Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

In the paper

“Studies have demonstrated high levels of senescence in premalignant lesions and lower levels in invasive disease, suggesting a role for senescence in blocking malignant progression [2,31,32].”

What the sources say

• Not checked yetcites [2] Collado, 2005, Tumour biology: Senescence in premalignant tumours, Nature source
• Not checked yetcites [31] Chen, 2005, Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis, Nature source
• Not checked yetcites [32] Michaloglou, 2005, BRAFE600-associated senescence-like cell cycle arrest of human naevi, Nature source

In the paper

“In breast cancer cases treated with neoadjuvant chemotherapy, 41% of tumours were stained by senescence markers compared to only 10% of untreated cases, showing that senescence is induced by CAF (cyclophosphamide, Adriamycin, and fluorouracil) chemotherapy [53].”

What the sources say

• Not checked yetcites [53] Okorokov, 2002, DNA damage is able to induce senescence in tumor cells in vitro and in vivo, Cancer Res.

In the paper

“In breast cancer, p16 levels correlate with breast cancer subtype, proliferative status, and prognosis [42].”

What the sources say

• Not checked yetcites [42] Shin, 2015, Expression of p16 and pRB in invasive breast cancer, Int. J. Clin. Exp. Pathol.

In the paper

“although none are yet in routine use clinically.”

In the paper

“Acute senescence is a short-term process, often triggered to limit an inflammatory response or physiological process, such as wound healing or embryological development [12].”

What the sources say

• Not checked yetcites [12] Davaapil, 2017, Conserved and novel functions of programmed cellular senescence during vertebrate development, Development

In the paper

“Senescence is generally regarded as a tumour suppressive process, both by preventing cancer cell proliferation and suppressing malignant progression from pre-malignant to malignant disease.”

What the sources say

• Not checked yetcites [18] Campisi, 2005, Senescent cells, tumor suppression, and organismal aging: Good citizens, bad neighbors, Cell source

In the paper

“Chronic senescence is triggered by feedback loops when the senescent stimulus is prolonged, and may cause diseases such as atherosclerosis, arthritis, neurodegenerative disease, and diabetes [13] as well as effecting classical age-related decline in tissue function [14].”

What the sources say

• Not checked yetcites [13] Calcinotto, 2019, Cellular Senescence: Aging, Cancer, and Injury, Physiol. Rev. source
• Not checked yetcites [14] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat. Med. source

In the paper

“Aging is integral to the causation of many cancers and also impacts on treatment response, prognosis, treatment allocation, and treatment tolerance.”

What the sources say

• Not checked yetcites [6] Partridge, 2018, Facing up to the global challenges of ageing, Nature source
• Not checked yetcites [7] Hanahan, 2011, Hallmarks of cancer: The next generation, Cell source

In the paper

“Senescent cells release a complex, cell type-specific, mixture of bioactive molecules (senescence-associated secretory phenotype or SASP), which impacts on the adjacent cells and extracellular matrix and contributes to age-related tissue degeneration.”

In the paper

“Senescent cells are rare in the tissues of young organisms but become more common as tissues age, especially in adipose tissue, muscle, and skin [10].”

What the sources say

• Not checked yetcites [10] Tchkonia, 2010, Fat tissue, aging, and cellular senescence, Aging Cell source

In the paper

“A range of factors may trigger senescence, including cell stressors, such as reactive oxygen species, DNA damage due to aging, radiation, and genotoxic substances (including many chemotherapy agents), age-related telomere shortening, adverse growth conditions, tumour suppressor gene activation, and oncogene activity.”

In the paper

“Cells have a finite ability to replicate (the Hayflick Limit [26]) and once this limit is reached, they lose the ability to divide but remain alive and metabolically active as senescent cells.”

What the sources say

• Not checked yetcites [26] Hayflick, 1961, The serial cultivation of human diploid cell strains, Exp. Cell Res. source

In the paper

“Again, if this DNA damage cannot be repaired, the cell may die (usually via apoptosis) or enter senescence via the p53/cyclin E/CDK2/RB signaling pathway. Whether a cell undergoes apoptosis or senescence depends on the degree of damage, and whether it is repairable.”

In the paper

“As telomere shortening is irreversible in normal cells and cannot be repaired, it triggers senescence rather than temporary proliferative arrest.”

In the paper

“Once again, mild stimulation induces senescence whereas severe stimulation induces cell death.”

In the paper

“Some oncogenes, such as the BRAF oncogene (which is commonly mutated in melanoma), may trigger senescence acting via mitochondrial pyruvate kinase metabolism to regulate cell cycle progression.”

In the paper

“Whereas acute senescence is largely beneficial in the regulation of transient injury or stress, if a cell experiences prolonged non-lethal stress, a chronic senescent state is entered where the continued production of SASP perpetuates cellular and extracellular matrix damage and results in the acquisition of an aging or disease linked phenotype.”

In the paper

“The precise content of the SASP released by a senescent cell may vary according to the host tissue and the degree and type of senescent stimulus.”

In the paper

“The same pathway is triggered by non-lethal DNA damage, which again activates the DDR. DNA damage accumulates progressively with age but also occurs in the majority of cancers, where a key initiation event is often the loss of function of critical DNA repair pathways via loss of function of tumour suppressor genes.”

In the paper

“There are also potential interactions with cancer therapies, in particular, radiotherapy and chemotherapy, which may trigger either cell death at high doses or senescence at non-lethal doses.”

What the sources say

• Not checked yetcites [20] Saleh, 2019, Tumor Cell Escape from Therapy-Induced Senescence as a Model of Disease Recurrence after Dormancy, Cancer Res. source
• Not checked yetcites [21] Bharadwaj, 2020, Senescence in polyploid giant cancer cells: A road that leads to chemoresistance, Cytokine Growth Factor Rev. source
• Not checked yetcites [22] Lee, 2019, The dynamic nature of senescence in cancer, Nat. Cell Biol. source

In the paper

“For example, the p53 and BRCA genes are key tumour suppressor genes that are mutated and lose function at an early stage in the process of cancer development.”

In the paper

“In contrast there is also evidence that stromal cell senescence may have a tumour promoting effect in some models—this may be because of the proangiogenic influence of some components of SASP, such as vascular endothelial growth factor (VEGF) or the impact of senescent fibroblasts on adjacent tumour cells [17,36].”

What the sources say

• Not checked yetcites [17] Coppe, 2006, Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence, J. Biol. Chem. source
• Not checked yetcites [36] Bavik, 2006, The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms, Cancer Res. source

In the paper

“In turn, senescence may impact on these same pathways via positive or negative feedback loops as well as other intracellular pathways and extracellular processes, such as the immune modulation, inflammation [16], regulation, and maintenance of the extracellular matrix, and angiogenesis [17].”

What the sources say

• Not checked yetcites [16] Freund, 2010, Inflammatory networks during cellular senescence: Causes and consequences, Trends Mol. Med. source
• Not checked yetcites [17] Coppe, 2006, Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence, J. Biol. Chem. source

In the paper

“No one marker alone is sufficient to identify senescence and most researchers use a panel of biomarkers, such as senescence-associated β-galactosidase, p21, and p16INK4A, as well as a number of other biomarkers, such as heterochromatin and proliferation markers (Table 1) combined [24] with a marker of cellular proliferation (Ki-67, for instance).”

What the sources say

• Not checked yetcites [23] Gorgoulis, 2019, Cellular Senescence: Defining a Path Forward, Cell source
• Not checked yetcites [24] Matjusaitis, 2016, Biomarkers to identify and isolate senescent cells, Ageing Res. Rev. source

In the paper

“There is also evidence that “immune senescence”, associated with the aging of the immune system in older age may contribute to the failure of immune surveillance and contribute to cancer development in older people.”

What the sources say

• Not checked yetcites [37] Falci, 2013, Immune senescence and cancer in elderly patients: Results from an exploratory study, Exp. Gerontol. source

In the paper

“The SASP of a particular senescent cell type may have a tumour suppressive function and trigger immune activation or promote tumour growth and inflammation depending on the host tissue.”

In the paper

“Senescent cells release SASP factors that damage nearby non-senescent cells and the extracellular matrix, triggering inflammation, fibrosis, and apoptosis of adjacent healthy cells, but the senescent cells themselves are resistant to these effects and accumulate, thus generating more SASP factors.”

In the paper

“Several key pathways into senescence have been described: replicative senescence, oncogene-induced senescence, stress-induced senescence, and therapy-induced senescence.”

In the paper

“It has been proposed that, whilst senescence itself is largely tumour suppressive [18], the SASP of chronically senescent cells may promote tumour recurrence or progression [19].”

What the sources say

• Not checked yetcites [19] Campisi, 2011, Cellular senescence: A link between cancer and age-related degenerative disease?, Semin. Cancer Biol.

In the paper

“The SASP is a melange of over 100 molecules, including inflammatory cytokines, growth factors, and proteases.”

In the paper

“Another regulatory pathway for senescence activation is via the p16 inhibitor of kinase 4(INK4), a regulatory protein that inhibits CDK4/6 and cyclin 2 and so blocks cell cycle progression via the RB protein. This pathway may be stimulated by the loss of tumour suppressor function, oncogene activation, epigenetic changes (DNA methylation, for example, which may alter gene expression), or damage to”

In the paper

“Consequently, senescence induced by some cancer therapies may be harmful and promote tumour growth.”

What the sources say

• Not checked yetcites [55] Basisty, N., Kale, A., Jeon, O.H., Kuehnemann, C., Payne, T., Rao, C., Holtz, A., Shah, S., Sharma, V., and Ferrucci, L. (2020). A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol., 18. source

In the paper

“Cyclophosphamide causes DNA cross linking, which again may trigger a DDR.”

In the paper

“senescence is a complex process closely related to cell cycle regulatory processes and is integral to human aging and the genesis of many human diseases.”

In the paper

“the diabetic drug, metformin has senostatic properties and reduces the stimulatory effect of SASP intermediates on prostate cancer cells [123]”

What the sources say

• Not checked yetcites [123] Moiseeva, 2013, Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation, Aging Cell source

In the paper

“They are also present in cancer and in premalignant lesions and have been evaluated as prognostic markers [41].”

What the sources say

• Not checked yetcites [41] Pare, R., Soon, P.S., Shah, A., and Lee, C.S. (2019). Differential expression of senescence tumour markers and its implications on survival outcomes of breast cancer patients. PLoS ONE, 14. source

In the paper

“Conversely, it may be a route to tumour resistance and recurrence if the senescent cells reacquire the ability to proliferate when they may become more stem-cell like or via the proinflammatory and apoptosis inhibitory effects of the SASP.”

In the paper

“Moderate chemotherapy doses are more likely to cause senescence and higher doses more likely to cause cell death [54].”

What the sources say

• Not checked yetcites [54] Roninson, 2003, Tumor cell senescence in cancer treatment, Cancer Res.

In the paper

“For example, doxorubicin prevents the resealing of the DNA double helix by inhibiting topoisomerase 2, which triggers a DDR and thereby may cause senescence [54].”

What the sources say

• Not checked yetcites [54] Roninson, 2003, Tumor cell senescence in cancer treatment, Cancer Res.

In the paper

“Others, such as vinca alkaloids and taxanes, work by causing damage to the mitotic spindle during mitosis, resulting in cell death.”

In the paper

“There is another way in which senolytics may impact on cancer outcomes—by enhancing resilience and reducing frailty.”

In the paper

“Many types of chemotherapy cause DNA damage (DNA strand breaks or cross linking), which can, if severe, cause cell death via the DNA damage response, or they may trigger a non-lethal DDR, leading to acute or chronic senescence, depending on the extent and duration of the stimulus [52].”

What the sources say

• Not checked yetcites [52] 2014, The role of senescent cells in ageing, Nature source

In the paper

“In terms of clinical trials, this 100 mg dose has been used in a colorectal cancer chemotherapy study and has been shown to reduce inflammatory markers, although numbers were small and no clinical cancer end points were assessed [121].”

What the sources say

• Not checked yetcites [121] Alizadeh, 2018, Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients, Food Funct. source

In the paper

“Senescence is also an important mechanism of efficacy in the treatment of breast cancer with PARP inhibitors [59] and many typical chemotherapy agents used to treat breast cancer, such as epirubicin and cyclophosphamide [60].”

What the sources say

• Not checked yetcites [59] Fleury, 2019, Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence, Nat. Commun. source
• Not checked yetcites [60] Munoz, D.P., Yannone, S.M., Daemen, A., Sun, Y., Vakar-Lopez, F., Kawahara, M., Freund, A.M., Rodier, F., Wu, J.D., and Desprez, P.Y. (2019). Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging. JCI Insight, 5. source

In the paper

“Chemotherapy may cause cell death, often by apoptosis, resulting clinically in tumour regression. It may also cause cellular senescence, leading clinically to tumour stasis (growth arrest) (Figure 2).”

In the paper

“Senotherapies may become a valuable adjunct to cancer therapies both by direct destruction of the chemotherapy-induced senescent cell population within a tumour and by the inhibition of the proinflammatory SASP, which may enhance treatment tolerance by the patient.”

In the paper

“It is thought to be a tumour suppressive process, inhibiting both the formation of cancer by blocking transition from premalignant to malignant disease and preventing damaged cells from proliferating after suffering DNA damage or cellular stress, which is one of the key events promoting cancer development.”