‘Stemness’ and ‘senescence’ related escape pathways are dose dependent in lung cancer cells surviving post irradiation

Tsolou, Avgi; Lamprou, Ioannis; Fortosi, Alexandra-Ourania; Liousia, Maria; Giatromanolaki, Alexandra; Koukourakis, Michael I.

doi:10.1016/j.lfs.2019.116562

Cited by 17 publications

(9 citation statements)

References 40 publications

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“…The DNA damage response is triggered and if repair is not possible, cells either die if the damage is severe or enter senescence if less severe. In irradiated cancer cells, the percentage of senescent cells therefore increases in the remaining “radio-resistant” clones [ 70 ]. The concern is that these senescent cells may be released from senescence and assume a more “stem cell”-like phenotype, which may result in aggressive recurrence [ 71 ].…”

Section: Role Of Senescence In Radiotherapymentioning

confidence: 99%

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

Wyld

Bellantuono

Tchkonia

et al. 2020

Cancers

170

145

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Cellular senescence is a key component of human aging that can be induced by a range of stimuli, including DNA damage, cellular stress, telomere shortening, and the activation of oncogenes. 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. It may also be a key effector mechanism of many types of anticancer therapies, such as chemotherapy, radiotherapy, and endocrine therapies, both directly and via bioactive molecules released by senescent cells that may stimulate an immune response. However, senescence may contribute to reduced patient resilience to cancer therapies and may provide a pathway for disease recurrence after cancer therapy. A new group of drugs, senotherapies, (drugs which interact with senescent cells to interfere with their pro-aging impacts by either selectively destroying senescent cells (senolytic drugs) or inhibiting their function (senostatic drugs)) are under active investigation to determine whether they can enhance the efficacy of cancer therapies and improve resilience to cancer treatments. Senolytic drugs include quercetin, navitoclax, and fisetin and preclinical and early phase clinical data are emerging of their potential role in cancer treatments, although none are yet in routine use clinically. This article provides a review of these issues.

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Section: Role Of Senescence In Radiotherapymentioning

confidence: 99%

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

Wyld

Bellantuono

Tchkonia

et al. 2020

Cancers

170

145

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“…Lung cancer is the leading fatal malignancy worldwide, causing over 1.5 million cancer-related deaths annually [1,2]; and it is classified into two main subtypes: non-small cell lung cancer (NSCLC, making up 80-85% of all lung cancers) and small-cell lung cancer (SCLC, making up 15-20% of cases) [3,4]. The NSCLCs are histologically divided into three forms: adenocarcinoma (ADC), squamous cell carcinoma (SCC), and large cell carcinoma (LCC) [5,6].…”

Section: Introductionmentioning

confidence: 99%

mRNAsi Index: Machine Learning in Mining Lung Adenocarcinoma Stem Cell Biomarkers

Zhang

Tseng

Lien

et al. 2020

Genes

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Cancer stem cells (CSCs), characterized by self-renewal and unlimited proliferation, lead to therapeutic resistance in lung cancer. In this study, we aimed to investigate the expressions of stem cell-related genes in lung adenocarcinoma (LUAD). The stemness index based on mRNA expression (mRNAsi) was utilized to analyze LUAD cases in the Cancer Genome Atlas (TCGA). First, mRNAsi was analyzed with differential expressions, survival analysis, clinical stages, and gender in LUADs. Then, the weighted gene co-expression network analysis was performed to discover modules of stemness and key genes. The interplay among the key genes was explored at the transcription and protein levels. The enrichment analysis was performed to annotate the function and pathways of the key genes. The expression levels of key genes were validated in a pan-cancer scale. The pathological stage associated gene expression level and survival probability were also validated. The Gene Expression Omnibus (GEO) database was additionally used for validation. The mRNAsi was significantly upregulated in cancer cases. In general, the mRNAsi score increases according to clinical stages and differs in gender significantly. Lower mRNAsi groups had a better overall survival in major LUADs, within five years. The distinguished modules and key genes were selected according to the correlations to the mRNAsi. Thirteen key genes (CCNB1, BUB1, BUB1B, CDC20, PLK1, TTK, CDC45, ESPL1, CCNA2, MCM6, ORC1, MCM2, and CHEK1) were enriched from the cell cycle Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, relating to cell proliferation Gene Ontology (GO) terms, as well. Eight of the thirteen genes have been reported to be associated with the CSC characteristics. However, all of them have been previously ignored in LUADs. Their expression increased according to the pathological stages of LUAD, and these genes were clearly upregulated in pan-cancers. In the GEO database, only the tumor necrosis factor receptor associated factor-interacting protein (TRAIP) from the blue module was matched with the stemness microarray data. These key genes were found to have strong correlations as a whole, and could be used as therapeutic targets in the treatment of LUAD, by inhibiting the stemness features.

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“…The resistance to radiation therapy in NSCLC could be caused by a selected radioresistant population of CSCs as suggested by studies on cell lines or animal models. Indeed, X-ray photon irradiation resulted in an increase in cancer stem cells markers (CD44, CD133, OCT4, SOX2, and NANOG) [ 14 , 15 ] and increased the pool of cancer stem cells in xenograft mouse models [ 16 ]. Cancer stem cells develop particularly in hypoxic tumor niches.…”

Section: Molecular Radioresistance Mechanismsmentioning

confidence: 99%

Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives

Césaire

Montanari

Curcio

et al. 2022

Cancers

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Survival in unresectable locally advanced stage non-small cell lung cancer (NSCLC) patients remains poor despite chemoradiotherapy. Recently, adjuvant immunotherapy improved survival for these patients but we are still far from curing most of the patients with only a 57% survival remaining at 3 years. This poor survival is due to the resistance to chemoradiotherapy, local relapses, and distant relapses. Several biological mechanisms have been found to be involved in the chemoradioresistance such as cancer stem cells, cancer mutation status, or the immune system. New drugs to overcome this radioresistance in NSCLCs have been investigated such as radiosensitizer treatments or immunotherapies. Different modalities of radiotherapy have also been investigated to improve efficacity such as dose escalation or proton irradiations. In this review, we focused on biological mechanisms such as the cancer stem cells, the cancer mutations, the antitumor immune response in the first part, then we explored some strategies to overcome this radioresistance in stage III NSCLCs with new drugs or radiotherapy modalities.

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‘Stemness’ and ‘senescence’ related escape pathways are dose dependent in lung cancer cells surviving post irradiation

Cited by 17 publications

References 40 publications

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

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

mRNAsi Index: Machine Learning in Mining Lung Adenocarcinoma Stem Cell Biomarkers

Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives

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