Journal articles on the topic 'Chronic hypoxia, dormancy, breast cancer'
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Carcereri de Prati, Alessandra, Elena Butturini, Antonella Rigo, Elisa Oppici, Michele Rossin, Diana Boriero, and Sofia Mariotto. "Metastatic Breast Cancer Cells Enter Into Dormant State and Express Cancer Stem Cells Phenotype Under Chronic Hypoxia." Journal of Cellular Biochemistry 118, no. 10 (May 3, 2017): 3237–48. http://dx.doi.org/10.1002/jcb.25972.
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Ferrer, Alejandra, Christopher T. Roser, Markos H. El-Far, Vibha Harindra Savanur, Adam Eljarrah, Marina Gergues, Joshua A. Kra, Jean-Pierre Etchegaray, and Pranela Rameshwar. "Hypoxia-mediated changes in bone marrow microenvironment in breast cancer dormancy." Cancer Letters 488 (September 2020): 9–17. http://dx.doi.org/10.1016/j.canlet.2020.05.026.
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Endo, Hiroko, Hiroaki Okuyama, Masayuki Ohue, and Masahiro Inoue. "Dormancy of Cancer Cells with Suppression of AKT Activity Contributes to Survival in Chronic Hypoxia." PLoS ONE 9, no. 6 (June 6, 2014): e98858. http://dx.doi.org/10.1371/journal.pone.0098858.
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YILDIRIM ŞİMŞİR, Ilgın, Utku Erdem SOYALTIN, and Candeğer YILMAZ. "Obesity and Breast Cancer: Adipose Tissue, Adipocytokines, Chronic Inflammation, and Hypoxia." Turkish Journal of Endocrinology and Metabolism 22, no. 4 (2018): 244–53. http://dx.doi.org/10.25179/tjem.2017-57808.
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Li, Li-Ting, Fang-Fang Zhao, Zhi-Mei Jia, Li-Qing Qi, Xi-Zhu Zhang, Lu Zhang, Ying-Ying Li, et al. "Cannabinoid receptors promote chronic intermittent hypoxia-induced breast cancer metastasis via IGF-1R/AKT/GSK-3β." Molecular Therapy - Oncolytics 23 (December 2021): 220–30. http://dx.doi.org/10.1016/j.omto.2021.09.007.
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Jain, Nityanand, Ingrida Mitre, Dina Nitisa, Valdis Pirsko, and Inese Cakstina-Dzerve. "Identification of Novel Endogenous Controls for qPCR Normalization in SK-BR-3 Breast Cancer Cell Line." Genes 12, no. 10 (October 17, 2021): 1631. http://dx.doi.org/10.3390/genes12101631.
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Normalization of gene expression using internal controls or reference genes (RGs) has been the method of choice for standardizing the technical variations in reverse transcription quantitative polymerase chain reactions (RT-qPCR). Conventionally, ACTB and GAPDH have been used as reference genes despite evidence from literature discouraging their use. Hence, in the present study we identified and investigated novel reference genes in SK-BR-3, an HER2-enriched breast cancer cell line. Transcriptomic data of 82 HER2-E breast cancer samples from TCGA database were analyzed to identify twelve novel genes with stable expression. Additionally, thirteen RGs from the literature were analyzed. The expression variations of the candidate genes were studied over five successive passages (p) in two parallel cultures S1 and S2 and in acute and chronic hypoxia using various algorithms. Finally, the most stable RGs were selected and validated for normalization of the expression of three genes of interest (GOIs) in normoxia and hypoxia. Our results indicate that HSP90AB1, DAD1, PFN1 and PUM1 can be used in any combination of three (triplets) for optimizing intra- and inter-assay gene expression differences in the SK-BR-3 cell line. Additionally, we discourage the use of conventional RGs (ACTB, GAPDH, RPL13A, RNA18S and RNA28S) as internal controls for RT-qPCR in SK-BR-3 cell line.
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Scherbakov, Alexander M., Yulia S. Lobanova, Valentina A. Shatskaya, and Mikhail A. Krasil’nikov. "The breast cancer cells response to chronic hypoxia involves the opposite regulation of NF-kB and estrogen receptor signaling." Steroids 74, no. 6 (June 2009): 535–42. http://dx.doi.org/10.1016/j.steroids.2009.02.003.
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Zihlif, M., and F. Hamadan. "173 Hepatocyte nuclear factor 4, alpha (HNF4A): A potential biomarker in MCF7 breast cancer cell line response to chronic hypoxia." European Journal of Cancer 51 (September 2015): S21. http://dx.doi.org/10.1016/s0959-8049(16)30070-3.
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Zarzynska, Joanna Magdalena. "The Importance of Autophagy Regulation in Breast Cancer Development and Treatment." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/710345.
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Breast cancer (BC) is a potentially life-threatening malignant tumor that still causes high mortality among women. One of the mechanisms through which cancer development could be controlled is autophagy. This process exerts different effects during the stages of cancer initiation and progression due to the occurring superimposition of signaling pathways of autophagy and carcinogenesis. Chronic inhibition of autophagy or autophagy deficiency promotes cancer, due to instability of the genome and defective cell growth and as a result of cell stress. However, increased induction of autophagy can become a mechanism which allows tumor cells to survive the conditions of hypoxia, acidosis, or chemotherapy. Therefore, in the development of cancer, autophagy is regarded as a double-edged sword. Determination of the molecular mechanisms underlying autophagy regulation and its role in tumorigenesis is an essential component of modern anticancer strategies. Results of scientific studies show that inhibition of autophagy may enhance the effectiveness of currently used anticancer drugs and other therapies (like radiotherapy). However, in some cases, the promotion of autophagy can induce death and, hence, elimination of the cancer cells and reduction of tumor size. This review summarizes the current knowledge on autophagy regulation in BC and up-to-date anticancer strategies correlated with autophagy.
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Mirabelli, Caitlynn N., Rachel La Selva, John Heath, Steven Hébert, Jutta Steinberger, Jialin Jiang, Claudia Kleinman, Sidong Huang, and Josie Ursini-Siegel. "Abstract 126: Defining how oxidative stress drives the evolution of aggressive breast cancers." Cancer Research 82, no. 12_Supplement (June 15, 2022): 126. http://dx.doi.org/10.1158/1538-7445.am2022-126.
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Abstract Breast cancer is the most commonly diagnosed malignancy in women worldwide. It is a molecularly heterogeneous disease, which poses difficulties in the treatment of more advanced cancers. Despite this fact, the mechanisms contributing to the emergence of aggressive breast cancers remains poorly understood. We focus on reactive oxygen species (ROS), which are induced by a variety of stimuli in breast cancer cells. Moderately elevated ROS levels are tumor-promoting and facilitate the emergence of more aggressive tumours. Our laboratory has developed a unique model of HER2+ breast cancer that evolved to acquire more aggressive properties under conditions of chronic oxidative stress. We identified 20 transcription factors/co-regulators that were specifically overexpressed in these aggressive breast cancers, compared to their parental counterparts. We hypothesize that these transcription factors are central to the ability of breast tumors to adapt to chronic oxidative stress and acquire more aggressive properties. To test this, I have performed an in vivo functional shRNA screen to identify those transcriptional regulators that drive an aggressive phenotype. This will be followed by functional validation studies to interrogate whether and how these unique transcription factors overexpressed in aggressive breast cancers impact tumour growth, metastasis, and drug resistance. Mechanistically, we will explore whether and how these transcriptional responses mediate adaptive responses to tumor microenvironmental stressors, including altered metabolism, hypoxia, and tumor immune responses. This research will broaden our understanding of how breast cancers adapt to oxidative stress responses and represents a necessary first step in the development of novel therapeutics against these invulnerable malignancies. Citation Format: Caitlynn N. Mirabelli, Rachel La Selva, John Heath, Steven Hébert, Jutta Steinberger, Jialin Jiang, Claudia Kleinman, Sidong Huang, Josie Ursini-Siegel. Defining how oxidative stress drives the evolution of aggressive breast cancers [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 126.
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Biganzoli, Elia, and Romano Demicheli. "From Oncological Paradigms to Non-Communicable Disease Pandemic. The Need of Recovery Human Biology Evolution." International Journal of Environmental Research and Public Health 18, no. 19 (September 25, 2021): 10087. http://dx.doi.org/10.3390/ijerph181910087.
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The paradigm of the Somatic Mutation Theory (SMT) is failing, and a new paradigm is underway but not yet established. What is being challenged is a conceptual approach that involves the entire human biology and the development of chronic diseases. The behavior of breast and other solid cancers is compatible with the concept that the primary tumor is able to control its microscopic metastases, in the same way that an organ (e.g., the liver) is able to control its physiological size. This finding suggested that cancer and its metastases may behave as an organoid. The new paradigm under construction considers the origin of tumors as a disturbance in the communication network between tissue cell populations and between cells and extracellular matrix, and supports a systemic approach to the study of both healthy and pathologic tissues. The commentary provides a rationale for the role of physical exercise in the control of tumor dormancy according to a human evolutionary perspective.
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De Pergola, Giovanni, and Franco Silvestris. "Obesity as a Major Risk Factor for Cancer." Journal of Obesity 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/291546.
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The number of cancer cases caused by being obese is estimated to be 20% with the increased risk of malignancies being influenced by diet, weight change, and body fat distribution together with physical activity. Reports from the International Agency for Research into Cancer and the World Cancer Research Fund (WCRF) have shown that the strongest evidence exists for an association of obesity with the following cancer types: endometrial, esophageal adenocarcinoma, colorectal, postmenopausal breast, prostate, and renal, whereas the less common malignancies are leukemia, non-Hodgkin’s lymphoma, multiple myeloma, malignant melanoma, and thyroid tumours. To be able to develop novel methods in prevention and treatment, we first must understand the underlying processes which link cancer to obesity. Four main systems have been identified as potential producers of cancer in obesity: insulin, insulin-like growth factor-I, sex steroids, and adipokines. Various novel candidate mechanisms have been proposed: chronic inflammation, oxidative stress, crosstalk between tumour cells and surrounding adipocytes, migrating adipose stromal cells, obesity-induced hypoxia, shared genetic susceptibility, and the functional defeat of immune function. Herein, we review the major pathogenic links between obesity and susceptibility to cancer.
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Rencelj, Andrej, Nada Gvozdenovic, and Maja Cemazar. "MitomiRs: their roles in mitochondria and importance in cancer cell metabolism." Radiology and Oncology 55, no. 4 (November 19, 2021): 379–92. http://dx.doi.org/10.2478/raon-2021-0042.
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Abstract Background MicroRNAs (miRNAs) are short non-coding RNAs that play important roles in almost all biological pathways. They regulate post-transcriptional gene expression by binding to the 3’untranslated region (3’UTR) of messenger RNAs (mRNAs). MitomiRs are miRNAs of nuclear or mitochondrial origin that are localized in mitochondria and have a crucial role in regulation of mitochondrial function and metabolism. In eukaryotes, mitochondria are the major sites of oxidative metabolism of sugars, lipids, amino acids, and other bio-macromolecules. They are also the main sites of adenosine triphosphate (ATP) production. Conclusions In the review, we discuss the role of mitomiRs in mitochondria and introduce currently well studied mitomiRs, their target genes and functions. We also discuss their role in cancer initiation and progression through the regulation of mRNA expression in mitochondria. MitomiRs directly target key molecules such as transporters or enzymes in cell metabolism and regulate several oncogenic signaling pathways. They also play an important role in the Warburg effect, which is vital for cancer cells to maintain their proliferative potential. In addition, we discuss how they indirectly upregulate hexokinase 2 (HK2), an enzyme involved in glucose phosphorylation, and thus may affect energy metabolism in breast cancer cells. In tumor tissues such as breast cancer and head and neck tumors, the expression of one of the mitomiRs (miR-210) correlates with hypoxia gene signatures, suggesting a direct link between mitomiR expression and hypoxia in cancer. The miR-17/92 cluster has been shown to act as a key factor in metabolic reprogramming of tumors by regulating glycolytic and mitochondrial metabolism. This cluster is deregulated in B-cell lymphomas, B-cell chronic lymphocytic leukemia, acute myeloid leukemia, and T-cell lymphomas, and is particularly overexpressed in several other cancers. Based on the current knowledge, we can conclude that there is a large number of miRNAs present in mitochondria, termed mitomiR, and that they are important regulators of mitochondrial function. Therefore, mitomiRs are important players in the metabolism of cancer cells, which need to be further investigated in order to develop a potential new therapies for cancer.
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Kober, Kord M., Man-Cheung Lee, Adam Olshen, Yvette P. Conley, Marina Sirota, Michael Keiser, Marilyn J. Hammer, et al. "Differential methylation and expression of genes in the hypoxia-inducible factor 1 signaling pathway are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors and with preclinical models of chemotherapy-induced neuropathic pain." Molecular Pain 16 (January 2020): 174480692093650. http://dx.doi.org/10.1177/1744806920936502.
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Background Paclitaxel is an important chemotherapeutic agent for the treatment of breast cancer. Paclitaxel-induced peripheral neuropathy (PIPN) is a major dose-limiting toxicity that can persist into survivorship. While not all survivors develop PIPN, for those who do, it has a substantial negative impact on their functional status and quality of life. No interventions are available to treat PIPN. In our previous studies, we identified that the HIF-1 signaling pathway (H1SP) was perturbed between breast cancer survivors with and without PIPN. Preclinical studies suggest that the H1SP is involved in the development of bortezomib-induced and diabetic peripheral neuropathy, and sciatic nerve injury. The purpose of this study was to identify H1SP genes that have both differential methylation and differential gene expression between breast cancer survivors with and without PIPN. Methods A multi-staged integrated analysis was performed. In peripheral blood, methylation was assayed using microarray and gene expression was assayed using RNA-seq. Candidate genes in the H1SP having both differentially methylation and differential expression were identified between survivors who received paclitaxel and did (n = 25) and did not (n = 25) develop PIPN. Then, candidate genes were evaluated for differential methylation and differential expression in public data sets of preclinical models of PIPN and sciatic nerve injury. Results Eight candidate genes were identified as both differential methylation and differential expression in survivors. Of the eight homologs identified, one was found to be differential expression in both PIPN and “normal” mice dorsal root ganglia; three were differential methylation in sciatic nerve injury versus sham rats in both pre-frontal cortex and T-cells; and two were differential methylation in sciatic nerve injury versus sham rats in the pre-frontal cortex. Conclusions This study is the first to evaluate for methylation in cancer survivors with chronic PIPN. The findings provide evidence that the expression of H1SP genes associated with chronic PIPN in cancer survivors may be regulated by epigenetic mechanisms and suggests genes for validation as potential therapeutic targets.
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Melillo, G., M. Gutierrez, B. Holkova, A. Rapisarda, M. Raffeld, Y. Horneffer, R. Chang, A. J. Murgo, J. H. Doroshow, and S. Kummar. "A pilot trial of topotecan administered orally in patients with advanced solid tumors expressing hypoxia inducible factor (HIF)- 1α." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14103. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14103.
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14103 Background: HIF-1 is a transcription factor frequently over-expressed in common human cancers that mediates a transcriptional program leading to tumor angiogenesis, survival and metastases. Previous studies have demonstrated that daily administration of topotecan (TPT), a topoisomerase I poison, inhibits HIF-1a expression, angiogenesis and tumor growth in human xenograft models. The primary aim of this study is to investigate whether TPT inhibits HIF-1a expression in human cancers. Methods: TPT was administered orally at 1.6 mg/m2 daily x 5 for 2 weeks, on a 28-day cycle, to adult patients with advanced solid tumors expressing HIF-1a in at least 10% of tumor cells, as assessed by IHC. Tumor biopsies are obtained before and at the end of treatment in cycle 2 and tested for HIF-1a protein expression by IHC and mRNA expression of HIF-1 target genes by real-time PCR. 18FDG-PET, to assess tumor metabolism, and DCE-MRI, to assess blood flow and permeability, were obtained at baseline, at the end of 2 weeks of therapy and then at the end of treatment on cycle 2. CT scans were performed before and after 2 cycles of therapy. Serial blood samples are obtained for PK analysis. Results: Seven patients, median age 54 (range 35–70), have been treated so far, with 6 patients being evaluable for the primary endpoint with paired tumor biopsies for analyses: melanoma (1), colorectal cancer (2), bladder (1), breast (1), ovarian (1). First two patients received the planned dose of 1.6 mg/m2; patient # 2 developed grade 3 neutropenia and grade 4 thrombocytopenia. As the objective was to develop a regimen for chronic dosing that was well tolerated and not directly cytotoxic, the protocol was amended to reduce the dose. Four patients have received a median of 2 cycles at 1.2 mg/m2, which has been well tolerated. A decrease of VEGF mRNA expression by more than 70% was observed in the 2 patients treated at 1.6 mg/m2 after 2 cycles of treatment. However, no consistent decrease of HIF-1a protein levels was detected in the corresponding tumor tissue. Enrollment continues. Conclusion: This is the first study aimed to validate inhibition of the HIF-1 signaling pathway in cancer patients. Funded in part by NCI Contract N01- CO-12400. No significant financial relationships to disclose.
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Silvestri, Giovannino, Rossana Trotta, Lorenzo Stramucci, Shuzhen Wang, Ann-Kathrin Eisfeld, Bin Zhang, Klara Srutova, et al. "A 14q32.31 Genomic-Imprinted DLK1-DIO3 microrna promotes Leukemogenesis By Inducing Stem Cell Quiescence and Inhibiting NK Cell Anti-Cancer Immunity." Blood 134, Supplement_1 (November 13, 2019): 4141. http://dx.doi.org/10.1182/blood-2019-131113.
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Leukemia emergence, maintenance, relapse and/or progression are causally linked to the presence of drug-resistant leukemia-initiating cells and impaired natural killer (NK) cell anti-tumor immune-response. Bone marrow microenvironment (BMM)- and/or leukemia-derived signals induce aberrant non-coding RNA expression and inhibit protein phosphatase 2A (PP2A) tumor suppressor activity. PP2A loss-of-function is essential for NK cell activity and leukemic but not normal stem and progenitor cell proliferation and survival. The human MIR300 gene is an intergenic miRNA that belongs to the 14q32.31 DLK1-DIO3 genomic-imprinted tumor suppressor miRNA cluster B. MIR300 was found involved in loss-of heterozygosity, inhibited in several tumor types with high mitotic index and during epithelial-to-mesenchymal transition (EMT), and associated with a cancer stem cell phenotype. By using primary cells from Philadelphia-positive (Ph+) chronic myelogenous leukemia (CML) in chronic (CP) and blastic (BC) phase, and complex karyotype (CK) acute myeloid leukemia (AML) patients, as paradigmatic examples of stem cell-derived neoplasms characterized by constitutive expression of oncogenic kinases, PP2A loss-of-function, altered microRNA expression and impaired NK cell proliferation and cytotoxicity, we found that MIR300 is a cell context-independent tumor suppressor with anti-proliferative and PP2A-dependent pro-apoptotic activities which are sequentially activated in a MIR300 dose-dependent manner through inhibition of CCND2/CDK6 and SET (PP2A inhibitor), respectively. To prevent PP2A-induced apoptosis, MIR300 is inhibited by oncogenic signals in CD34+CML (CP and BC) and CK-AML progenitors. Conversely, tumor-naïve BMM-induced C/EBPbeta-mediated signals (hypoxia and MSC exosomes) markedly upregulate MIR300 expression in primary CML and AML CD34+CFSEmax leukemic stem (LSC) and CD56+CD3-NK cells to induce/maintain quiescence (increased CD34+leukemic blasts in G0) and impair immune-response (suppression of NK cell proliferation and cytotoxic activity toward CD34+ leukemic blasts and CFSEmaxCD34+ CML-BC quiescent LSCs), respectively. Inhibition of MIR300 expression/activity rescues NK cell proliferation and anti-tumor cytotoxicity and prevented MSC- and hypoxia-induced growth-suppression of CD34+leukemic blasts by inhibiting degradation of MIR300 targets (e.g. SET, CCND2). We found that CML and AML LSCs escape MIR300-induced PP2A-mediated apoptosis through the hypoxia- and tumor-dependent TGFb1-FoxM1-mediated upregulation of TUG1 lncRNA. TUG1 is an oncogenic lncRNA described as a MIR300sponge and found upregulated in solid tumors, in which it has strong diagnostic, prognostic and therapeutic relevance and is associated with cancer stem cell maintenance and EMT. In quiescent CML and AML LSCs, TUG1 uncouples and limits MIR300 tumor suppressor functions to cytostasis by maintaining unbound MIR300 at levels sufficient to inhibit CCND2 and CDK6 but not SET expression. Exposure to clinically-relevant CpG-modified oligonucleotides modulating MIR300levels and/or inhibiting TUG1 MIR300-sponging activity, restores NK cell proliferation and cytotoxic activity, and suppresses human leukemic but not normal hematopoiesis by eradicating nearly all (> 95% reduction) CFSEmaxCD34+ and CD45+CD34+CD38-CD90+ LSCs and CD34+leukemic CML (CP and BC) and CK-AML blasts in vitro (CFCs, LTC-IC, and CFSEmaxCD34+cell tracking) and/or in NRG-SGM3 PDX mouse models of acute and chronic myeloid leukemias. Altogether, this work highlights the therapeutic importance of altering MIR300 expression in anti-LSC and NK cell-based approaches for myeloid leukemias, and indicates that tumor-naïve BMM-induced MIR300 tumor suppressor anti-proliferative and PP2A-activating functions may support leukemogenesis by promoting the formation and initial expansion of the quiescent LSC pool through the induction of LSC dormancy and inhibition of quiescent LSC killing by cytokine-activated NK cells, respectively. (G.S. and R.T. equally contributed to this work) Disclosures Stagno: BMS: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Deininger:TRM: Consultancy; Sangoma: Consultancy; Incyte: Honoraria; Novartis: Honoraria; Sangamo: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Humana: Honoraria; Ascentage Pharma: Consultancy, Honoraria; Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Fusion Pharma: Consultancy; Adelphi: Consultancy. Milojkovic:BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Apperley:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baer:Takeda: Research Funding; Incyte: Research Funding; Kite: Research Funding; Forma: Research Funding; AI Therapeutics: Research Funding; Abbvie: Research Funding; Astellas: Research Funding.
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Drevs, Joachim, Susanne D'Urso, Martin Dayton, Lukas Martinez, Jonas Mueller-Huebenthal, Izumi Kamijo, and Werner Kreutz. "Update on pilot study on antitumor efficacy of intravenously applied synergistic combinations of diflunisal, PAS, and aspirin in patients with advanced solid tumors." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e22114-e22114. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22114.
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e22114 Background: Due to chronic hypoxia cancer cells are growing in a more acidic environment compared to physiological tissue. Recent preclinical in vitro and in vivo data have shown direct pH-sensitive anti-tumor activity by pore formation and apoptosis when synergistically acting combinations of Diflunisal, Paraaminosalicylic acid (PAS) and Aspirin were applied. Therefore, a pilot study was performed to evaluate its clinical relevance and its update is presented. Methods: A total of 65 patients (n=65) with advanced solid tumors and the lack of standard treatments were treated with a protocol consisting of 3-5 weeks with 2 daily i.v. infusions of Diflunisal and Aspirin for 4 days per week after they had signed an informed consent form. Response evaluation was assessed by PET/CT differentiating in metabolic and metric (RECIST) response and tumor marker where available. Results: Out of 65 patients treated 8 patients suffered from colorectal cancer, 17 from breast cancer, 6 from ovarian cancer, 3 from lung cancer, 3 from gastric cancer, 3 from glioblastoma, 3 from CUP, 1 from hemangioendothelioma, 1 from pleuramesothelioma, 1 from non-Hodgkin lymphoma, 2 from pancreatic cancer, 1 from choledochus cancer, 3 from prostate cancer, 5 from sarcomas, 2 from head and neck cancer, 1 from melanoma, 1 from cervical cancer, and 1 from thyroid cancer, respectively. Side effects related to the therapy have been fatigue grade I (30%), nausea grade I (13,3%), tinnitus (25%), hypertension (2,5%), dyspnea (3,3%) and burning sensation in tumor areas (65%). 33 patients were evaluable for metric response, 20 for metabolic and 19 for tumor marker response assessment. For tumor marker follow up 11 % had a CR, 53 % a PR, 26 % a SD of > 3 month and 11 % a PD. For metric follow up 3 % had a CR, 33 % a PR, 39 % a SD of > 3 month and 24 % a PD. For metabolic follow up 10 % had a CR, 35 % a PR, 35 % a SD of > 3 month and 20 % a PD. Conclusions: This continuing pilot study confirms a direct pH-sensitive synergistic anti-tumor activity of intravenous Diflunisal, PAS and Aspirin in patients with advanced solid tumors. Therefore, a further evaluation in a controlled clinical phase II study should be performed.
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Drevs, Joachim, Holger Spangenberger, Matthias Jenny, Jonas Mueller-Huebenthal, Izumi Kamijo, and Werner Kreutz. "Pilot study on antitumor efficacy of intravenously applied synergistic combinations of salicylic acids in patients with advanced solid tumors." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e13508-e13508. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13508.
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e13508 Background: Due to chronic hypoxia cancer cells are growing in a more acidic environment compared to physiological tissue. Using this differentiation a new therapy method has been developed for targeted chemotherapy. Recent preclinical in vitro and in vivo data have shown direct pH-sensitive anti-tumor activity by pore formation and apoptosis when synergistically acting combinations of diflunisal, paraaminosalicylic acid (PAS) and aspirin were applied. Therefore, a pilot study was performed to evaluate its clinical relevance. Methods: A total of 30 patients (n=30) with advanced solid tumors and the lack of standard treatments were treated with a protocol consisting of 3-5 weeks with 2 daily i.v. infusions of diflunisal and aspirin for 4 days per week after they had signed an informed consent form. Response evaluation was assessed by PET/CT differentiating in metabolic and metric (RECIST) response. Results: Out of 30 patients treated 4 patients suffered from colorectal cancer, 11 from breast cancer, 2 from ovarian cancer, 2 from lung cancer, 2 from gastric cancer, 2 from glioblastoma, 1 from CUP, 1 from hemangioendothelioma, 1 from pleuramesothelioma, 1 from non-Hodgkin lymphoma, 1 from pancreatic cancer, 1 from choledochus cancer, 1 from prostate cancer, respectively. Side effects related to the therapy have been fatigue (6,7%), nausea (13,3%), tinnitus (10%), hypertension (6,7%), dyspnea (3,3%) and burning sensation in tumor areas (3,3%). Out of 30 patients treated, until today 14 were evaluable for metric response, 12 for metabolic and 13 for tumor marker response assessment. For tumor marker follow up 2 patientis (6,7 %) had a CR, 6 (20 %) a PR, 4 (13,3 %) a SD of > 3 month and 1 (3,3 %) a PD. For metric follow up 0 patients (0 %) had a CR, 6 (20 %) a PR, 5 (16,7 %) a SD of > 3 month and 3 (10 %) a PD. For metabolic follow up 1 patients (3,3 %) had a CR, 3 (10 %) a PR, 5 (16,7 %) a SD of > 3 month and 3 (10 %) a PD. Conclusions: This pilot study confirms a direct pH-sensitive synergistic anti-tumor activity of intravenous salicylic acids in patients with advanced solid tumors. Therefore, a further evaluation in a controlled clinical phase II study will be performed.
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Liu, Qiuyu, Nasi Liu, Vera van der Noord, Wanda van der Stel, Bob van de Water, Erik H. J. Danen, and Sylvia E. Le Dévédec. "Differential response of luminal and basal breast cancer cells to acute and chronic hypoxia." Breast Cancer Research and Treatment, February 24, 2023. http://dx.doi.org/10.1007/s10549-023-06863-w.
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AbstractHypoxia is linked to disease progression and poor prognosis in several cancers, including breast cancer. Cancer cells can encounter acute, chronic, and/or intermittent periods of oxygen deprivation and it is poorly understood how the different breast cancer subtypes respond to such hypoxia regimes. Here, we assessed the response of representative cell lines for the luminal and basal A subtype to acute (24 h) and chronic hypoxia (5 days). High throughput targeted transcriptomics analysis showed that HIF-related pathways are significantly activated in both subtypes. Indeed, HIF1⍺ nuclear accumulation and activation of the HIF1⍺ target gene CA9 were comparable. Based on the number of differentially expressed genes: (i) 5 days of exposure to hypoxia induced a more profound transcriptional reprogramming than 24 h, and (ii) basal A cells were less affected by acute and chronic hypoxia as compared to luminal cells. Hypoxia-regulated gene networks were identified of which hub genes were associated with worse survival in breast cancer patients. Notably, while chronic hypoxia altered the regulation of the cell cycle in both cell lines, it induced two distinct adaptation programs in these subtypes. Mainly genes controlling central carbon metabolism were affected in the luminal cells whereas genes controlling the cytoskeleton were affected in the basal A cells. In agreement, in response to chronic hypoxia, lactate secretion was more prominently increased in the luminal cell lines which were associated with the upregulation of the GAPDH glycolytic enzyme. This was not observed in the basal A cell lines. In contrast, basal A cells displayed enhanced cell migration associated with more F-actin stress fibers whereas luminal cells did not. Altogether, these data show distinct responses to acute and chronic hypoxia that differ considerably between luminal and basal A cells. This differential adaptation is expected to play a role in the progression of these different breast cancer subtypes.
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Liu, Qiuyu, Victoria A. C. Palmgren, Erik HJ Danen, and Sylvia E. Le Dévédec. "Acute vs. chronic vs. intermittent hypoxia in breast Cancer: a review on its application in in vitro research." Molecular Biology Reports, September 3, 2022. http://dx.doi.org/10.1007/s11033-022-07802-6.
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AbstractHypoxia has been linked to elevated instances of therapeutic resistance in breast cancer. The exposure of proliferating cancer cells to hypoxia has been shown to induce an aggressive phenotype conducive to invasion and metastasis. Regions of the primary tumors in the breast may be exposed to different types of hypoxia including acute, chronic or intermittent. Intermittent hypoxia (IH), also called cyclic hypoxia, is caused by exposure to cycles of hypoxia and reoxygenation (H-R cycles). Importantly, there is currently no consensus amongst the scientific community on the total duration of hypoxia, the oxygen level, and the possible presence of H-R cycles. In this review, we discuss current methods of hypoxia research, to explore how exposure regimes used in experiments are connected to signaling by different hypoxia inducible factors (HIFs) and to distinct cellular responses in the context of the hallmarks of cancer. We highlight discrepancies in the existing literature on hypoxia research within the field of breast cancer in particular and propose a clear definition of acute, chronic, and intermittent hypoxia based on HIF activation and cellular responses: (i) acute hypoxia is when the cells are exposed for no more than 24 h to an environment with 1% O2 or less; (ii) chronic hypoxia is when the cells are exposed for more than 48 h to an environment with 1% O2 or less and (iii) intermittent hypoxia is when the cells are exposed to at least two rounds of hypoxia (1% O2 or less) separated by at least one period of reoxygenation by exposure to normoxia (8.5% O2 or higher). Our review provides for the first time a guideline for definition of hypoxia related terms and a clear foundation for hypoxia related in vitro (breast) cancer research.
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Baram, Tamir, Linor Rubinstein-Achiasaf, Hagar Ben-Yaakov, and Adit Ben-Baruch. "Inflammation-Driven Breast Tumor Cell Plasticity: Stemness/EMT, Therapy Resistance and Dormancy." Frontiers in Oncology 10 (January 26, 2021). http://dx.doi.org/10.3389/fonc.2020.614468.
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Cellular heterogeneity poses an immense therapeutic challenge in cancer due to a constant change in tumor cell characteristics, endowing cancer cells with the ability to dynamically shift between states. Intra-tumor heterogeneity is largely driven by cancer cell plasticity, demonstrated by the ability of malignant cells to acquire stemness and epithelial-to-mesenchymal transition (EMT) properties, to develop therapy resistance and to escape dormancy. These different aspects of cancer cell remodeling are driven by intrinsic as well as by extrinsic signals, the latter being dominated by factors of the tumor microenvironment. As part of the tumor milieu, chronic inflammation is generally regarded as a most influential player that supports tumor development and progression. In this review article, we put together recent findings on the roles of inflammatory elements in driving forward key processes of tumor cell plasticity. Using breast cancer as a representative research system, we demonstrate the critical roles played by inflammation-associated myeloid cells (mainly macrophages), pro-inflammatory cytokines [such as tumor necrosis factor α (TNFα) and interleukin 6 (IL-6)] and inflammatory chemokines [primarily CXCL8 (interleukin 8, IL-8) and CXCL1 (GROα)] in promoting tumor cell remodeling. These inflammatory components form a common thread that is involved in regulation of the three plasticity levels: stemness/EMT, therapy resistance, and dormancy. In view of the fact that inflammatory elements are a common denominator shared by different aspects of tumor cell plasticity, it is possible that their targeting may have a critical clinical benefit for cancer patients.
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Avtanski, Dimiter, Karin Chen, Leo Satlof, Guillaume Stoffels, Udithi Kothapalli, Noah Ziluck, Maribel Lema, and Leonid Poretsky. "SAT-136 Hypoxia Effect on Cytokine Production by Breast Cancer Cells." Journal of the Endocrine Society 4, Supplement_1 (April 2020). http://dx.doi.org/10.1210/jendso/bvaa046.1328.
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Abstract Inflammation is a critical component of tumor initiation and progression. Chronic inflammation triggers molecular events that can promote carcinogenesis, tumor vascularization and metastasis. As inflammatory mediators, cytokines play an important role in the interplay between the tumor cells and tumor microenvironment. Cytokines released by the tumor-associated macrophages modulate cancer cell survival, stemness, invasiveness, and tumor vascularization. Breast cancer cells, however, also produce a variety of cytokines, whose role in cancer development is poorly understood. The aim of our study was to characterize the basal cytokine secretory activity in commonly used human breast cancer cell lines (MDA-MB-231, MCF-7, BT-474, and T-47D). Using MILLIPLEX assay, we measured the expression of 41 cytokines, including interleukins, monokines, interferons and growth factors. We also compared cytokine expression profile of breast cancer cells with those of non-tumorigenic human breast epithelial MCF-10A cells. Further, we investigated whether hypoxia modulates cytokine secretion of breast cancer cells. Using cobalt(II) chloride (CoCl2) to mimic hypoxia, we compared the effect of various treatment doses and intervals on cytokine production in the breast cancer cells. Results demonstrated that CoCl2 affects the release of multiple cytokines in a dose- and concentration-dependent manner, thus highlighting the role of cancer cell-derived cytokines on breast tumor progression. Understanding the molecular actions of cytokines in the tumor microenvironment is important for understanding the mechanism of cancer initiation and progression.
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Minoves, Mélanie, Sylvain Kotzki, Florence Hazane-Puch, Emeline Lemarié, Sophie Bouyon, Julien Vollaire, Brigitte Gonthier, et al. "Chronic intermittent hypoxia, a hallmark of obstructive sleep apnea, promotes 4T1 breast cancer development through endothelin-1 receptors." Scientific Reports 12, no. 1 (July 28, 2022). http://dx.doi.org/10.1038/s41598-022-15541-8.
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AbstractThe association between obstructive sleep apnea (OSA) and cancer is still debated and data are scarce regarding the link between OSA and breast cancer progression. Since conclusive epidemiological studies require large sample sizes and sufficient duration of exposure before incident cancer occurrence, basic science studies represent the most promising approach to appropriately address the topic. Here we assessed the impact of intermittent hypoxia (IH), the major hallmark of OSA, on the development of breast cancer and explored the specific involvement of the endothelin signaling pathway. Original in vitro and in vivo models were used where 3D-spheroids or cultures of murine 4T1 breast cancer cells were submitted to IH cycles, and nude NMRI mice, orthotopically implanted with 4T1 cells, were submitted to chronic IH exposure before and after implantation. The role of the endothelin-1 in promoting cancer cell development was investigated using the dual endothelin receptor antagonist, macitentan. In vitro exposure to IH significantly increased 4T1 cell proliferation and migration. Meta-analysis of 4 independent in vivo experiments showed that chronic IH exposure promoted tumor growth, assessed by caliper measurement (overall standardized mean difference: 1.00 [0.45–1.55], p < 0.001), bioluminescence imaging (1.65 [0.59–2.71]; p < 0.01) and tumor weight (0.86 [0.31–1.41], p < 0.01), and enhanced metastatic pulmonary expansion (0.77 [0.12–1.42]; p = 0.01). Both in vitro and in vivo tumor-promoting effects of IH were reversed by macitentan. Overall, these findings demonstrate that chronic intermittent hypoxia exposure promotes breast cancer growth and malignancy and that dual endothelin receptor blockade prevents intermittent hypoxia-induced tumor development.
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Durrani, Ilhaam Ayaz, Attya Bhatti, and Peter John. "The prognostic outcome of ‘type 2 diabetes mellitus and breast cancer’ association pivots on hypoxia-hyperglycemia axis." Cancer Cell International 21, no. 1 (July 5, 2021). http://dx.doi.org/10.1186/s12935-021-02040-5.
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AbstractType 2 diabetes mellitus and breast cancer are complex, chronic, heterogeneous, and multi-factorial diseases; with common risk factors including but not limited to diet, obesity, and age. They also share mutually inclusive phenotypic features such as the metabolic deregulations resulting from hyperglycemia, hypoxic conditions and hormonal imbalances. Although, the association between diabetes and cancer has long been speculated; however, the exact molecular nature of this link remains to be fully elucidated. Both the diseases are leading causes of death worldwide and a causal relationship between the two if not addressed, may translate into a major global health concern. Previous studies have hypothesized hyperglycemia, hyperinsulinemia, hormonal imbalances and chronic inflammation, as some of the possible grounds for explaining how diabetes may lead to cancer initiation, yet further research still needs to be done to validate these proposed mechanisms. At the crux of this dilemma, hyperglycemia and hypoxia are two intimately related states involving an intricate level of crosstalk and hypoxia inducible factor 1, at the center of this, plays a key role in mediating an aggressive disease state, particularly in solid tumors such as breast cancer. Subsequently, elucidating the role of HIF1 in establishing the diabetes-breast cancer link on hypoxia-hyperglycemia axis may not only provide an insight into the molecular mechanisms underlying the association but also, illuminate on the prognostic outcome of the therapeutic targeting of HIF1 signaling in diabetic patients with breast cancer or vice versa. Hence, this review highlights the critical role of HIF1 signaling in patients with both T2DM and breast cancer, potentiates its significance as a prognostic marker in comorbid patients, and further discusses the potential prognostic outcome of targeting HIF1, subsequently establishing the pressing need for HIF1 molecular profiling-based patient selection leading to more effective therapeutic strategies emerging from personalized medicine.
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Balcioglu, Ozlen, Richard E. Heinz, David W. Freeman, Brooke L. Gates, Berhane M. Hagos, Evan Booker, Elnaz Mirzaei Mehrabad, et al. "CRIPTO antagonist ALK4L75A-Fc inhibits breast cancer cell plasticity and adaptation to stress." Breast Cancer Research 22, no. 1 (November 13, 2020). http://dx.doi.org/10.1186/s13058-020-01361-z.
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Abstract Background CRIPTO is a multi-functional signaling protein that promotes stemness and oncogenesis. We previously developed a CRIPTO antagonist, ALK4L75A-Fc, and showed that it causes loss of the stem cell phenotype in normal mammary epithelia suggesting it may similarly inhibit CRIPTO-dependent plasticity in breast cancer cells. Methods We focused on two triple negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) to measure the effects of ALK4L75A-Fc on cancer cell behavior under nutrient deprivation and endoplasmic reticulum stress. We characterized the proliferation and migration of these cells in vitro using time-lapse microscopy and characterized stress-dependent changes in the levels and distribution of CRIPTO signaling mediators and cancer stem cell markers. We also assessed the effects of ALK4L75A-Fc on proliferation, EMT, and stem cell markers in vivo as well as on tumor growth and metastasis using inducible lentiviral delivery or systemic administration of purified ALK4L75A-Fc, which represents a candidate therapeutic approach. Results ALK4L75A-Fc inhibited adaptive responses of breast cancer cells under conditions of nutrient and ER stress and reduced their proliferation, migration, clonogenicity, and expression of EMT and cancer stem cell markers. ALK4L75A-Fc also inhibited proliferation of human breast cancer cells in stressed tumor microenvironments in xenografts and reduced both primary tumor size and metastatic burden. Conclusions Cancer cell adaptation to stresses such as nutrient deprivation, hypoxia, and chemotherapy can critically contribute to dormancy, metastasis, therapy resistance, and recurrence. Identifying mechanisms that govern cellular adaptation, plasticity, and the emergence of stem-like cancer cells may be key to effective anticancer therapies. Results presented here indicate that targeting CRIPTO with ALK4L75A-Fc may have potential as such a therapy since it inhibits breast cancer cell adaptation to microenvironmental challenges and associated stem-like and EMT phenotypes.
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Webb, Chrisopher, Natalia Partain, Prasad Koduru, Helena Hwang, and Venetia R. Sarode. "Secondary Angiosarcoma With C-MYC Amplification Following Prophylactic Bilateral Mastectomy and Autologous Breast Reconstruction: Report of a Case and Review of the Literature." International Journal of Surgical Pathology, June 18, 2020, 106689692093010. http://dx.doi.org/10.1177/1066896920930100.
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In this article, we report a very rare case of secondary angiosarcoma in a young woman with no prior history of breast cancer who had bilateral prophylactic mastectomies with autologous reconstruction due to a strong family history of breast cancer and BRCA1 gene variant of uncertain significance. The surgery was complicated by recurrent fat necrosis requiring several excisions and additional reconstruction followed by the development of localized lymphedema and subsequent angiosarcoma in the reconstructed breast 10 years later. The angiosarcoma was high grade with prominent epithelioid features associated with abundant tumor-infiltrating lymphocytes. Amplification of C-MYC locus 8q21.24 was demonstrated by fluorescence in situ hybridization study. We postulate that chronic trauma from several surgeries including tissue hypoxia and impaired lymphatic drainage may have provided a milieu for angiogenesis and mutagenic transformation. Amplification of C-MYC locus 8q21.24 was most likely a strong oncogenic driver of angiosarcoma. To the best of our knowledge, this is the first report of its kind in the literature.
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Qiu, Jian, Zhongyi Shen, Guoqin Jiang, and Qichao Ni. "Isoproterenol-induced upregulation of HPSE accelerates triple-negative breast cancer cell proliferation and migration through enhancing the transcriptional activity of HIF-1α." Anti-Cancer Agents in Medicinal Chemistry 22 (August 17, 2022). http://dx.doi.org/10.2174/1871520622666220817125817.
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Backgrounds: Triple-negative breast cancer (TNBC) is considered to be the most malignant subtype of breast cancer (BC). Heparanase (HPSE) has been reported to contribute to tumor development, but its potential function in TNBC is not clear. The intention of this study was to investigate whether HPSE affects TNBC progression and to explore the possible mechanisms. Methods: Bioinformatics analyses were applied to analyze the expression of HPSE in TNBC samples and normal breast samples. The mRNA and protein levels of HPSE in TNBC cells were detected by RT-qPCR and western blot. Function assays, including CCK-8 assay, colony formation assay, transwell assay and wound healing assay were conducted to validate the effects of HPSE silencing on TNBC cell proliferation and migration. Mechanism experiments were performed to explore the upstream molecular mechanism of HPSE in TNBC cells. Results: Silencing of HPSE suppressed the proliferation and migration of TNBC cells. Moreover, hypoxia inducible factor-1 alpha (HIF-1α) interacted with HPSE promoter and promoted the transcription of HPSE. Isoproterenol (ISO), a pharmacological substitute for chronic stress-induced sympathetic activation, was proven to induce HIF-1α upregulation, so as to transcriptionally activate HPSE in TNBC cells. Furthermore, it manifested that ISO facilitated TNBC cell proliferation and migration in a HPSE-dependent way. Conclusion: HPSE activated by ISO-induced HIF-1α promoted TNBC cell proliferation and migration, which might offer a novel sight for TNBC treatment.
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Shah, Mili, and Arvind Kulkarni. "Evaluation of Ozone Therapy as adjuvant therapy in cancer patients and reduction of side effects of Radiation therapy- Indian experiences [abstract]." Journal of Ozone Therapy 3, no. 4 (December 19, 2019). http://dx.doi.org/10.7203/jo3t.3.4.2019.15540.
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PURPOSE: India is new cancer capital of world with almost one third of cases registered from India, In this century, cancer is projected to be the leading cause of death. Neoplasia is a multifactorial process that can be broadly categorized into five etiologies: genetic, viral, chemical, physical and inflammatory. Chemical, physical and inflammatory are closely linked to reactive oxygen species (ROS), which can readily induce genomic damage. Although the precise mechanisms responsible for increased ROS stress in cancer cells have not be defined, the increase in ROS generation is attributed to active cellular metabolic activity under the influence of oncogenic signals and/or to mitochondrial malfunction in cancer cells. Ozone therapy (OT) biological effects are: cellular redox balance (OT can exert its protective effects by means of an oxidative preconditioning, stimulating and/or preserving the endogenous antioxidant systems); regulation of the immunological system, increase of prostacyclin, as well as the increase of oxygenation in tumours. Tumour Hypoxia is a well-recognized mechanism for resistance of neoplastic cells to anticancer drugs and radiation.
MATERIAL and METHODS: The clinical trial included only 83 patients with mainly oral, breast and brain cancer patients in treatment with cobalt-60 therapy at Lady Ratan Tata memorial radiation department were also treated with Rectal Insufflation of an ozone-oxygen at a dose of 7mg (200 ml at 35 mcrg/ml), 6 days per week along with Minor auto haemotherapy(100 mcrg) alternatively for 6 weeks till the duration radiotherapy.
RESULTS: The appearance of side effects (dermatitis, pigmentation, ulceration) minimized to 24% in the ozone group that means a significant difference post radiation. When compared to patients not treated with OT. One month after finishing the treatment, with significant difference in patients supported by OT. The clinical observation were:
- Improvement in Energy Level
- Feeling of Cheerfulness
- Improved Appetite
- Improved WBC, RBC and Hb levels
- Reduction in Tumor Markers, CEA, AFP, CA125
CONCLUSION: OT is effective as adjuvant to conventional approach of Radiation in reducing side effects of radiation by improvement of blood circulation and oxygen delivery to ischemic and neoplastic tissues. Furthermore, it correct the chronic oxidative stress by upregulating the antioxidant system procuring a state of well-being in patients by activating the neuro-endocrine system.