Articles de revues sur le sujet « Tumor chemoresistance »
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Yeldag, Gulcen, Alistair Rice et Armando Del Río Hernández. « Chemoresistance and the Self-Maintaining Tumor Microenvironment ». Cancers 10, no 12 (28 novembre 2018) : 471. http://dx.doi.org/10.3390/cancers10120471.
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The progression of cancer is associated with alterations in the tumor microenvironment, including changes in extracellular matrix (ECM) composition, matrix rigidity, hypervascularization, hypoxia, and paracrine factors. One key malignant phenotype of cancer cells is their ability to resist chemotherapeutics, and elements of the ECM can promote chemoresistance in cancer cells through a variety of signaling pathways, inducing changes in gene expression and protein activity that allow resistance. Furthermore, the ECM is maintained as an environment that facilitates chemoresistance, since its constitution modulates the phenotype of cancer-associated cells, which themselves affect the microenvironment. In this review, we discuss how the properties of the tumor microenvironment promote chemoresistance in cancer cells, and the interplay between these external stimuli. We focus on both the response of cancer cells to the external environment, as well as the maintenance of the external environment, and how a chemoresistant phenotype emerges from the complex signaling network present.
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Oplt, Alyssa, Elizabeth Stock, Hollie Noia, Patrick Cannon, Gregory Longmore et Katherine C. Fuh. « Abstract 3235 : The role of DDR2 in chemoresistant ovarian cancer ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 3235. http://dx.doi.org/10.1158/1538-7445.am2022-3235.
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Abstract Ovarian cancer is the fifth leading cause of cancer death for women in the United States. As many as 80% of ovarian cancer patients experience recurrent disease and the majority of recurrences become resistant to treatment. Once patients no longer respond to chemotherapy, there are minimal treatment options and they succumb to their disease. Therefore, there is a need to create new targeted therapies to overcome chemoresistance in ovarian cancer and improve patient survival. We have assembled a tumor microarray from 164 patient tumors to characterize the changes in protein expression that lead to resistance in clinical samples. We have found using IHC staining, that patients with high tyrosine kinase receptor discoidin domain receptor 2 (DDR2) protein expression (>70%) have significantly shorter overall survival times regardless of stage at diagnosis (HR= 2.108, p=0.002) as well as reduced platinum free interval (p=0.046). Additionally, platinum refractory tumors have higher DDR2 protein expression than platinum sensitive tumors (p=0.036). To further understand the mechanisms of chemoresistance, we created a novel, chemoresistant, syngeneic, mouse ovarian cancer cell line derived from ID8 trp53-/-BRCA2-/- GFP LUC cells from Walton et. al 2016, and have designated them CHRP5. DDR2 expression assessed via western blot increased significantly in the chemoresistance cells, suggesting that DDR2 is associated with chemoresistance. We knocked down DDR2 using a stable shRNA transfection in CHRP5 and used MTS survival assays to determine if decreased DDR2 expression increases sensitivity to chemotherapy. CHRP5 shDDR2 cells were significantly more sensitive to carboplatin than CHRP5 shControl cells (CHRP5 shControl IC50=213.6uM, CHRP5 shDDR2 IC50=128.5uM, p<0.000001), suggesting that DDR2 is involved in regulating chemoresistance in these cells. Additionally, we have submitted matched chemoresistant and chemosensitive mouse tumor samples for RNA-sequencing. We will use this data to determine which chemoresistant mechanisms are utilized, and if DDR2 is involved in regulating those mechanisms. In the future, we plan to rescue DDR2 in the knockdown cells to confirm that off target effects are not influencing the change in sensitivity. We also have access to a specific, allosteric inhibitor of DDR2 and plan to use this drug to determine if inhibiting DDR2 pharmacologically can overcome chemoresistance and reduce tumor burden in vivo and in vitro. In conclusion, DDR2 is more highly expressed in chemoresistant patients, and higher DDR2 expression correlates with reduced survival and platinum free interval. Additionally, knocking down DDR2 in chemoresistant cells increases sensitivity to chemotherapy. Therefore, DDR2 is a potential new target for ovarian cancer therapy and may be targeted to overcome chemoresistant disease and extend patient survival. Citation Format: Alyssa Oplt, Elizabeth Stock, Hollie Noia, Patrick Cannon, Gregory Longmore, Katherine C. Fuh. The role of DDR2 in chemoresistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3235.
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Gronlund, B., E. V. S. Høgdall, I. J. Christensen, J. S. Johansen, B. Nørgaard-Pedersen, S. A. Engelholm et C. Høgdall. « Pre-Treatment Prediction of Chemoresistance in Second-Line Chemotherapy of Ovarian Carcinoma : Value of Serological Tumor Marker Determination (Tetranectin, YKL-40, CASA, CA 125) ». International Journal of Biological Markers 21, no 3 (juillet 2006) : 141–48. http://dx.doi.org/10.1177/172460080602100302.
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Objective To examine if the determination of the levels of serological tumor markers at time of relapse had any predictive value for chemoresistance in the second-line treatment of ovarian cancer patients. Methods From a registry of consecutive single-institution patients with epithelial ovarian carcinoma pretreated with paclitaxel plus platinum, we selected 82 patients with (a) solid tumor recurrence, and (b) second-line chemotherapy consisting of topotecan (platinum-resistant disease) or paclitaxel plus carboplatin (platinum-sensitive disease). Stored serum samples were analyzed for the biochemical tumor markers tetranectin, YKL-40, CASA (cancer-associated serum antigen), and CA 125. The serum tumor marker levels at time of relapse were correlated with response status at landmark time after 4 cycles of second-line chemotherapy. Univariate and multivariate logistic regression analyses (chemoresistant vs non-chemoresistant disease) were performed. Results At landmark time, 26% of patients had progression according to the GCIG (Gynecologic Cancer Intergroup) progression criteria. In univariate logistic regression analysis, the tumor markers tetranectin (OR 0.4; 95% CI: 0.2–0.8; p=0.008), YKL-40 (OR 1.8; 95% CI: 1.0–3.3; p=0.045), and CASA (OR 1.8; 95% CI: 1.2–2.7; p=0.007) had predictive value for second-line chemoresistance, whereas serum CA 125 had no predictive value. In a multivariate logistic regression analysis, serum tetranectin and CASA both had independent predictive value for chemoresistance. The combined determination of tetranectin and CASA had a specificity of 90% with 33% sensitivity for the prediction of chemoresistance (area under the receiver operating characteristic curve = 0.78; 95% CI: 0.66–0.91; p=0.001). Conclusion Low serum levels of tetranectin, or high serum levels of CASA or YKL-40, are associated with increased risk of second-line chemoresistance in patients with ovarian cancer.
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Wu, Qitong, Sumit Siddharth et Dipali Sharma. « Triple Negative Breast Cancer : A Mountain Yet to Be Scaled Despite the Triumphs ». Cancers 13, no 15 (23 juillet 2021) : 3697. http://dx.doi.org/10.3390/cancers13153697.
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Metastatic progression and tumor recurrence pertaining to TNBC are certainly the leading cause of breast cancer-related mortality; however, the mechanisms underlying TNBC chemoresistance, metastasis, and tumor relapse remain somewhat ambiguous. TNBCs show 77% of the overall 4-year survival rate compared to other breast cancer subtypes (82.7 to 92.5%). TNBC is the most aggressive subtype of breast cancer, with chemotherapy being the major approved treatment strategy. Activation of ABC transporters and DNA damage response genes alongside an enrichment of cancer stem cells and metabolic reprogramming upon chemotherapy contribute to the selection of chemoresistant cells, majorly responsible for the failure of anti-chemotherapeutic regime. These selected chemoresistant cells further lead to distant metastasis and tumor relapse. The present review discusses the approved standard of care and targetable molecular mechanisms in chemoresistance and provides a comprehensive update regarding the recent advances in TNBC management.
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Belisario, Dimas Carolina, Joanna Kopecka, Martina Pasino, Muhlis Akman, Enrico De Smaele, Massimo Donadelli et Chiara Riganti. « Hypoxia Dictates Metabolic Rewiring of Tumors : Implications for Chemoresistance ». Cells 9, no 12 (4 décembre 2020) : 2598. http://dx.doi.org/10.3390/cells9122598.
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Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor tumor progression and chemoresistance. The increase in glucose and amino acid uptake, glycolytic flux, and lactate production; the alterations in glutamine metabolism, tricarboxylic acid cycle, and oxidative phosphorylation; the high levels of mitochondrial reactive oxygen species; the modulation of both fatty acid synthesis and oxidation are hallmarks of the metabolic rewiring induced by hypoxia. This review discusses how metabolic-dependent factors (e.g., increased acidification of tumor microenvironment coupled with intracellular alkalinization, and reduced mitochondrial metabolism), and metabolic-independent factors (e.g., increased expression of drug efflux transporters, stemness maintenance, and epithelial-mesenchymal transition) cooperate in determining chemoresistance in hypoxia. Specific metabolic modifiers, however, can reverse the metabolic phenotype of hypoxic tumor areas that are more chemoresistant into the phenotype typical of chemosensitive cells. We propose these metabolic modifiers, able to reverse the hypoxia-induced metabolic rewiring, as potential chemosensitizer agents against hypoxic and refractory tumor cells.
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Trevino, J. G., S. R. Pillai et S. P. Chellappan. « Effect of nicotine on chemoresistant phenotype as mediated through Src-dependent Id1 expression in pancreatic adenocarcinoma cells. » Journal of Clinical Oncology 29, no 4_suppl (1 février 2011) : 216. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.216.
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216 Background: The signaling pathways contributing to DNA-binding protein inhibitor Id1 expression and chemoresistance in pancreatic cancer remain unknown. Id1 plays a role in pancreatic tumor progression with tumor-promoting effects of nicotine regulating protein tyrosine kinase Src activation and Id1 expression, both associated with chemoresistance in other systems. We hypothesize Id1 expression regulates chemoresistance in pancreatic cancer through a nicotine-promoting Src-dependent pathway. Methods: We probed pancreatic cancer cell lines (L3.6pl, PANC-1, Mia-PaCa-2) for innate gemcitabine chemoresistance with cell viability MTT assay and western blot analysis of PARP cleavage programmed cell death. Gemcitabine-sensitive cells were exposed to rising gemcitabine concentrations to establish a resistant subtype, L3.6plGemRes. Protein analysis and mRNA expression were determined by western blot analysis and RT-PCR respectively. Induction of Src phosphorylation or Id1 expression was performed with nicotine (1 μM). Results: Inhibition of c-Src expression was performed with short-interfering RNA (siRNA). Nicotine-induced Src phosphorylation and Id1 expression. Inhibition of Src by siRNA resulted in decreased nicotine-induced Id1 expression. Inhibition of Src and Id1 expression by siRNA in innate or established gemcitabine resistant pancreatic cancer cells resulted in gemcitabine sensitization. To determine if nicotine contributes to gemcitabine chemoresistance, we exposed gemcitabine-sensitive cells to nicotine with subsequent exposure to gemcitabine IC50, 250 ng/ml, and cell viability assays confirmed a 2-fold increase in cell prolilferation and a 4.5-fold reduction in apoptosis. Further, nicotine induced phosphorylation of key signaling enzymes involved in proliferation and apoptosis, Erk1/2 and Akt respectively. Conclusions: In summary, we demonstrate that Id1, through a nicotine-promoting Src-dependent pathway, is necessary for establishment of a chemoresistant phenotype in pancreatic cancer cells. Understanding the signaling pathways involved in pancreatic tumor chemoresistance will lead to therapies resulting in improved tumor responses. No significant financial relationships to disclose.
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Ji, Ping, Kristen M. Turner et Wei Zhang. « OverAKT3 : tumor progression and chemoresistance ». Cell Cycle 14, no 13 (4 juin 2015) : 1993–94. http://dx.doi.org/10.1080/15384101.2015.1046787.
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Brown, Elizabeth, et Maurie Markman. « Tumor chemosensitivity and chemoresistance assays ». Cancer 77, no 6 (15 mars 1996) : 1020–25. http://dx.doi.org/10.1002/(sici)1097-0142(19960315)77:6<1020 ::aid-cncr3>3.0.co;2-l.
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Cree, Ian A., Russell D. Petty, Christian M. Kurbacher et Michael Untch. « Tumor chemosensitivity and chemoresistance assays ». Cancer 78, no 9 (1 novembre 1996) : 2031–32. http://dx.doi.org/10.1002/(sici)1097-0142(19961101)78:9<2031 ::aid-cncr27>3.0.co;2-x.
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Kern, David H. « Tumor chemosensitivity and chemoresistance assays ». Cancer 79, no 7 (1 avril 1997) : 1447–49. http://dx.doi.org/10.1002/(sici)1097-0142(19970401)79:7<1447 ::aid-cncr23>3.0.co;2-z.
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Lou, Emil, Rachel Isaksson Vogel, Spencer Hoostal, Aaron Grad, Minnu Monu, Tomasz Lukaszewski, Jaai Deshpande et al. « Tumor stroma proportion to predict platinum chemoresistance in primary ovarian carcinomas : A prospective study. » Journal of Clinical Oncology 37, no 15_suppl (20 mai 2019) : 5581. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5581.
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5581 Background: Platinum chemotherapy resistance occurs in approximately 25% of patients with ovarian carcinoma and represents a major barrier to effective care of this patient population. To date there are no effective nor validate predictive biomarkers of chemoresistance of ovarian carcinomas. We performed a prospective trial designed to enroll patients with ovarian masses suspicious for ovarian cancer, with the goal of identifying tumor-based predictive biomarkers of platinum resistance. Methods: 60 women were enrolled on the study. Tumor specimens were collected from 49 of these women with newly diagnosed pelvic masses, of which 29 were found to have histopathologically proven primary ovarian carcinoma. Of these primary malignant cases, 24 had specimens accessible for assessment of tumor-stroma proportion and data available regarding chemosensitive vs chemoresistance status via review of the medical record using a UMN IRB-approved protocol. Tumor slices were stained with H&E and also for antibodies against two microRNAs (29b and 199a) differentially expressed in ovarian cancer cell lines. Tumor-stroma proportions were assessed by two experienced pathologists blinded to chemoresistance status, with <50% stroma scored as low proportion, >50% scored as high proportion. Results: The average age of assessed patients with malignant tumors was 62. 87.5% had high-grade epithelial carcinomas. Baseline median CA-125 was 416 (range 32-2782). 80% of ovarian cancer patients with chemoresistance had tumor stroma proportions >50%; 73.7% of cancer patients with chemosensitive tumors had proportions <50% (p-value: 0.047). Expression of miR29b or 199a did not significantly correlate with chemoresistance. Conclusions: Tumor-stroma proportion is a useful predictive biomarker of platinum chemoresistance. If validated in larger datasets, it would be a relatively inexpensive and helpful tool for tailoring treatment strategies and clinical decision-making in women with ovarian cancer.
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Scholler, Nathalie, et Claire Repellin. « Role of natural killer cells in ovarian cancer chemoresistance (TUM3P.1050) ». Journal of Immunology 194, no 1_Supplement (1 mai 2015) : 70.7. http://dx.doi.org/10.4049/jimmunol.194.supp.70.7.
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Abstract Novel immunotherapeutic approaches revolutionize cancer prognosis but the role of innate immunity in chemoresistance remains poorly understood. For example, toll-like receptor (TLR) ligands in combination with anticancer treatments yielded unpredictable effects, either beneficial or deleterious. We hypothesized that the function of tumor-infiltrating immune cells depends on constitutive TLR variants. We characterized healthy donor T cells, B cells, monocytes and natural killer (NK) for functional polymorphism after transwell co-culture with chemosensitive (OVCAR5) vs. chemoresistant (SKOV3TR) ovarian tumor cells +/- (1) medium only; (2) LPS; (3) PamCys3; (4) Paclitaxel (PTX); (5) OVCAR5; (6) OVCAR5+PTX; (7) SKOV3TR; (8) SKOV3TR+PTX. CD8+ T cell activation was measured by perforin staining, monocyte and B cell maturations by cytokine expression array, and NK-mediated cytotoxicity by PI staining of GFP-transfected K562 after 4 hour-incubation. We observed minor functional variations between donor T cells, B cells and monocytes. However, while all NK cells killed GFP-K562 cells as expected, in some donors NK cytotoxicity was specifically inhibited by SKOV3RT co-culture. NK genotyping and phenotyping are ongoing including tumor-dependent NKG2D expression, and PTX-dependent MICA release by tumor cells. These results support the hypothesis that chemoresistant tumors release soluble factors that modulate NK function though specific interactions with innate immune receptor variants.
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Lee, Catherine A. A., Pallavi Banerjee, Brian J. Wilson, Siyuan Wu, Qin Guo, Gretchen Berg, Svetlana Karpova et al. « Targeting the ABC transporter ABCB5 sensitizes glioblastoma to temozolomide-induced apoptosis through a cell-cycle checkpoint regulation mechanism ». Journal of Biological Chemistry 295, no 22 (20 avril 2020) : 7774–88. http://dx.doi.org/10.1074/jbc.ra120.013778.
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Glioblastoma multiforme (GBM) is a malignant brain tumor with a poor prognosis resulting from tumor resistance to anticancer therapy and a high recurrence rate. Compelling evidence suggests that this is driven by subpopulations of cancer stem cells (CSCs) with tumor-initiating potential. ABC subfamily B member 5 (ABCB5) has been identified as a molecular marker for distinct subsets of chemoresistant tumor-initiating cell populations in diverse human malignancies. In the current study, we examined the potential role of ABCB5 in growth and chemoresistance of GBM. We found that ABCB5 is expressed in primary GBM tumors, in which its expression was significantly correlated with the CSC marker protein CD133 and with overall poor survival. Moreover, ABCB5 was also expressed by CD133-positive CSCs in the established human U-87 MG, LN-18, and LN-229 GBM cell lines. Antibody- or shRNA-mediated functional ABCB5 blockade inhibited proliferation and survival of GBM cells and sensitized them to temozolomide (TMZ)-induced apoptosis in vitro. Likewise, in in vivo human GBM xenograft experiments with immunodeficient mice, mAb treatment inhibited growth of mutant TP53, WT PTEN LN-229 tumors, and sensitized LN-229 tumors to TMZ therapy. Mechanistically, we demonstrate that ABCB5 blockade inhibits TMZ-induced G2/M arrest and augments TMZ-mediated cell death. Our results identify ABCB5 as a GBM chemoresistance marker and point to the potential utility of targeting ABCB5 to improve current GBM therapies.
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Chen, Xun, Shangwu Chen et Dongsheng Yu. « Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance ». Metabolites 10, no 7 (16 juillet 2020) : 289. http://dx.doi.org/10.3390/metabo10070289.
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Metabolic reprogramming is one of the hallmarks of tumors. Alterations of cellular metabolism not only contribute to tumor development, but also mediate the resistance of tumor cells to antitumor drugs. The metabolic response of tumor cells to various chemotherapy drugs can be analyzed by metabolomics. Although cancer cells have experienced metabolic reprogramming, the metabolism of drug resistant cancer cells has been further modified. Metabolic adaptations of drug resistant cells to chemotherapeutics involve redox, lipid metabolism, bioenergetics, glycolysis, polyamine synthesis and so on. The proposed metabolic mechanisms of drug resistance include the increase of glucose and glutamine demand, active pathways of glutaminolysis and glycolysis, promotion of NADPH from the pentose phosphate pathway, adaptive mitochondrial reprogramming, activation of fatty acid oxidation, and up-regulation of ornithine decarboxylase for polyamine production. Several genes are associated with metabolic reprogramming and drug resistance. Intervening regulatory points described above or targeting key genes in several important metabolic pathways may restore cell sensitivity to chemotherapy. This paper reviews the metabolic changes of tumor cells during the development of chemoresistance and discusses the potential of reversing chemoresistance by metabolic regulation.
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Souza, Leonel Cardozo de Menezes e., Anderson Faletti, Carla Pires Veríssimo, Mariana Paranhos Stelling et Helena Lobo Borges. « p53 Signaling on Microenvironment and Its Contribution to Tissue Chemoresistance ». Membranes 12, no 2 (9 février 2022) : 202. http://dx.doi.org/10.3390/membranes12020202.
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Chemoresistance persists as a significant, unresolved clinical challenge in many cancer types. The tumor microenvironment, in which cancer cells reside and interact with non-cancer cells and tissue structures, has a known role in promoting every aspect of tumor progression, including chemoresistance. However, the molecular determinants of microenvironment-driven chemoresistance are mainly unknown. In this review, we propose that the TP53 tumor suppressor, found mutant in over half of human cancers, is a crucial regulator of cancer cell-microenvironment crosstalk and a prime candidate for the investigation of microenvironment-specific modulators of chemoresistance. Wild-type p53 controls the secretion of factors that inhibit the tumor microenvironment, whereas altered secretion or mutant p53 interfere with p53 function to promote chemoresistance. We highlight resistance mechanisms promoted by mutant p53 and enforced by the microenvironment, such as extracellular matrix remodeling and adaptation to hypoxia. Alterations of wild-type p53 extracellular function may create a cascade of spatial amplification loops in the tumor tissue that can influence cellular behavior far from the initial oncogenic mutation. We discuss the concept of chemoresistance as a multicellular/tissue-level process rather than intrinsically cellular. Targeting p53-dependent crosstalk mechanisms between cancer cells and components of the tumor environment might disrupt the waves of chemoresistance that spread across the tumor tissue, increasing the efficacy of chemotherapeutic agents.
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Kiwit, Jurgen Carl Walther, Anja Hertel et Alexander E. Matuschek. « Reversal of chemoresistance in malignant gliomas by calcium antagonists : correlation with the expression of multidrug-resistant p-glycoprotein ». Journal of Neurosurgery 81, no 4 (octobre 1994) : 587–94. http://dx.doi.org/10.3171/jns.1994.81.4.0587.
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✓ Resistance to multiple drugs is often observed in malignant gliomas. The authors used a microtiter tetrazolium test to analyze primary in vitro chemoresistance and chemosensitivity of 15 early cultures of human malignant glioma exposed to 50 µg/ml (1,4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), 50 µg/ml cisplatin, 1 µg/ml vincristine, or combinations of these chemotherapeutic agents. Primary chemoresistance was observed in 87% of tumors for ACNU, in 87% for cisplatin, and in 83% for vincristine. All tumors were examined for expression of multidrug-resistant p-glycoprotein, a transport protein of 170,000 D, by means of immunohistochemical staining with the JSB-1 antibody on paraffinized tumor sections. Eight of 15 specimens (53%) showed positive staining for the monoclonal antibody. Primary chemoresistance was overcome by addition of the calcium antagonists verapamil or nimodipine to the cultures if the original tumor expressed p-glycoprotein (p < 0.01 for verapamil, p < 0.05 for nimodipine). In tumors not expressing p-glycoprotein, addition of calcium antagonists to the cell cultures did not influence primary chemoresistance. It is concluded from these data that addition of calcium antagonists to the adjuvant chemotherapy of malignant gliomas might overcome primary chemoresistance in tumors expressing the multidrugresistant phenotype.
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González-Ortiz, Alina, Angel Pulido-Capiz, César Y. Castañeda-Sánchez, Esmeralda Ibarra-López, Octavio Galindo-Hernández, Maritza Anahí Calderón-Fernández, Leslie Y. López-Cossio et al. « eIF4A/PDCD4 Pathway, a Factor for Doxorubicin Chemoresistance in a Triple-Negative Breast Cancer Cell Model ». Cells 11, no 24 (15 décembre 2022) : 4069. http://dx.doi.org/10.3390/cells11244069.
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Cells employ several adaptive mechanisms under conditions of accelerated cell division, such as the unfolded protein response (UPR). The UPR is composed of a tripartite signaling system that involves ATF6, PERK, and IRE1, which maintain protein homeostasis (proteostasis). However, deregulation of protein translation initiation could be associated with breast cancer (BC) chemoresistance. Specifically, eukaryotic initiation factor-4A (eIF4A) is involved in the unfolding of the secondary structures of several mRNAs at the 5′ untranslated region (5′-UTR), as well as in the regulation of targets involved in chemoresistance. Importantly, the tumor suppressor gene PDCD4 could modulate this process. This regulation might be disrupted in chemoresistant triple negative-BC (TNBC) cells. Therefore, we characterized the effect of doxorubicin (Dox), a commonly used anthracycline medication, on human breast carcinoma MDA-MB-231 cells. Here, we generated and characterized models of Dox chemoresistance, and chemoresistant cells exhibited lower Dox internalization levels followed by alteration of the IRE1 and PERK arms of the UPR and triggering of the antioxidant Nrf2 axis. Critically, chemoresistant cells exhibited PDCD4 downregulation, which coincided with a reduction in eIF4A interaction, suggesting a sophisticated regulation of protein translation. Likewise, Dox-induced chemoresistance was associated with alterations in cellular migration and invasion, which are key cancer hallmarks, coupled with changes in focal adhesion kinase (FAK) activation and secretion of matrix metalloproteinase-9 (MMP-9). Moreover, eIF4A knockdown via siRNA and its overexpression in chemoresistant cells suggested that eIF4A regulates FAK. Pro-atherogenic low-density lipoproteins (LDL) promoted cellular invasion in parental and chemoresistant cells in an MMP-9-dependent manner. Moreover, Dox only inhibited parental cell invasion. Significantly, chemoresistance was modulated by cryptotanshinone (Cry), a natural terpene purified from the roots of Salvia brandegeei. Cry and Dox co-exposure induced chemosensitization, connected with the Cry effect on eIF4A interaction. We further demonstrated the Cry binding capability on eIF4A and in silico assays suggest Cry inhibition on the RNA-processing domain. Therefore, strategic disruption of protein translation initiation is a druggable pathway by natural compounds during chemoresistance in TNBC. However, plasmatic LDL levels should be closely monitored throughout treatment.
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Tondo-Steele, Katelyn, et Karen McLean. « The “Sweet Spot” of Targeting Tumor Metabolism in Ovarian Cancers ». Cancers 14, no 19 (27 septembre 2022) : 4696. http://dx.doi.org/10.3390/cancers14194696.
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The objective of this review is to explore the metabolomic environment of epithelial ovarian cancer that contributes to chemoresistance and to use this knowledge to identify possible targets for therapeutic intervention. The Warburg effect describes increased glucose uptake and lactate production in cancer cells. In ovarian cancer, we require a better understanding of how cancer cells reprogram their glycogen metabolism to overcome their nutrient deficient environment and become chemoresistant. Glucose metabolism in ovarian cancer cells has been proposed to be influenced by altered fatty acid metabolism, oxidative phosphorylation, and acidification of the tumor microenvironment. We investigate several markers of altered metabolism in ovarian cancer including hypoxia-induced factor 1, VEGF, leptin, insulin-like growth factors, and glucose transporters. We also discuss the signaling pathways involved with these biomarkers including PI3K/AKT/mTOR, JAK/STAT and OXPHOS. This review outlines potential metabolic targets to overcome chemoresistance in ovarian cancer. Continued research of the metabolic changes in ovarian cancer is needed to identify and target these alterations to improve treatment approaches.
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Mehraj, Umar, Abid Hamid Dar, Nissar A. Wani et Manzoor A. Mir. « Tumor microenvironment promotes breast cancer chemoresistance ». Cancer Chemotherapy and Pharmacology 87, no 2 (9 janvier 2021) : 147–58. http://dx.doi.org/10.1007/s00280-020-04222-w.
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Wollenzien, Hannah, Yohannes Afeworki et Michael S. Kareta. « Abstract A005 : Transcriptional profiling of tumor heterogeneity and chemoresistance in small cell lung cancer ». Cancer Research 82, no 10_Supplement (15 mai 2022) : A005. http://dx.doi.org/10.1158/1538-7445.evodyn22-a005.
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Abstract Small Cell Lung Cancer (SCLC) is often a heterogeneous tumor, where multiple populations of phenotypically different cells exist and contribute differentially to tumor dynamics. This tumor is characterized by a very low 2- year survival rate, high metastatic rates, and rapid acquisition of chemoresistance. Beyond first-line chemotherapy, targeted treatment options are scarce, and none take in to consideration the complex genetics of the tumor. The heterogeneous nature of this tumor makes it difficult to study and to treat, as current attempts to understand tumor dynamics use a bulk approach that averages the contribution of all cells within a tumor. This work uses a cellular barcoding lineage tracing approach combined with single-cell RNA sequencing (scRNA-seq) to understand tumor heterogeneity and evolution of SCLC in both a xenograft of human SCLC cell lines and an in vivo system using a genetically modified mouse model with alterations in the same driver genes as the majority of humans with SCLC. Tumors are sampled pre-growth, post-growth and metastasis, and pre- and post- chemotherapy. By paring the barcode populations that exist in samples over time, in metastasis, or in chemoresistance, a clonal evolution map of growth, metastasis, and chemoresistance can be generated, based on shared barcodes and convergent or divergent transcriptomic profiles. In validation of scRNA-seq data, we have identified the cancer testis antigens (CTA) PAGE5 and GAGE2A as markers of chemoresistance in human SCLC. CTAs have been successfully targeted in other tumor types and may be a promising avenue for targeted therapy in SCLC. In mouse tumors, we have identified an AP-1-high population of early tumor cells that are maintained throughout the course of the disease. The knowledge gained in this work will pave the way for the identification of new therapeutic targets for SCLC. Citation Format: Hannah Wollenzien, Yohannes Afeworki, Michael S. Kareta. Transcriptional profiling of tumor heterogeneity and chemoresistance in small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A005.
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Lee, Amy H., Carolina Mejia Peña et Michelle R. Dawson. « Comparing the Secretomes of Chemorefractory and Chemoresistant Ovarian Cancer Cell Populations ». Cancers 14, no 6 (10 mars 2022) : 1418. http://dx.doi.org/10.3390/cancers14061418.
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High-grade serous ovarian cancer (HGSOC) constitutes the majority of all ovarian cancer cases and has staggering rates of both refractory and recurrent disease. While most patients respond to the initial treatment with paclitaxel and platinum-based drugs, up to 25% do not, and of the remaining that do, 75% experience disease recurrence within the subsequent two years. Intrinsic resistance in refractory cases is driven by environmental stressors like tumor hypoxia which alter the tumor microenvironment to promote cancer progression and resistance to anticancer drugs. Recurrent disease describes the acquisition of chemoresistance whereby cancer cells survive the initial exposure to chemotherapy and develop adaptations to enhance their chances of surviving subsequent treatments. Of the environmental stressors cancer cells endure, exposure to hypoxia has been identified as a potent trigger and priming agent for the development of chemoresistance. Both in the presence of the stress of hypoxia or the therapeutic stress of chemotherapy, cancer cells manage to cope and develop adaptations which prime populations to survive in future stress. One adaptation is the modification in the secretome. Chemoresistance is associated with translational reprogramming for increased protein synthesis, ribosome biogenesis, and vesicle trafficking. This leads to increased production of soluble proteins and extracellular vesicles (EVs) involved in autocrine and paracrine signaling processes. Numerous studies have demonstrated that these factors are largely altered between the secretomes of chemosensitive and chemoresistant patients. Such factors include cytokines, growth factors, EVs, and EV-encapsulated microRNAs (miRNAs), which serve to induce invasive molecular, biophysical, and chemoresistant phenotypes in neighboring normal and cancer cells. This review examines the modifications in the secretome of distinct chemoresistant ovarian cancer cell populations and specific secreted factors, which may serve as candidate biomarkers for aggressive and chemoresistant cancers.
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Mii, Sumiyuki, Yasunori Tome, Yukihiko Hiroshima, Fuminari Uehara, Shinji Miwa, Toshiyoshi Fujiwara, Robert M. Hoffman et Shuya Yano. « Effect of dormant cancer cells on angiogenesis after resisting chemotherapy. » Journal of Clinical Oncology 31, no 15_suppl (20 mai 2013) : e13577-e13577. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13577.
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e13577 Background: Dormant cancer cells are a significant problem in clinical cancer as they are usually chemoresistant and can give rise to recurrence years after treatment. Methods: Dormant cancer cells were identified with a fluorescence ubiquitination cell cycle indicator (FUCCI) and confocal microscopy. FUCCI-expressing xenografts were established from MKN45 gastric cancer cells. Results: Within 7 days after implantation in nude mice, FUCCI-expressing tumors contained a mixture of cancer cells in G0/G1 and S/G2/M phases. Cancer cells in G0/G1 phase survived and become dormant after treatment with cytotoxic agents. As the tumors grew, proliferating cells were only found at the surface. Chemotherapy killed only the proliferating cancer cells at the surface and had little effect on the majority of dormant cancer cells in the tumor center. Furthermore, we investigated tumor chemoresistance using nestin-driven green fluorescent protein (GFP) transgenic mice that have GFP-expressing nascent tumor vessels. Chemotherapy-treated tumors had much more and deeper tumor vessels than control tumors. Conclusions: These results suggest that dormant cancer cells may protect themselves by inducing angiogenesis.
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De Milito, Angelo, et Stefano Fais. « Tumor acidity, chemoresistance and proton pump inhibitors ». Future Oncology 1, no 6 (décembre 2005) : 779–86. http://dx.doi.org/10.2217/14796694.1.6.779.
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velaei, Kobra, Nasser Samadi, Balal Barazvan et Jafar Soleimani Rad. « Tumor microenvironment-mediated chemoresistance in breast cancer ». Breast 30 (décembre 2016) : 92–100. http://dx.doi.org/10.1016/j.breast.2016.09.002.
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Pan, C., T. Li, M. He, R. de Vere White, D. Gandara, P. Mack, P. N. Lara, K. Turteltaub et P. Henderson. « Design of a phase 0 microdosing trial for correlation of platinum-induced DNA damage to chemotherapy outcomes ». Journal of Clinical Oncology 27, no 15_suppl (20 mai 2009) : 2543. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2543.
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2543 Background: DNA damage is the critical step in cancer cell response to platinum (Pt) chemotherapy. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance. Accelerator mass spectrometry (AMS), an ultrasensitive method for measuring radiocarbon, can detect [14C]carboplatin bound to the DNA of cancer cells from cell culture, mice bearing tumor xenografts and patients receiving subtoxic microdoses of compound. Methods: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1/100th of the therapeutic dose) or one therapeutic dose of [14C]carboplatin. Relevant parameters such as drug influx/efflux, intracellular drug inactivation, DNA damage and repair, were measured and correlated with response to chemotherapy. A Phase 0 microdosing trial has been designed to study patients with non-small cell lung or bladder transitional cell cancers who are planning to receive Pt-based chemotherapy. One microdose of [14C]carboplatin is administered to these patients 4 hours before biopsy. Pt-induced DNA damage and repair in tumor biopsy specimens and other relevant parameters will be measured and correlated with the response and toxicity of chemotherapy. Results: Preclinical studies showed that AMS can detect Pt-DNA damage when cancer cells and mice with tumor xenografts are exposed to one microdose of [14C]carboplatin. The levels of microdose-induced DNA damage are directly proportional to the damage caused by a therapeutic drug dose (p<0.001); and these levels of DNA damage correlate with chemoresistance as measured by MTT assay. Measuring drug uptake/efflux and intracellular inactivation allows insights into resistance mechanisms. These data support the conclusion that the levels of DNA damage induced by microdosing can potentially predict chemoresistance in patients. Consequently, a Phase 0 microdosing trial is in progress. Conclusions: These results support a phase 0 microdosing trial employing AMS to identify chemoresistance and determine the underlying chemoresistant mechanisms for personalized therapy before patients receive cytotoxic chemotherapy. [Table: see text]
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Malier, Marie, Khaldoun Gharzeddine, Marie-Hélène Laverriere, Sabrina Marsili, Fabienne Thomas, Thomas Decaens, Gael Roth et Arnaud Millet. « Hypoxia Drives Dihydropyrimidine Dehydrogenase Expression in Macrophages and Confers Chemoresistance in Colorectal Cancer ». Cancer Research 81, no 23 (13 octobre 2021) : 5963–76. http://dx.doi.org/10.1158/0008-5472.can-21-1572.
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Abstract Colorectal adenocarcinoma is a leading cause of death worldwide, and immune infiltration in colorectal tumors has been recognized recently as an important pathophysiologic event. In this context, tumor-associated macrophages (TAM) have been related to chemoresistance to 5-fluorouracil (5-FU), the first-line chemotherapeutic agent used in treating colorectal cancers. Nevertheless, the details of this chemoresistance mechanism are still poorly elucidated. In the current study, we report that macrophages specifically overexpress dihydropyrimidine dehydrogenase (DPD) in hypoxia, leading to macrophage-induced chemoresistance to 5-FU via inactivation of the drug. Hypoxia-induced macrophage DPD expression was controlled by HIF2α. TAMs constituted the main contributors to DPD activity in human colorectal primary or secondary tumors, while cancer cells did not express significant levels of DPD. In addition, contrary to humans, macrophages in mice do not express DPD. Together, these findings shed light on the role of TAMs in promoting chemoresistance in colorectal cancers and identify potential new therapeutic targets. Significance: Hypoxia induces HIF2α-mediated overexpression of dihydropyrimidine dehydrogenase in TAMs, leading to chemoresistance to 5-FU in colon cancers.
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Lainetti, Patrícia de Faria, Antonio Fernando Leis-Filho, Renee Laufer-Amorim, Alexandre Battazza et Carlos Eduardo Fonseca-Alves. « Mechanisms of Resistance to Chemotherapy in Breast Cancer and Possible Targets in Drug Delivery Systems ». Pharmaceutics 12, no 12 (9 décembre 2020) : 1193. http://dx.doi.org/10.3390/pharmaceutics12121193.
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Breast cancer (BC) is one of the most important cancers worldwide, and usually, chemotherapy can be used in an integrative approach. Usually, chemotherapy treatment is performed in association with surgery, radiation or hormone therapy, providing an increased outcome to patients. However, tumors can develop resistance to different drugs, progressing for a more aggressive phenotype. In this scenario, the use of nanocarriers could help to defeat tumor cell resistance, providing a new therapeutic perspective for patients. Thus, this systematic review aims to bring the molecular mechanisms involved in BC chemoresistance and extract from the previous literature information regarding the use of nanoparticles as potential treatment for chemoresistant breast cancer.
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Asare-Werehene, Meshach, Hideaki Tsuyoshi, Huilin Zhang, Reza Salehi, Chia-Yu Chang, Euridice Carmona, Clifford L. Librach et al. « Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes ». Cancers 14, no 4 (18 février 2022) : 1039. http://dx.doi.org/10.3390/cancers14041039.
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Ovarian cancer (OVCA) is the most lethal gynaecological cancer with a 5-year survival rate less than 50%. Despite new therapeutic strategies, such as immune checkpoint blockers (ICBs), tumor recurrence and drug resistance remain key obstacles in achieving long-term therapeutic success. Therefore, there is an urgent need to understand the cellular mechanisms of immune dysregulation in chemoresistant OVCA in order to harness the host’s immune system to improve survival. The over-expression of plasma gelsolin (pGSN) mRNA is associated with a poorer prognosis in OVCA patients; however, its immuno-modulatory role has not been elucidated. In this study, for the first time, we report pGSN as an inhibitor of M1 macrophage anti-tumor functions in OVCA chemoresistance. Increased epithelial pGSN expression was associated with the loss of chemoresponsiveness and poor survival. While patients with increased M1 macrophage infiltration exhibited better survival due to nitric-oxide-induced ROS accumulation in OVCA cells, cohorts with poor survival had a higher infiltration of M2 macrophages. Interestingly, increased epithelial pGSN expression was significantly associated with the reduced survival benefits of infiltrated M1 macrophages, through apoptosis via increased caspase-3 activation and reduced production of iNOS and TNFα. Additionally, epithelial pGSN expression was an independent prognostic marker in predicting progression-free survival. These findings support our hypothesis that pGSN is a modulator of inflammation and confers chemoresistance in OVCA, in part by resetting the relative abundance and function of macrophage subtypes in the ovarian tumor microenvironment. Our findings raise the possibility that pGSN may be a potential therapeutic target for immune-mediated chemoresistance in OVCA.
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Just, Christina, Juliana Knief, Pamela Lazar-Karsten, Ekaterina Petrova, Richard Hummel, Christoph Röcken, Ulrich Wellner et Christoph Thorns. « MicroRNAs as Potential Biomarkers for Chemoresistance in Adenocarcinomas of the Esophagogastric Junction ». Journal of Oncology 2019 (29 juillet 2019) : 1–11. http://dx.doi.org/10.1155/2019/4903152.
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Concerning adenocarcinomas of the esophagogastric junction, neoadjuvant chemotherapy is regularly implemented, but patients’ response varies greatly, with some cases showing no therapeutic effect, being deemed as chemoresistant. Small, noncoding RNAs (miRNAs) have evolved as key players in biological processes, including malignant diseases, often promoting tumor growth and expansion. In addition, specific miRNAs have been implicated in the development of chemoresistance through evasion of apoptosis, cell cycle alterations, and drug target modification. We performed a retrospective study of 33 patients receiving neoadjuvant chemotherapy by measuring their miRNA expression profiles. Histologic tumor regression was evaluated using resection specimens, while miRNA profiles were prepared using preoperative biopsies without prior therapy. A preselected panel of 96 miRNAs, known to be of importance in various malignancies, was used to test for significant differences between responsive (chemosensitive) and nonresponsive (chemoresistant) cases. The cohort consisted of 12 nonresponsive and 21 responsive cases with the following 4 miRNAs differentially expressed between both the groups: hsa-let-7f-5p, hsa-miRNA-221-3p, hsa-miRNA-31-5p, and hsa-miRNA-191-5p. The former 3 showed upregulation in chemoresistant cases, while the latter showed upregulation in chemosensitive cases. In addition, significant correlation between high expression of hsa-miRNA-194-5p and prolonged survival could be demonstrated (p value <0.0001). In conclusion, we identified a panel of 3 miRNAs predicting chemoresistance and a single miRNA contributing to chemosensitivity. These miRNAs might function as prognostic biomarkers and enable clinicians to better predict the effect of one or more reliably select patients benefitting from (neoadjuvant) chemotherapy.
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Tang, Yen-An, Yu-feng Chen, Yi Bao, Sylvia Mahara, Siti Maryam J. M. Yatim, Gokce Oguz, Puay Leng Lee et al. « Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer ». Proceedings of the National Academy of Sciences 115, no 26 (11 juin 2018) : E5990—E5999. http://dx.doi.org/10.1073/pnas.1801348115.
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Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-β2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1α/TGF-β2−mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF-1α/TGF-β2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in colorectal cancer. Our study thus uncovers a molecular mechanism by which hypoxic colorectal tumor microenvironment promotes cancer cell stemness and resistance to chemotherapy and suggests a potentially targeted treatment approach to mitigating chemoresistance.
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Li, Qian, Salih Demir, Álvaro Del Río-Álvarez, Rebecca Maxwell, Alexandra Wagner, Juan Carrillo-Reixach, Carolina Armengol et al. « Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma ». Cancers 14, no 17 (30 août 2022) : 4196. http://dx.doi.org/10.3390/cancers14174196.
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Resistance to conventional chemotherapy remains a huge challenge in the clinical management of hepatoblastoma, the most common liver tumor in childhood. By integrating the gene expression data of hepatoblastoma patients into the perturbation prediction tool Connectivity Map, we identified the clinical widely used anthelmintic mebendazole as a drug to circumvent chemoresistance in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner. The combination of mebendazole and cisplatin revealed a strong synergistic effect, which was comparable to the one seen with cisplatin and doxorubicin, the current treatment for high-risk hepatoblastoma patients. Moreover, mebendazole treatment resulted in reduced colony and tumor spheroid formation capabilities, cell cycle arrest, and induction of apoptosis of hepatoblastoma cells. Mechanistically, mebendazole causes blockage of microtubule formation and transcriptional downregulation of genes encoding the unwindosome, which are highly expressed in chemoresistant tumors. Most importantly, mebendazole significantly reduced tumor growth in a subcutaneous xenograft transplantation mouse model without side effects. In conclusion, our results strongly support the clinical use of mebendazole in the treatment of chemoresistant hepatoblastoma and highlight the potential theranostic value of unwindosome-associated genes.
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Di Mitri, Diletta, Alberto Toso et Andrea Alimonti. « Tumor-infiltrating myeloid cells drive senescence evasion and chemoresistance in tumors ». OncoImmunology 4, no 9 (3 juin 2015) : e988473. http://dx.doi.org/10.4161/2162402x.2014.988473.
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Rinkenbaugh, Amanda L., Vidya C. Sinha, Pankaj Singh, Yuan Qi, Jiansu Shao, Xiaomei Zhang, Gloria V. Echeverria, W. Fraser Symmans, Stacy L. Moulder et Helen Piwnica-Worms. « Abstract 1595 : Analysis of spatiotemporal phenotypic heterogeneity in chemoresistant triple negative breast cancer using imaging mass cytometry ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 1595. http://dx.doi.org/10.1158/1538-7445.am2022-1595.
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Abstract Shifts in tumor cell phenotype in response to selective pressures (i.e. changing microenvironments, drug treatments) pose one of the biggest obstacles to successful breast cancer therapies. Phenotypically diverse breast tumor and stroma subpopulations, and interactions between them that alter tumor cell biology, represent unique and spatially distinct niches. We hypothesize that localized neighborhoods of breast tumor cells possess specialized phenotypes that mediate chemoresistance and represent novel therapeutic vulnerabilities. In order to assess these potential phenotypes, we utilized imaging mass cytometry (IMC), a highly multiplexed imaging modality that allows simultaneous measurement of 30-40 antigens while retaining the spatial architecture of the cancer tissue. We constructed an IMC antibody panel that combines markers for tissue architecture, tumor and stromal cell phenotyping, and signaling pathway activation. IMC was applied to patient-derived xenograft (PDX) models of triple negative breast cancer (TNBC).Our TNBC PDX collection was established from tumors obtained before and after neoadjuvant Adriamycin and cyclophosphamide (AC). IMC analysis of 18 PDX models representing eight patients revealed that stromal cell phenotypes were generally shared between all models, but tumor cell phenotypes were largely patient-specific. While every model was comprised primarily of a few major tumor cell phenotypes, we noted that each case also harbored several minor, unique populations, suggesting that specialized neighborhoods may exist within the tumor mass. Comparison of paired PDX models showed a wide range of phenotypic responses to chemotherapy, ranging from stable tumor composition to widespread changes in tumor phenotypes. These phenotypic changes arose despite relatively consistent genomic architecture. Vimentinhi fibroblasts were present more often in post-AC models, while SMAhi fibroblasts were unchanged after treatment. Comparison of pre-/post-AC PDX pairs revealed spatially constrained MAPK activation emerged after treatment. To capture acute changes in tumor phenotype, we treated treatment-naïve PDX models with AC and evaluated tumors by IMC. As tumors regressed and then regrew, we identified novel phenotypic shifts, again including increased MAPK signaling localized to discrete neighborhoods, suggesting this property may be a common feature of chemoresistant TNBC. Analysis of adjacent cells revealed seven distinct neighborhoods, and ongoing work is aimed at determining whether these neighborhoods are altered in response to chemotherapy treatment. Taken together, our findings suggest that distinct tumor phenotypes arise following treatment. Our goal is to determine whether these unique phenotypic niches functionally contribute to chemoresistance and if disruption of these niches enhances chemosensitivity. Citation Format: Amanda L. Rinkenbaugh, Vidya C. Sinha, Pankaj Singh, Yuan Qi, Jiansu Shao, Xiaomei Zhang, Gloria V. Echeverria, W. Fraser Symmans, Stacy L. Moulder, Helen Piwnica-Worms. Analysis of spatiotemporal phenotypic heterogeneity in chemoresistant triple negative breast cancer using imaging mass cytometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1595.
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Hodge, McKaela A., Tasha Miller, Marcus A. Weinman, Brandan Wustefeld-Janssens, Shay Bracha et Brian W. Davis. « Cellular Transcriptomics of Carboplatin Resistance in a Metastatic Canine Osteosarcoma Cell Line ». Genes 14, no 3 (23 février 2023) : 558. http://dx.doi.org/10.3390/genes14030558.
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Osteosarcoma prognosis has remained unchanged for the past three decades. In both humans and canines, treatment is limited to excision, radiation, and chemotherapy. Chemoresistance is the primary cause of treatment failure, and the trajectory of tumor evolution while under selective pressure from treatment is thought to be the major contributing factor in both species. We sought to understand the nature of platinum-based chemotherapy resistance by investigating cells that were subjected to repeated treatment and recovery cycles with increased carboplatin concentrations. Three HMPOS-derived cell lines, two resistant and one naïve, underwent single-cell RNA sequencing to examine transcriptomic perturbation and identify pathways leading to resistance and phenotypic changes. We identified the mechanisms of acquired chemoresistance and inferred the induced cellular trajectory that evolved with repeated exposure. The gene expression patterns indicated that acquired chemoresistance was strongly associated with a process similar to epithelial–mesenchymal transition (EMT), a phenomenon associated with the acquisition of migratory and invasive properties associated with metastatic disease. We conclude that the observed trajectory of tumor adaptability is directly correlated with chemoresistance and the phase of the EMT-like phenotype is directly affected by the level of chemoresistance. We infer that the EMT-like phenotype is a critical component of tumor evolution under treatment pressure and is vital to understanding the mechanisms of chemoresistance and to improving osteosarcoma prognosis.
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Melcher, Viktoria, Monika Graf, Marta Interlandi, Natalia Moreno, Flavia W. de Faria, Su Na Kim, Dennis Kastrati et al. « ATRT-14. MACROPHAGE-TUMOR CELL INTERACTION PROMOTES ATRT PROGRESSION AND CHEMORESISTANCE ». Neuro-Oncology 22, Supplement_3 (1 décembre 2020) : iii278. http://dx.doi.org/10.1093/neuonc/noaa222.013.
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Abstract Atypical teratoid/rhabdoid tumors (ATRT) are pediatric brain neoplasms that are known for their heterogeneity concerning pathophysiology and outcome. The three genetically rather uniform but epigenetically distinct molecular subgroups of ATRT alone do not sufficiently explain the clinical heterogeneity. Therefore, we examined the tumor microenvironment (TME) in the context of tumor diversity. By using multiplex-immunofluorescent staining and single-cell RNA sequencing (scRNA-seq) we unveiled the pan-macrophage marker CD68 as a subgroup-independent negative prognostic marker for survival of ATRT patients. ScRNA-seq analysis of murine ATRT-SHH, ATRT-MYC and extracranial RT (eRT) provide a delineation of the TME, which is predominantly infiltrated by myeloid cells: more specifically a microglia-enriched niche in ATRT-SHH and a bone marrow-derived macrophage infiltration in ATRT-MYC and eRT. Exploring the cell-cell communication of tumor cells with tumor-associated immune cells, we found that Cd68+ tumor-associated macrophages (TAMs) are central to intercellular communication with tumor cells. Moreover, we uncovered distinct tumor phenotypes in murine ATRT-MYC that share genetic traits with TAMs. These intermediary cells considerably increase the intratumoral heterogeneity of ATRT-MYC tumors. In vitro co-culture experiments recapitulated the capability of ATRT-MYC cells to interchange cell material with macrophages extensively, in contrast to ATRT-SHH cells. We found that microglia are less involved in the exchange of information with ATRT cells and that direct contact is a prerequisite for incorporation. A relapse xenograft model implied that intermediary cells are involved in the acquisition of chemotherapy resistance. We show evidence that TAM-tumor cell interaction is one mechanism of chemotherapy resistance and relapse in ATRT.
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Wang, Xu, Xin Wang, Midie Xu et Weiqi Sheng. « Effects of CAF-Derived MicroRNA on Tumor Biology and Clinical Applications ». Cancers 13, no 13 (24 juin 2021) : 3160. http://dx.doi.org/10.3390/cancers13133160.
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Cancer-associated fibroblasts (CAFs), prominent cell components of the tumor microenvironment (TME) in most types of solid tumor, play an essential role in tumor cell growth, proliferation, invasion, migration, and chemoresistance. MicroRNAs (miRNAs) are small, non-coding, single-strand RNAs that negatively regulate gene expression by post-transcription modification. Increasing evidence has suggested the dysregulation of miRNAs in CAFs, which facilitates the conversion of normal fibroblasts (NFs) into CAFs, then enhances the tumor-promoting capacity of CAFs. To understand the process of tumor progression, as well as the development of chemoresistance, it is important to explore the regulatory function of CAF-derived miRNAs and the associated molecular mechanisms, which may become potential diagnostic and prognostic biomarkers and targets of anti-tumor therapeutics. In this review, we describe miRNAs that are differentially expressed by NFs and CAFs, summarize the modulating role of CAF-derived miRNAs in fibroblast activation and tumor advance, and eventually identify a potential clinical application for CAF-derived miRNAs as diagnostic/prognostic biomarkers and therapeutic targets in several tumors.
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Thege, Fredrik I., Ian I. Cardle, Conor N. Gruber, Megan J. Siemann, Sophie Cong, Katharina Wittmann, Justin Love et Brian J. Kirby. « Acquired chemoresistance drives spatial heterogeneity, chemoprotection and collective migration in pancreatic tumor spheroids ». PLOS ONE 17, no 5 (26 mai 2022) : e0267882. http://dx.doi.org/10.1371/journal.pone.0267882.
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Tumors display rich cellular heterogeneity and typically consist of multiple co-existing clones with distinct genotypic and phenotypic characteristics. The acquisition of resistance to chemotherapy has been shown to contribute to the development of aggressive cancer traits, such as increased migration, invasion and stemness. It has been hypothesized that collective cellular behavior and cooperation of cancer cell populations may directly contribute to disease progression and lack of response to treatment. Here we show that the spontaneous emergence of chemoresistance in a cancer cell population exposed to the selective pressure of a chemotherapeutic agent can result in the emergence of collective cell behavior, including cell-sorting, chemoprotection and collective migration. We derived several gemcitabine resistant subclones from the human pancreatic cancer cell line BxPC3 and determined that the observed chemoresistance was driven of a focal amplification of the chr11p15.4 genomic region, resulting in over-expression of the ribonucleotide reductase (RNR) subunit RRM1. Interestingly, these subclones display a rich cell-sorting behavior when cultured as mixed tumor spheroids. Furthermore, we show that chemoresistant cells are able to exert a chemoprotective effect on non-resistant cells in spheroid co-culture, whereas no protective effect is seen in conventional 2D culture. We also demonstrate that the co-culture of resistant and non-resistant cells leads to collective migration where resistant cells enable migration of otherwise non-migratory cells.
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Faruqi, Fahad Ahmed, Mohammad Jalalirad, Antonino Bonaventura D'Assoro, Tufia C. Haddad, Jodi M. Carter, Judy Caroline Boughey, Leiwei Wang, Matthew P. Goetz et James N. Ingle. « Dual TGF-β and AURKA targeting enhances chemosensitivity in triple-negative breast cancer. » Journal of Clinical Oncology 38, no 15_suppl (20 mai 2020) : e13106-e13106. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13106.
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e13106 Background: Chemotherapy resistance remains a significant barrier in the effective treatment of patients with triple negative breast cancer (TNBC). TGF-β signaling is a well characterized oncogenic pathway in TNBC that promotes chemoresistance by inducing epithelial to mesenchymal transition (EMT) and tumor stemness. Aurora-A kinase (AURKA) is a serine/threonine kinase responsible for chromosomal stability during mitosis. Significantly, aberrant expression of AURKA induces breast cancer progression. We hypothesized that aberrant activation of TGF-β and AURKA signaling pathways contributes to chemoresistance in TNBC by promoting EMT and tumor stemness and that dual-targeting of these oncoproteins will enhance chemosensitivity. Methods: RNA-Seq data were analyzed from patient derived xenografts (PDx) established from patients with Stage I-III TNBC who received pre-operative taxane and anthracycline based chemotherapy. Chemoresistance was defined as an RCB score of 1-3, and chemosensitivity was defined as an RCB score of 0. Unique TNBC cell lines developed from brain metastasis PDxs (TNBC M14, TNBC M25) were treated in vitro with 10nM docetaxel (DTX), 50nM LY2157299 (TGF-β inhibitor) and 50nM MLN8237 (AURKA inhibitor). EMT reprogramming was determined by measuring the expression of vimentin, ALDH activity and mammosphere growth. Apoptotic cells following drug treatment were labeled with Red Annexin-V marker and monitored in real time using the IncuCyte instrument. Results: RNA-Seq revealed that there was no baseline difference in expression of AURKA between chemoresistant and chemosensitive TNBC PDxs. However, there was a 2.7-fold increase in AURKA expression in the post-treatment PDx models compared to pre-treatment PDx models. In vitro treatment of the M14 and M25 cell lines with DTX demonstrated no significant increase in apoptotic cells compared to control, whereas treatment with the combination of DTX, LY2157299 and MLN8237 resulted in a two-fold increase in apoptosis compared to treatment with DTX alone (p = 0.0068 M14, p = 0.003 M25). Dual-targeting with LY2157299 and MLN8237 reduced the expression of vimentin and ALDH activity. Conclusions: TGF-β and AURKA play a central role inducing EMT and a stem-cell-like phenotype in TNBC that confers chemoresistance. AURKA is up-regulated after exposure to chemotherapy in chemoresistant TNBC PDx models. LY2157299 and MLN8237 reduce TNBC stemness in M14 and M25 cell lines and enhance DTX chemosensitivity. Dual-targeting of TGF-β and AURKA is a potentially promising approach in chemoresistant TNBC.
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Lee, Jiyeon, Ji-Hyun Hwang, Harim Chun, Wonjin Woo, Sekyung Oh, Jungmin Choi et Lark Kyun Kim. « PLEKHA8P1 Promotes Tumor Progression and Indicates Poor Prognosis of Liver Cancer ». International Journal of Molecular Sciences 22, no 14 (16 juillet 2021) : 7614. http://dx.doi.org/10.3390/ijms22147614.
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Hepatocellular carcinoma (HCC) records the second-lowest 5-year survival rate despite the avalanche of research into diagnosis and therapy. One of the major obstacles in treatment is chemoresistance to drugs such as 5-fluorouracil (5-FU), making identification and elucidation of chemoresistance regulators highly valuable. As the regulatory landscape grows to encompass non-coding genes such as long non-coding RNAs (lncRNAs), a relatively new class of lncRNA has emerged in the form of pseudogene-derived lncRNAs. Through bioinformatics analyses of the TCGA LIHC dataset, we have systematically identified pseudogenes of prognostic value. Initial experimental validation of selected pseudogene-derived lncRNA (PLEKHA8P1) and its parental gene (PLEKHA8), a well-studied transport protein in Golgi complex recently implicated as an oncogene in both colorectal and liver cancer, indicates that the pseudogene/parental gene pair promotes tumor progression and that their dysregulated expression levels affect 5-FU-induced chemoresistance in human HCC cell line FT3-7. Our study has thus confirmed cancer-related functions of PLEKHA8, and laid the groundwork for identification and validation of oncogenic pseudogene-derived lncRNA that shows potential as a novel therapeutic target in circumventing chemoresistance induced by 5-FU.
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Ceccarelli, Simona, Francesca Megiorni, Diana Bellavia, Cinzia Marchese, Isabella Screpanti et Saula Checquolo. « Notch3 Targeting : A Novel Weapon against Ovarian Cancer Stem Cells ». Stem Cells International 2019 (6 janvier 2019) : 1–8. http://dx.doi.org/10.1155/2019/6264931.
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Notch signaling is frequently activated in ovarian cancer (OC) and contributes to the proliferation and survival of cultured OC cells as well as to tumor formation and angiogenesis in xenograft models. Several studies demonstrate that Notch3 expression renders cancer cells more resistant to carboplatin, contributing to chemoresistance and poor survival of OC-bearing patients. This suggests that Notch3 can represent both a biomarker and a target for therapeutic interventions in OC patients. Although it is still unclear how chemoresistance arises, different lines of evidence support a critical role of cancer stem cells (CSCs), suggesting that CSC targeting by innovative therapeutic approaches might represent a promising tool to efficiently reduce OC recurrence. To date, CSC-directed therapies in OC tumors are mainly targeted to the inhibition of CSC-related signaling pathways, including Notch. As it is increasingly evident the involvement of Notch signaling, and in particular of Notch3, in regulating stem-like cell maintenance and expansion in several tumors, here we provide an overview of the current knowledge of Notch3 role in CSC-mediated OC chemoresistance, finally exploring the potential design of innovative Notch3 inhibition-based therapies for OC treatment, aimed at eradicating tumor through the suppression of CSCs.
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He, Lin, Neda Wick, Sharon Koorse Germans et Yan Peng. « The Role of Breast Cancer Stem Cells in Chemoresistance and Metastasis in Triple-Negative Breast Cancer ». Cancers 13, no 24 (9 décembre 2021) : 6209. http://dx.doi.org/10.3390/cancers13246209.
Texte intégralRésumé :
Triple negative breast cancer (TNBC) remains an aggressive disease due to the lack of targeted therapies and low rate of response to chemotherapy that is currently the main treatment modality for TNBC. Breast cancer stem cells (BCSCs) are a small subpopulation of breast tumors and recognized as drivers of tumorigenesis. TNBC tumors are characterized as being enriched for BCSCs. Studies have demonstrated the role of BCSCs as the source of metastatic disease and chemoresistance in TNBC. Multiple targets against BCSCs are now under investigation, with the considerations of either selectively targeting BCSCs or co-targeting BCSCs and non-BCSCs (majority of tumor cells). This review article provides a comprehensive overview of recent advances in the role of BCSCs in TNBC and the identification of cancer stem cell biomarkers, paving the way for the development of new targeted therapies. The review also highlights the resultant discovery of cancer stem cell targets in TNBC and the ongoing clinical trials treating chemoresistant breast cancer. We aim to provide insights into better understanding the mutational landscape of BCSCs and exploring potential molecular signaling pathways targeting BCSCs to overcome chemoresistance and prevent metastasis in TNBC, ultimately to improve the overall survival of patients with this devastating disease.
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Ogbu, Stella C., Samuel Rojas, John Weaver, Phillip R. Musich, Jinyu Zhang, Zhi Q. Yao et Yong Jiang. « DSTYK Enhances Chemoresistance in Triple-Negative Breast Cancer Cells ». Cells 11, no 1 (29 décembre 2021) : 97. http://dx.doi.org/10.3390/cells11010097.
Texte intégralRésumé :
Breast cancer, as the most prevalent cancer in women, is responsible for more than 15% of new cancer cases and about 6.9% of all cancer-related death in the US. A major cause of therapeutic failure in breast cancer is the development of resistance to chemotherapy, especially for triple-negative breast cancer (TNBC). Therefore, how to overcome chemoresistance is the major challenge to improve the life expectancy of breast cancer patients. Our studies demonstrate that TNBC cells surviving the chronic treatment of chemotherapeutic drugs show significantly higher expression of the dual serine/threonine and tyrosine protein kinase (DSTYK) than non-treated parental cells. In our in vitro cellular models, DSTYK knockout via the CRISPR/Cas9-mediated technique results in apoptotic cell death of chemoresistant cells upon drug treatment. Moreover, DSTYK knockout promotes chemotherapeutic drug-induced tumor cell death in an orthotopic mouse model. These findings suggest that DSTYK exerts an important and previously unknown role in promoting chemoresistance. Our studies provide fundamental insight into the role of DSTYK in chemoresistance in TNBC cells and lay the foundation for the development of new strategies targeting DSTYK for improving TNBC therapy.
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Huang, Menggui, Duo Zhang, Janet Y. Wu, Kun Xing, Eujin Yeo, Chunsheng Li, Lin Zhang et al. « Wnt-mediated endothelial transformation into mesenchymal stem cell–like cells induces chemoresistance in glioblastoma ». Science Translational Medicine 12, no 532 (26 février 2020) : eaay7522. http://dx.doi.org/10.1126/scitranslmed.aay7522.
Texte intégralRésumé :
Therapeutic resistance remains a persistent challenge for patients with malignant tumors. Here, we reveal that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)–like cells in glioblastoma (GBM), driving tumor resistance to cytotoxic treatment. Transcriptome analysis by RNA sequencing (RNA-seq) revealed that ECs undergo mesenchymal transformation and stemness-like activation in GBM microenvironment. Furthermore, we identified a c-Met–mediated axis that induces β-catenin phosphorylation at Ser675 and Wnt signaling activation, inducing multidrug resistance–associated protein-1(MRP-1) expression and leading to EC stemness-like activation and chemoresistance. Last, genetic ablation of β-catenin in ECs overcome GBM tumor resistance to temozolomide (TMZ) chemotherapy in vivo. Combination of Wnt inhibition and TMZ chemotherapy eliminated tumor-associated ECs, inhibited GBM growth, and increased mouse survival. These findings identified a cell plasticity–based, microenvironment-dependent mechanism that controls tumor chemoresistance, and suggest that targeting Wnt/β-catenin–mediated EC transformation and stemness activation may overcome therapeutic resistance in GBM.
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Palliyage, Gayathri Heenatigala, Rajib Ghosh et Yon Rojanasakul. « Cancer chemoresistance and therapeutic strategies targeting tumor microenvironment ». ScienceAsia 46, no 6 (2020) : 639. http://dx.doi.org/10.2306/scienceasia1513-1874.2020.092.
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Ganapathy-Kanniappan, Shanmugasundaram. « Rac1 repression reverses chemoresistance by targeting tumor metabolism ». Cancer Biology & ; Therapy 21, no 10 (31 août 2020) : 888–90. http://dx.doi.org/10.1080/15384047.2020.1809923.
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Testa, U., L. Pasquini et E. Petrucci. « In vitro assays of tumor chemosensitivity and chemoresistance ». Drugs of the Future 29, no 10 (2004) : 1035. http://dx.doi.org/10.1358/dof.2004.029.10.863394.
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Tao, Shuang, Zhengyang Bai, Yaobang Liu, Yali Gao, Jia Zhou, Yangyang Zhang et Jinping Li. « Exosomes Derived from Tumor Cells Initiate Breast Cancer Cell Metastasis and Chemoresistance through a MALAT1-Dependent Mechanism ». Journal of Oncology 2022 (30 juin 2022) : 1–16. http://dx.doi.org/10.1155/2022/5483523.
Texte intégralRésumé :
Background. Chemoresistance poses a great hindrance in the treatment of breast cancer (BC). Interestingly, exosome (Exo)-mediated transfer of long noncoding RNAs (lncRNAs) has been reported to regulate chemoresistance in diverse diseases. We herein investigate the potential role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) transferred by BC cell-derived Exo in chemoresistance of BC cells. Methods. BC-related lncRNAs were identified. Exosomes were isolated and verified from BC cells. The expression patterns of MALAT1 were then examined in the adriamycin (ADR)-sensitive and resistant cells and the isolated Exo, followed by the analysis of the downstream microRNA (miRNA) of MALAT1. The role and mechanism of MALAT1 transmitted by BC cell-derived Exo in BC cell metastasis and chemoresistance were assessed. Results. MALAT1 was highly expressed in BC cells and their Exo. In addition, MALAT1 delivered by BC cell-derived Exo augmented the malignant properties and chemoresistance of BC cells. Mechanistically, MALAT1 bound to miR-1-3p and limited the miR-1-3p expression, which sequentially targeted the vasodilator-stimulated phosphoprotein (VASP) protein. Moreover, silencing of VASP inhibited the activation of the RAP1 member of RAS oncogene family (Rap1) signaling pathway, which led to the attenuation of BC cell malignant properties and chemoresistance. In vivo assay further validated the tumor-promoting effect of Exo-MALAT1 via regulation of the miR-1-3p/VASP/Rap1 axis. Conclusion. Collectively, MALAT1 loaded by BC cell-derived Exo can accelerate BC cell metastasis and chemoresistance via disruption of miR-1-3p-mediated inhibition of the VASP/Rap1 signaling axis.
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Peri, Sara, Alessio Biagioni, Giampaolo Versienti, Elena Andreucci, Fabio Staderini, Giuseppe Barbato, Lisa Giovannelli et al. « Enhanced Vasculogenic Capacity Induced by 5-Fluorouracil Chemoresistance in a Gastric Cancer Cell Line ». International Journal of Molecular Sciences 22, no 14 (19 juillet 2021) : 7698. http://dx.doi.org/10.3390/ijms22147698.
Texte intégralRésumé :
Chemotherapy is still widely used as a coadjutant in gastric cancer when surgery is not possible or in presence of metastasis. During tumor evolution, gatekeeper mutations provide a selective growth advantage to a subpopulation of cancer cells that become resistant to chemotherapy. When this phenomenon happens, patients experience tumor recurrence and treatment failure. Even if many chemoresistance mechanisms are known, such as expression of ATP-binding cassette (ABC) transporters, aldehyde dehydrogenase (ALDH1) activity and activation of peculiar intracellular signaling pathways, a common and universal marker for chemoresistant cancer cells has not been identified yet. In this study we subjected the gastric cancer cell line AGS to chronic exposure of 5-fluorouracil, cisplatin or paclitaxel, thus selecting cell subpopulations showing resistance to the different drugs. Such cells showed biological changes; among them, we observed that the acquired chemoresistance to 5-fluorouracil induced an endothelial-like phenotype and increased the capacity to form vessel-like structures. We identified the upregulation of thymidine phosphorylase (TYMP), which is one of the most commonly reported mutated genes leading to 5-fluorouracil resistance, as the cause of such enhanced vasculogenic ability.
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Valle, Sandra, Laura Martin-Hijano, Sonia Alcalá, Marta Alonso-Nocelo et Bruno Sainz Jr. « The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer ». Cancers 10, no 2 (26 janvier 2018) : 33. http://dx.doi.org/10.3390/cancers10020033.
Texte intégralRésumé :
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the 4th most frequent cause of cancer-related death worldwide, primarily due to the inherent chemoresistant nature and metastatic capacity of this tumor. The latter is believed to be mainly due to the existence of a subpopulation of highly plastic “stem”-like cells within the tumor, known as cancer stem cells (CSCs), which have been shown to have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. As such, current treatments for the majority of PDAC patients are not effective and do not significantly impact overall patient survival (<7 months) as they do not affect the pancreatic CSC (PaCSC) population. In this context, it is important to highlight the need to better understand the characteristics of the PaCSC population in order to develop new therapies to target these cells. In this review, we will provide the latest updates and knowledge on the inherent characteristics of PaCSCs, particularly their unique biological properties including chemoresistance, epithelial to mesenchymal transition, plasticity, metabolism and autophagy.
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Richards, Katherine E., Weikun Xiao et Reginald Hill. « Cancer-Associated Fibroblasts Confer Gemcitabine Resistance to Pancreatic Cancer Cells through PTEN-Targeting miRNAs in Exosomes ». Cancers 14, no 11 (6 juin 2022) : 2812. http://dx.doi.org/10.3390/cancers14112812.
Texte intégralRésumé :
Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-related death in the United States. Even though the poor prognosis of PDAC is often attributed to late diagnosis, patients with an early diagnosis who undergo tumor resection and adjuvant chemotherapy still show tumor recurrence, highlighting a need to develop therapies which can overcome chemoresistance. Chemoresistance has been linked to the high expression of microRNAs (miRs), such as miR-21, within tumor cells. Tumor cells can collect miRs through the uptake of miR-containing lipid extracellular vesicles called exosomes. These exosomes are secreted in high numbers from cancer-associated fibroblasts (CAFs) within the tumor microenvironment during gemcitabine treatment and can contribute to cell proliferation and chemoresistance. Here, we show a novel mechanism in which CAF-derived exosomes may promote proliferation and chemoresistance, in part, through suppression of the tumor suppressor PTEN. We identified five microRNAs: miR-21, miR-181a, miR-221, miR-222, and miR-92a, that significantly increased in number within the CAF exosomes secreted during gemcitabine treatment which target PTEN. Furthermore, we found that CAF exosomes suppressed PTEN expression in vitro and that treatment with the exosome inhibitor GW4869 blocked PTEN suppression in vivo. Collectively, these findings highlight a mechanism through which the PTEN expression loss, often seen in PDAC, may be attained and lend support to investigations into the use of exosome inhibitors as potential therapeutics to improve the effectiveness of chemotherapy.