Resistance #1: Senescence as a mechanism to resistance?

Discovery of senescence

This first blog post will be about senescence. Senescence is considered the state in which a cell has permanently stopped to divide. It is a stress response that is distinct from quiescence (= reversible cell cycle arrest), terminal differentiation and contact-inhibition. In 1961 Hayflick and Moorhead discovered that fibroblasts divide around 50 times before they stop to proliferate (1). This so-called “Hayflick limit” was later linked to shortening of telomeres with every cell cycle (2, 3). It was found that not only fibroblasts, but that non-cancerous cells in general across species and tissue origins, have a limited number of divisions after which replicative senescence is initiated (4). This was a groundbreaking discovery, because this means cells can’t divide forever!

Senescence as a barrier, preventing cancer development

Surprisingly, senescence does not only occur when the Hayflick limit is reached and replicative senescence is initiated.  In 1997 the team of Scott Lowe discovered that overactivation of growth signals provided by so-called oncogenes, such as RAS can stop cells from dividing permanently  (5). Their discovery suggested that senescence is not merely activated after a number of cell divisions, but is a protective program, triggered by abnormal levels of cellular growth signals. Around 2005 several labs found that in the stage before transforming into full-blown cancer, many cells are senescent (6, 7). This suggested that our bodies are trying to prevent cancer from developing by catching them into a non-dividing cell state, before it actually develops into full-blown cancer. Unfortunately, this isn’t always successful, and a cancer cell is still able to escape/bypass this mechanism of senescence leading to the development of cancer. Indeed, senescence is highly prevalent in the pre-stages of cancer. Once a cell has become cancerous, it is considered to have unlimited potential to divide, essentially becoming immortal.

Senescence in cancer

Even though cancer cells are considered to have an unlimited capacity for cell division, apparently, some cancers still have the capability to senesce! It appears that some cancers are better in suppressing senescence than other cancers. The question whether cancer cells can escape senescence after becoming senescent is still somewhat controversial, since there’s an ongoing debate about whether senescence is reversible. There is accumulating data that senescence is potentially reversible (8-12).

Senescence as resistance mechanism?

So how does all of this tie into resistance to therapies? It’s been shown that certain cancer treatments can damage cancer cells so much that they stop dividing and senesce, we call this therapy-induced senescence. A whole list of cancer treatments are known to induce senescence. Check out this splendid review by the Gerwitz’s lab for the long list of treatments (13). Recent evidence suggests that senescent cancer cells can make their non-senescent neighbouring cancer cells more aggressive and potentially resistant to cancer therapies (14, 15).

In short, senescence isn’t just a boring state of cells that aren’t dividing. Even the non-dividing cancer cells seem functionally relevant and can’t be ignored. It seems plausible that senescence itself can be a way to generate resistance in cancer cells. The mechanisms through which senescence can drive resistance needs more investigation.

References

(This is not a comprehensive review, simply for education and entertainment, so forgive me if I didn’t refer to your seminal discoveries)

1.         Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585-621. 2.         Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345(6274):458-60. 3.         Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, et al. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998;279(5349):349-52. 4.         Röhme D. Evidence for a relationship between longevity of mammalian species and life spans of normal fibroblasts in vitro and erythrocytes in vivo. Proc Natl Acad Sci U S A. 1981;78(8):5009-13. 5.         Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88(5):593-602. 6.         Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444(7119):633-7. 7.         Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, et al. Senescence in premalignant tumours. Nature. 2005;436(7051):642-. 8.         Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature. 2003;424(6945):223-8. 9.         Martinez-Zamudio RI, Roux PF, de Freitas J, Robinson L, Dore G, Sun B, et al. AP-1 imprints a reversible transcriptional programme of senescent cells. Nat Cell Biol. 2020;22(7):842-55. 10.       Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 2003;22(16):4212-22. 11.       Yu Y, Schleich K, Yue B, Ji S, Lohneis P, Kemper K, et al. Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma. Cancer Cell. 2018;33(2):322-36 e8. 12.       Saleh T, Tyutyunyk-Massey L, Gewirtz DA. Tumor Cell Escape from Therapy-Induced Senescence as a Model of Disease Recurrence after Dormancy. Cancer Res. 2019;79(6):1044-6. 13.       Saleh T, Bloukh S, Carpenter VJ, Alwohoush E, Bakeer J, Darwish S, et al. Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy. Cancers (Basel). 2020;12(4). 14.       Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, et al. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2017;7(2):165-76. 15.       Milanovic M, Fan DNY, Belenki D, Dabritz JHM, Zhao Z, Yu Y, et al. Senescence-associated reprogramming promotes cancer stemness. Nature. 2018;553(7686):96-100.

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