December 4, 2022

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Exploring the role of cellular senescence in the treatment of cancer

Exploring the role of cellular senescence in the treatment of cancer



 

Nature Series Review: Exploring the role of cellular senescence in the treatment of cancer. 

 

Anti-aging is an eternal topic of human beings, but do you know about cellular aging ?

 

Before introducing cellular senescence, let’s take a look at the definition of aging : We define it broadly as the time-dependent functional decline that affects most organisms.


Cellular senescence isa permanent state of cell cycle termination. It causes major changes in the cell’s morphology and physiology.

 

 


Major changes after cellular senescence

1. Cell size and morphology (larger and more irregular morphology)
2. Cell membrane components (up-regulation of caveolin-1 and clearance of DPP4)
3. Increase in lysosomes (up-regulation of lysosomal proteins and increase in lysosomes)
4. Mitochondrial accumulation (senescent cells exhibit an increase in mitochondria)
5. Nuclear changes (deletion of the protein LaminB1)

 

 

Exploring the role of cellular senescence in the treatment of cancerCellular senescence morphological changes

 

 

In the third edition of cancer hallmarks, which is newly proposed in 2022, the cellular senescence of tumors can be assessed based on these markers .


Exploring the role of cellular senescence in the treatment of cancer
cancer hallmarks

 

 

The following briefly introduces a tumor therapy method based on senescent cells . The author mainly discusses some current anti-tumor strategies from two aspects: inducing tumor cell senescence and selectively killing senescent cells .

Exploring the role of cellular senescence in the treatment of cancer

 

 

 

 



Antitumor therapy that induces cellular senescence

 

1. Oncogene-induced cellular senescence

Activation of oncogenes such as HRASV12 triggers growth arrest called oncogenic-induced senescence (OIS) , which was first demonstrated in vivo in 1997.

Following this, in 2005, the concept of OIS was extended to multiple oncogenic models, including lymphoma, prostate cancer, lung adenoma, hyperplastic pituitary, and melanocytic nevi. Melanocytic nevi caused by mutations in the oncogene BRAF typically persist for decades to avoid progression to melanoma.

Likewise, loss of tumor suppressor genes, such as Pten, can also induce primary prostate epithelial senescence, termed PTEN loss-induced cellular senescence (PICS) . The p53 pathway plays a central role in OIS and PICS. In OIS, activation of oncogenes leads to DNA damage. This in turn activates P53, which leads to senescence.

 


2. Chemotherapy and radiation induce cellular senescence

Chemotherapy or radiation therapy can induce senescence in cancer cells . Low-dose chemotherapy specifically senesced human cancer cells, while high-dose chemotherapy induced apoptosis.

Mechanistically, many chemotherapy induces DNA damage in cancer cells, thereby triggering senescence through activation of the P53-Rb pathway mediated by ATM-CHK2 and ATR-CHK1 kinases.

Inhibitors of topoisomerase I and II, such as doxorubicin, etoposide, and camptothecin, are widely used to treat various types of cancer and have been shown to disrupt DNA strands after DNA supercoils are unwound Connection.

This results in massive DNA damage and increased expression of p53 and its downstream targets CDKN1A and PAI1 (also known as SERPINE1) , which leads to senescence.

Platinum-based drugs, such as cisplatin, carboplatin, and oxaliplatin, also cause extensive DNA damage through DNA cross-linking, leading to aging.

While a considerable number of existing chemotherapeutic agents have the ability to induce senescence, in most cancers the apoptotic response predominates.

 

Radiation therapy is widely used in the treatment of many types of cancer. This anticancer treatment can induce irreparable DNA damage responses, which in turn activate ATM or ATR and p53-p21 pathways to mediate apoptosis and cellular senescence.

Unlike chemotherapy, this treatment can be applied topically, so there is less collateral damage to normal tissue, so it may also reduce secondary cancers.

 


3. Inhibit cell cycle and induce cell senescence

A hallmark of senescent cells is the upregulation of cyclin-dependent kinase (CDK) inhibitory proteins , such as Ink4a and p21, to induce cell cycle arrest.

In contrast, cancer cells typically upregulate CDK levels in order to progress through the cell cycle.

Therefore, drugs that inhibit CDKs or increase levels of CDK inhibitory proteins are currently being investigated for use in cancer therapy to induce senescence.

In particular, CDK4 and CDK6 (hereinafter referred to as CDK4/6) play an important role in the progression from G1 phase to S phase and are overexpressed in many human cancers.

CDK4/6 inhibitors mimic the function of INK4A and can induce senescence in a variety of cancer cells. Finally, XL413 or TAK931 induced senescence in hepatoma cells by inhibiting DNA replication by inhibiting the kinase CDC7.

 

 

4. Inhibition of telomerase to induce cellular senescence

As discussed above, replicative senescence is a response to telomere attrition . Cancer cells often circumvent this by reactivating telomerase activity.

So far, many compounds that inhibit the telomerase complex have been identified as candidates for anticancer therapy.

Among them, BIBR15 and GRN163L are potent telomerase inhibitors that induce senescence and inhibit cancer cell proliferation .

However, the use of GRN163L for anti-aging therapy requires further investigation, as this compound can also induce apoptosis in human pancreatic cancer cells .

 


5. Modulation of the epigenome to induce cellular senescence

Another way to induce senescence is by modulating the epigenome of cancer cells.

Inhibition of DNA methyltransferases by decitabine results in demethylation of the CDKN2A promoter CpG-rich region, induction of Ink4a and ARF expression and senescence .

The histone deacetylase inhibitor Vorinostat can also upregulate the expression of multiple tumor suppressor genes, such as CDKN2A and TP53, and can induce senescence in different cancer cell lines through these two major pathways.

 


6. Targeting tumor suppressor genes or oncogenes

The initiation and maintenance of cellular senescence is dependent on P53, which is frequently damaged in cancer cells . In mouse models, gene repair of Tp53 leads to regression of sarcomas and liver cancers by inducing a senescence response, while an apoptotic response is observed in lymphoma treatment.

Furthermore, senescence induction was accompanied by upregulation of SASP and recruitment of immune cells to tumors, suggesting that senescent cancer cells were efficiently cleared. Currently, several compounds that activate p53 are under development.

For example, the MDM2 inhibitors Nutlin 3 and RG7112 can interfere with the p53-MDM2 interaction, which can induce senescence in a human cancer cell model (wild-type TP53) . Notably, disruption of the p53-MDM2 complex can also induce apoptosis, but not senescence .

In addition, cells with mutations in the PTEN gene undergo premature senescence, while cancer cells expressing the PTEN gene undergo apoptosis.

Furthermore, inactivation of PTEN resulted in p53-mediated senescence and suppressed tumor formation in mice.

Considering the frequent mutations of the TP53 and RB1 pathways in human cancers and the involvement of these pathways in the senescence response, scientists speculate that cancer cells are mostly resistant to induction of senescence.

However, this is not the case: almost all cancer cells can senesce in vitro using DNA-damaging agents or AURK inhibitors, regardless of RB1 and TP53 mutational status. Obviously, these genes only play a regulatory role in tumor cell senescence, and are not necessary factors for inducing tumor cell senescence.

 

 

 

 


Depletion of senescent tumor cells

 

Interestingly, factors secreted by senescent cells, in addition to conveying the “please kill me” message, also have an effect on surrounding cells .

 

This effect may promote tumor migration and metastasis by promoting epithelial-mesenchymal transition (EMT) .

And to make matters worse, senescent tumor cells can promote tumor growth and metastasis by recruiting specialized macrophages to promote the formation of blood vessels and lymphatic vessels, providing other tumor cells with the oxygen and nutrients they need to survive .


The good news is that although senescent tumor cells can “strengthen” the surrounding tumor cells, the senescent cells themselves cannot divide and proliferate, so the “scavenger” of senescent cells comes in handy .

 

Exploring the role of cellular senescence in the treatment of cancerSenescence ‘scavenger’ removes senescent cells

 

 

One of the hallmarks of senescent cells is changes in chromatin structure that lead to changes in gene expression .

These changes can affect basic cellular processes, such as the regulation of apoptosis.

These processes may lead to the acquisition of new fragility specific to senescent cells that can be targeted by drugs that act as ” scavengers. ” The table below summarizes the current applications, mechanisms, preclinical evidence and clinical studies of “clearers” in cancer (see table below) .

 

 

 

 

 


Summary

 

In the journey of anti-aging, clearing senescent cells has received extensive attention as a potential strategy.

In the process of tumor development and development, senescent cells are also “credited”. Using senescent cells to fight tumors is an effective treatment.

However, in the special microenvironment of tumor, senescent cells will also accidentally become “accomplices”, so how to detect, utilize and remove senescent cells is the main direction for future researchers to explore .

 

Prospects for senescent cell-based therapy

 

 

 

 

 

 

 

 

 


References :
Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer. Nat Rev Cancer. 2022 Mar 3. doi: 10.1038/s41568-022-00450-9. Epub ahead of print. PMID: 35241831.
Some pictures are from: Medicine Times “One Article Understanding Cell Aging”

Exploring the role of cellular senescence in the treatment of cancer

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