Exploiting senescence for the treatment of cancer

Wang, Liqin; Lankhorst, Lina; Bernards, René

doi:10.1038/s41568-022-00450-9

Cited by 434 publications

(387 citation statements)

References 269 publications

(333 reference statements)

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“…Platinum-based compounds, such as cisplatin, could induce senescence through extensive DNA damage. Moreover, methotrexate and gemcitabine could both induce genotoxic stress by blocking DNA synthesis, thereby inducing cellular senescence ( 61 ). Methotrexate, gemcitabine, vinblastine, doxorubicin, and cisplatin were commonly used drugs for MIBC.…”

Section: Discussionmentioning

confidence: 99%

A Four-Cell-Senescence-Regulator-Gene Prognostic Index Verified by Genome-Wide CRISPR Can Depict the Tumor Microenvironment and Guide Clinical Treatment of Bladder Cancer

Sun

Liu

et al. 2022

Front. Immunol.

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Bladder cancer (BCa) is the 10th most commonly diagnosed cancer worldwide, and cellular senescence is defined as a state of permanent cell cycle arrest and considered to play important roles in the development and progression of tumor. However, the comprehensive effect of senescence in BCa has not ever been systematically evaluated. Using the genome-wide CRISPR screening data acquired from DepMap (Cancer Dependency Map), senescence genes from the CellAge database, and gene expression data from The Cancer Genome Atlas (TCGA), we screened out 12 senescence genes which might play critical roles in BCa. A four-cell-senescence-regulator-gene prognostic index was constructed using the least absolute shrinkage and selection operator (LASSO) and multivariate COX regression model. The transcriptomic data and clinical information of BCa patients were downloaded from TCGA and Gene Expression Omnibus (GEO). We randomly divided the patients in TCGA cohort into training and testing cohorts and calculated the risk score according to the expression of the four senescence genes. The validity of this risk score was validated in the testing cohort (TCGA) and validation cohort (GSE13507). The Kaplan–Meier curves revealed a significant difference in the survival outcome between the high- and low-risk score groups. A nomogram including the risk score and other clinical factors (age, gender, stage, and grade) was established with better predictive capacity of OS in 1, 3, and 5 years. Besides, we found that patients in the high-risk group had higher tumor mutation burden (TMB); lower immune, stroma, and ESTIMATE scores; higher tumor purity; aberrant immune functions; and lower expression of immune checkpoints. We also performed gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) to investigate the interaction between risk score and hallmark pathways and found that a high risk score was connected with activation of senescence-related pathways. Furthermore, we found that a high risk score was related to better response to immunotherapy and chemotherapy. In conclusion, we identified a four-cell-senescence-regulator-gene prognostic index in BCa and investigated its relationship with TMB, the immune landscape of tumor microenvironment (TME), and response to immunotherapy and chemotherapy, and we also established a nomogram to predict the prognosis of patients with BCa.

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Section: Discussionmentioning

confidence: 99%

A Four-Cell-Senescence-Regulator-Gene Prognostic Index Verified by Genome-Wide CRISPR Can Depict the Tumor Microenvironment and Guide Clinical Treatment of Bladder Cancer

Sun

Liu

et al. 2022

Front. Immunol.

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“…This would minimize both the collateral effect of long-term treatment with senescence-inducing activity, and the possibility of tumor resumption. There are mainly two lines of research in this context: targeting senescent cancer cells with senolytic drugs or with senolysis mediated by the immune response (reviewed in [ 43 ]). Thus, we explored the possibility of combining curcumin treatment with the administration of other natural compounds with senolytic activity, in an attempt to clear curcumin-induced senescent cells.…”

Section: Discussionmentioning

confidence: 99%

Specific Irreversible Cell-Cycle Arrest and Depletion of Cancer Cells Obtained by Combining Curcumin and the Flavonoids Quercetin and Fisetin

Barra

Chiavetta

Titoli

et al. 2022

Genes

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Background: Induced senescence could be exploited to selectively counteract the proliferation of cancer cells and target them for senolysis. We examined the cellular senescence induced by curcumin and whether it could be targeted by fisetin and quercetin, flavonoids with senolytic activity. Methods: Cell-cycle profiles, chromosome number and structure, and heterochromatin markers were evaluated via flow cytometry, metaphase spreads, and immunofluorescence, respectively. The activation of p21waf1/cip1 was assessed via RT-qPCR and immunoblotting. Senescent cells were detected via SA-β-Galactosidase staining. Results: We report that curcumin treatment specifically triggers senescence in cancer cells by inducing mitotic slippage and DNA damage. We show that curcumin-induced senescence is p21waf1/cip1-dependent and characterized by heterochromatin loss. Finally, we found that flavonoids clear curcumin-induced senescent cancer cells. Conclusions: Our findings expand the characterization of curcumin-induced cellular senescence in cancer cells and lay the foundation for the combination of curcumin and flavonoids as a possible anti-cancer therapy.

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“…Most research on cellular senescence has focused on non-tumor cells, but tumor cells can also undergo senescence. The treatment of cancer consisting of pro-senescence and senolytic therapy has also been explored, which is expected to become new approaches for targeted therapy of cancer ( Wang et al, 2022 ). Increasing evidence suggests that senescent cells can be eliminated by senescence-associated secretory phenotype (SASP)-elicited immune responses involving both innate and adaptive immunity, so activation of the host immune system is a particularly attractive approach to clearing senescent cancer cells ( Schneider et al, 2021 ; Wang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…The treatment of cancer consisting of pro-senescence and senolytic therapy has also been explored, which is expected to become new approaches for targeted therapy of cancer ( Wang et al, 2022 ). Increasing evidence suggests that senescent cells can be eliminated by senescence-associated secretory phenotype (SASP)-elicited immune responses involving both innate and adaptive immunity, so activation of the host immune system is a particularly attractive approach to clearing senescent cancer cells ( Schneider et al, 2021 ; Wang et al, 2022 ). However, the correlation between cellular senescence and TME remains unclear, and the value of cellular senescence-related genes in assessing immune infiltration and clinical outcome in CRC has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Relationship Between Senescence and Colorectal Cancer in Prognosis, Immunity, and Treatment

et al. 2022

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Background: Senescence, as an effective barrier against tumorigenesis, plays a critical role in cancer therapy. However, the role of senescence in colorectal cancer (CRC) has not yet been reported. This study aimed to build a prognostic signature for the prognosis of patients with CRC based on senescence-related genes.Methods: A prognostic signature was built from TCGA based on differentially expressed senescence-related genes by the least absolute shrinkage and selection operator (LASSO) and Cox regression analyses, which were further validated using two Gene Expression Omnibus (GEO) cohorts. The CIBERSORT and ssGSEA algorithms were utilized to analyze the infiltrating abundance of immune cells. The relationship of signature with the immune therapy and the sensitivity of different therapies was explored.Results: We found 93 genes associated with senescence that were differentially expressed. Based on expression and clinical parameters, we developed a senescence-related prognostic signature and its effectiveness was verified using two external validation cohorts. Overall survival was predicted using a prognostic nomogram that incorporated the predictive values of the risk score and clinical traits. Additionally, the risk score was significantly correlated with immune cells infiltration, tumor immune microenvironment (TME) score, immune checkpoints, immunotherapeutic efficacy, and chemotherapy sensitivity.Conclusion: The senescence-related prognostic model can well predict the prognosis, immunotherapeutic response, and identify potential drug targets, which can help guide individualized treatment.

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Exploiting senescence for the treatment of cancer

Abstract: Senescence-associated β-galactosidase (SAβ-gal). Acidic β-galactosidase activity that occurs in senescent cells; used as a senescence biomarker.

Cited by 434 publications

References 269 publications

A Four-Cell-Senescence-Regulator-Gene Prognostic Index Verified by Genome-Wide CRISPR Can Depict the Tumor Microenvironment and Guide Clinical Treatment of Bladder Cancer

A Four-Cell-Senescence-Regulator-Gene Prognostic Index Verified by Genome-Wide CRISPR Can Depict the Tumor Microenvironment and Guide Clinical Treatment of Bladder Cancer

Specific Irreversible Cell-Cycle Arrest and Depletion of Cancer Cells Obtained by Combining Curcumin and the Flavonoids Quercetin and Fisetin

Exploring the Relationship Between Senescence and Colorectal Cancer in Prognosis, Immunity, and Treatment

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