8.7 Senescence in Cancer

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Role of senescence in cancer

 

Senescent cells and cancer cells both have extensive DNA damage and the onset of cancer often coincides with advanced age (at which tissues are comprised of more senescent cells) (1). Senescence suppresses cancer development through the prevention of over-proliferation in normal cells. However, this onset of irreversible growth can also increase susceptibility to cancer. In fact, there is complex interplay between cancer development, regression, and cellular senescence.  Senescence can be induced by DNA damage or cell crisis due to the shortening of telomere length, also known as replicative senescence. In the case of DNA damage, there are several forms of senescence that are characterized by distinct features, and they are stress-induced premature senescence (SIPS), PTEN-induced senescence, and oncogene-induced senescence (1,2,3,4). The distinct features of these forms of irreversible growths will be elaborated further in the following sections.

 

Replicative Senescence

 

Cells with critically short telomeres typically acquire a senescent phenotype.  Those that continue to proliferate are pushed into crisis mortality stage (1).  Most of these cells apoptose, but cells that avoid crisis mortality stage 1 are halted at another checkpoint, termed crisis mortality stage 2.  The only way to escape crisis mortality stage 2 is telomerase activation, which lengthens the telomeres and drives immortalization (1,5).  Immortalization relieves cells of a replication limit, and they can divide indefinitely. TERT is the subunit of telomerase with catalytic activity, and expression of TERT is sufficient in many cell types to activate telomerase and immortalize the cells.  Some cell types require further mutations, examples including RB and p53 pathway inactivations (1,5).  Immortalized cells accumulate more genomic instability and can transform into malignant cells (1).

 

Oncogene-induced senescence


Oncogene-induced senescence (OIS) exhibits hyper-replication of DNA and consequently additional accumulation of DNA damage.  These genetic changes increase the potential for cells to become genomically unstable, thus increasing their mutability. This can lead to a transition from OIS to cancer cell development (2). As its name suggests, OIS is triggered by hyperproliferation and DNA hyperreplication induced by oncogenes, whereby the senescence response is applied to prevent cancer growth. In the case of OIS induction by HRAS-G12V, which is involved with the regulation of cell division, overepression of HRAS-G12V triggers the activation of an S phase specific DNA damage response (DDR) similar to replicative senescence (2). At this time, p53 is activated by phosphorylation which in turn mediates tumour suppression. In addition to p53, OIS also introduces the onset of other senescence effectors such as INK4A. The resulting reponse by OIC causes a cell to enter the senescent stage, however, it should be noted that cells with ATM-deficiency or aberrant DNA damage-sensor are resistant to the oncogene response.

 

PTEN-induced senescence

 

Cells can suppress tumorigenesis by becoming senescent when an oncogene is activated (given that OIS escape does not occur) or tumour suppressor activity is lost (1,2,6).  PTEN-induced senescence (PICS) occurs rapidly and is not accompanied by hyper-replication of DNA or a response to DNA damage (unlike OIS), so the concern of genomic instability, and ultimately tumorigenesis, is minimal. Quiescent cells with a cancer phenotype (cancer-initiating cells) may be suppressed by PICS, as PICS has no DNA replication requirement for induction (2).  OIS is now accepted as a profound repressor of tumour growth, and restoration of senescence function is thought to be inducible by suppressing oncogene c-Myc in lymphoma and hepatocellular carcinoma, among other cancers (7).  The literature indicates early tumour development can be suppressed by PICS or OIS; however, established tumours require senescence programs to be restored by inactivation of prominent oncogenes (2,10).

 

Senescent cells can also play a supportive role in cancer progression (12). Cells immediately adjacent to tumors are believed to create the tumor microenvironment, supplying tumor cells with inflammatory cytokines, interleukins, and growth factors that promote tumor growth and survival. Cells that acquire this ability are referred to as having a senescence-associated secretory phenotype (SASP) (12). These cells are poor targets of conventional chemotherapy, as are senescent tumor cells, since conventional approaches specifically target cells with abnormally high rates of proliferation (12).
 


 

References:

1. Ramakrishna, G., Anwar, T., Angara, R.K., Chatterjee, N., Kiran, S., and Singh, S. (2012). Role of cellular senescence in hepatic wound healing and carcinogenesis. European Journal of Cell Biology 91, 739–747.

2. Nardella, C., Clohessy, J.G., Alimonti, A., and Pandolfi, P.P. (2011). Pro-senescence therapy for cancer treatment. Nature Reviews Cancer 11, 503–511.

3. Chen, Z., Trotman, L.C., Shaffer, D., Lin, H.-K., Dotan, Z.A., Niki, M., Koutcher, J.A., Scher, H.I., Ludwig, T., Gerald, W., et al. (2005). Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730.

4. Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A.J., Barradas, M., Benguría, A., Zaballos, A., Flores, J.M., Barbacid, M., et al. (2005). Tumour biology: senescence in premalignant tumours. Nature 436, 642.

5. Hahn, W.C., and Weinberg, R.A. (2002). Modelling the molecular circuitry of cancer. Nature Reviews Cancer 2, 331–341.

6. Sharpless, N.E., and DePinho, R.A. (2005). Cancer: crime and punishment. Nature 436, 636–637.

7. Wu, C.-H., van Riggelen, J., Yetil, A., Fan, A.C., Bachireddy, P., and Felsher, D.W. (2007). Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proceedings of the National Academy of Sciences of the United States of America 104, 13028–13033.

8. Coppé, J.-P., Patil, C.K., Rodier, F., Sun, Y., Muñoz, D.P., Goldstein, J., Nelson, P.S., Desprez, P.-Y., and Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biology 6, 2853–2868.

9. Bavik, C., Coleman, I., Dean, J.P., Knudsen, B., Plymate, S., and Nelson, P.S. (2006). The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Research 66, 794–802.

10. Xue, W., Zender, L., Miething, C., Dickins, R.A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., and Lowe, S.W. (2007). Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660.

11. Mathon, N.F., and Lloyd, A.C. (2001). Cell senescence and cancer. Nature Reviews. Cancer 1, 203–213.

12. Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathological Mechanical Disease, 5, 99-118.