The Breast Cancer Stem Cells Traits and Drug Resistance

Zheng, Qinghui; Zhang, Mengdi; Zhou, Fangfang; Zhang, Long; Meng, Xuli

doi:10.3389/fphar.2020.599965

Cited by 57 publications

(45 citation statements)

References 297 publications

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“…Secondly, we found higher mRNA levels of EMT (vimentin, MMP9, CD44, ICAM1, SNAI1, SNAI2, TNFRS11B)- and CSC (ABCG2, OCT4, Nanog, Musashi)-related mRNAs (Fig. 4E ), all shown to contribute a clonogenic, chemo-resistant phenotype in MPM and other solid tumors [ 40 , 41 ]. Finally, we found increased mRNA of enzymes involved in downstream processing of AA, namely PGES, PTGIS, COX1 and COX2 [ 42 ](Fig.…”

Section: Resultsmentioning

confidence: 94%

Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma

Cioce

Canino

Pass

et al. 2021

J Exp Clin Cancer Res

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Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum and pemetrexed, have limited impact on the survival of MPM patients. Adaptive response to therapy-induced stress involves complex rearrangements of the MPM secretome, mediated by the acquisition of a senescence-associated-secretory-phenotype (SASP). This fuels the emergence of chemoresistant cell subpopulations, with specific gene expression traits and protumorigenic features. The SASP-driven rearrangement of MPM secretome takes days to weeks to occur. Thus, we have searched for early mediators of such adaptive process and focused on metabolites differentially released in mesothelioma vs mesothelial cell culture media, after treatment with pemetrexed. Methods Mass spectrometry-based (LC/MS and GC/MS) identification of extracellular metabolites and unbiased statistical analysis were performed on the spent media of mesothelial and mesothelioma cell lines, at steady state and after a pulse with pharmacologically relevant doses of the drug. ELISA based evaluation of arachidonic acid (AA) levels and enzyme inhibition assays were used to explore the role of cPLA2 in AA release and that of LOX/COX-mediated processing of AA. QRT-PCR, flow cytometry analysis of ALDH expressing cells and 3D spheroid growth assays were employed to assess the role of AA at mediating chemoresistance features of MPM. ELISA based detection of p65 and IkBalpha were used to interrogate the NFkB pathway activation in AA-treated cells. Results We first validated what is known or expected from the mechanism of action of the antifolate. Further, we found increased levels of PUFAs and, more specifically, arachidonic acid (AA), in the transformed cell lines treated with pemetrexed. We showed that pharmacologically relevant doses of AA tightly recapitulated the rearrangement of cell subpopulations and the gene expression changes happening in pemetrexed -treated cultures and related to chemoresistance. Further, we showed that release of AA following pemetrexed treatment was due to cPLA2 and that AA signaling impinged on NFkB activation and largely affected anchorage-independent, 3D growth and the resistance of the MPM 3D cultures to the drug. Conclusions AA is an early mediator of the adaptive response to pem in chemoresistant MPM and, possibly, other malignancies.

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Section: Resultsmentioning

confidence: 94%

Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma

Cioce

Canino

Pass

et al. 2021

J Exp Clin Cancer Res

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“…Such subpopulations are often endowed with stemness properties and are referred to as cancer stem cells. More specifically in breast cancer, CSCs have been described as manifesting remarkable resistance to standard treatments [58,59], making them prime candidates for the development of novel, targeted therapies that could be administered in combination with commonly used drugs, aiming to achieve complete tumor elimination [60,61].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling of Tumorspheres Reveals TRPM4 as a Novel Stemness Regulator in Breast Cancer

et al. 2021

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Cancer stem cells (CSCs) have been implicated in the development of chemoresistance, tumor recurrence and metastasis in breast cancer, thus emerging as a promising target for novel therapies. To identify novel stemness regulators that could potentially be targeted in luminal ER+ tumors, we performed RNA-sequencing (RNA-seq) in MCF-7 adherent monolayer cells and tumorspheres enriched in breast CSCs (bCSCs). We identified 1421 differentially expressed genes (DEGs), with 923 of them being upregulated and 498 downregulated in tumorspheres. Gene ontology and pathway enrichment analyses revealed that distinct gene networks underlie the biology of the two cell systems. We selected the transient receptor potential cation channel subfamily M member 4 (TRPM4) gene that had not been associated with cancer stemness before for further investigation. We confirmed that TRPM4 was overexpressed in tumorspheres and showed that its knock-down affected the stemness properties of bCSCs in vitro. TRPM4 inhibition revealed potential anti-tumor effects by directly targeting the bCSC subpopulation. We suggest that TRPM4 plays a key role in stemness mediation, and its inhibition may represent a novel therapeutic modality against bCSCs contributing in the improvement of breast cancer treatments.

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“…P-glycoprotein 1 (Pgp-1), also known as ATP-binding cassette subfamily B member 1, functions as a transmembrane efflux pump involved in the chemotherapy drug uptake and its efflux. Overexpression of aldehyde dehydrogenase-1 (ALDH-1) in breast cancer was also found to be correlated with the stemness features of CSCs [100][101][102]. The findings from a recent report have suggested that cotreatment of CUR and PTX inhibited the ALDH-1 and PTX-induced Pgp-1 expression in MCF-7 cells.…”

Section: Curcumin Enhances the Efficacy Of Paclitaxel In Breast Cance...mentioning

confidence: 98%

Curcumin as an Enhancer of Therapeutic Efficiency of Chemotherapy Drugs in Breast Cancer

Farghadani¹,

Naidu²

2022

IJMS

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Female breast cancer is the world’s most prevalent cancer in 2020. Chemotherapy still remains a backbone in breast cancer therapy and is crucial in advanced and metastatic breast cancer treatment. The clinical efficiency of chemotherapy regimens is limited due to tumor heterogeneity, chemoresistance, and side effects. Chemotherapeutic drug combinations with natural products hold great promise for enhancing their anticancer efficacy. Curcumin is an ideal chemopreventive and chemotherapy agent owning to its multitargeting function on various regulatory molecules, key signaling pathways, and pharmacological safety. This review aimed to elucidate the potential role of curcumin in enhancing the efficacy of doxorubicin, paclitaxel, 5-fluorouracil, and cisplatin via combinational therapy. Additionally, the molecular mechanisms underlying the chemosensitizing activity of these combinations have been addressed. Overall, based on the promising therapeutic potential of curcumin in combination with conventional chemotherapy drugs, curcumin is of considerable value to develop as an adjunct for combination chemotherapy with current drugs to treat breast cancer. Furthermore, this topic may provide the frameworks for the future research direction of curcumin–chemotherapy combination studies and may benefit in the development of a novel therapeutic strategy to maximize the clinical efficacy of anticancer drugs while minimizing their side effects in the future breast cancer treatment.

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The Breast Cancer Stem Cells Traits and Drug Resistance

Cited by 57 publications

References 297 publications

Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma

Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma

Transcriptional Profiling of Tumorspheres Reveals TRPM4 as a Novel Stemness Regulator in Breast Cancer

Curcumin as an Enhancer of Therapeutic Efficiency of Chemotherapy Drugs in Breast Cancer

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