specifically, the senescence-associated secretory phenotype (SASP) promotes chronic inflammation and drives degenerative pathologies and carcinogenesis (10).
The cellular mortality enforced by progressive telomere shortening can be circumvented by telomerase, the specialized reverse transcriptase (TERT) whose integral RNA component (TERC) serves as a template for de novo addition of telomeric repeats onto newly replicated chromosomal termini (11, 12). However, telomerase activity is sufficient to maintain telomere length only in highly proliferative populations, such as germline and stem cells, and the vast majority of cancer cells in which mutations in the TERT promoter region or alternative splicing of the TERT transcript endow them with unlimited replicative potential (13, 14). Telomerase also has extracurricular activities associated with increasing cell proliferation, inhibiting anti-growth signaling, and activating invasion, therefore telomerase has also been proposed as a central regulator of all the hallmarks of cancer (15).
This special Research Topic highlights recent research and advances specifically related to the hallmark of replicative immortality. Articles in the collection cover a range of tumor types, including glioblastoma, pancreatic, gastric, colon, colorectal, and canine oral squamous cell carcinoma, and investigate key players such as telomerase activity, telomere length dynamics and regulation, and the immune landscape. The ultimate goal of all such studies is to identify actionable targets that inform targeted therapies aimed at countering tumor cell proliferation and immortality and improving treatment outcomes. Future studies will need to further investigate the emerging hallmarks and enabling characteristics, including the contributing and seemingly contradictory roles of senescent cells.
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Author contributions
The author confirms being the sole contributor of this work and has approved it for publication.
Acknowledgments
A special thank you to Dr. Eli Rothenberg, NYU School of Medicine, for also serving as Guest Editor for this Research Topic.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
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MaciejowskiJDe LangeT. Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol (2017) 18:175–86.
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DratwaMWysoczanskaBLacinaPKubikTBogunia-KubikK. TERT-regulation and roles in cancer formation. Front Immunol (2020) 11:589929.
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Summary
Keywords
cancer, replicative immortality, telomeres, telomerase, immune response, senescence
Citation
Bailey SM (2023) Editorial: Hallmark of cancer: replicative immortality. Front. Oncol. 13:1204094. doi: 10.3389/fonc.2023.1204094
Received
11 April 2023
Accepted
17 April 2023
Published
25 April 2023
Volume
13 - 2023
Edited and reviewed by
Claudio Sette, Catholic University of the Sacred Heart, Rome, Italy
Updates
Copyright
© 2023 Bailey.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Susan M Bailey, Susan.Bailey@ColoState.EDU
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.