scholarly journals The metabolic flexibility of quiescent CSC: implications for chemotherapy resistance

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Kangchen Chen ◽  
Chenzhi Zhang ◽  
Sunbin Ling ◽  
Rongli Wei ◽  
Jianguo Wang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Metabolic Pathways ◽  
Tumor Recurrence ◽  
Immune Surveillance ◽  
Chemotherapy Resistance ◽  
Metabolic Flexibility ◽  
Quiescent State ◽  
Chemotherapeutic Drugs ◽  
Metabolic Substrates ◽  
Response To Stress

AbstractQuiescence has been observed in stem cells (SCs), including adult SCs and cancer SCs (CSCs). Conventional chemotherapies mostly target proliferating cancer cells, while the quiescent state favors CSCs escape to chemotherapeutic drugs, leaving risks for tumor recurrence or metastasis. The tumor microenvironment (TME) provides various signals that maintain resident quiescent CSCs, protect them from immune surveillance, and facilitates their recurrence potential. Since the TME has the potential to support and initiate stem cell-like programs in cancer cells, targeting the TME components may prove to be a powerful modality for the treatment of chemotherapy resistance. In addition, an increasing number of studies have discovered that CSCs exhibit the potential of metabolic flexibility when metabolic substrates are limited, and display increased robustness in response to stress. Accompanied by chemotherapy that targets proliferative cancer cells, treatments that modulate CSC quiescence through the regulation of metabolic pathways also show promise. In this review, we focus on the roles of metabolic flexibility and the TME on CSCs quiescence and further discuss potential treatments of targeting CSCs and the TME to limit chemotherapy resistance.

scholarly journals Aneuploidy-driven genome instability triggers resistance to chemotherapy

2020 ◽  
Author(s):  
Marica Rosaria Ippolito ◽  
Valentino Martis ◽  
Christy Hong ◽  
René Wardenaar ◽  
Johanna Zerbib ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Selective Pressure ◽  
Genome Instability ◽  
Gene Dosage ◽  
Chemotherapy Resistance ◽  
Causal Link ◽  
Chemotherapeutic Drugs ◽  
Mutational Burden ◽  
Cellular Stresses ◽  
Resistance To Chemotherapy

AbstractMitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of cellular stresses, including genome instability. Here, we show that cancer cells might exploit aneuploidy-induced genome instability to survive under conditions of selective pressure, such as chemotherapy. Resistance to chemotherapeutic drugs was dictated by the acquisition of recurrent karyotypes, indicating that gene dosage, together with mutational burden, might play a role in driving chemoresistance. Thus, our study establishes a causal link between aneuploidy-driven genome instability and chemoresistance and might explain why some chemotherapies fail to succeed.

scholarly journals Mechanism of Overcoming Oxaliplatin Resistance Using HT29 Subcloning

2020 ◽  
Author(s):  
Jisu Lee ◽  
MI YOON KIM ◽  
Woomi Yang ◽  
Il-woung Kim ◽  
Seung-Kiel Park ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Cell Line ◽  
Chemotherapy Resistance ◽  
Cancer Drug ◽  
Cancer Tissue ◽  
Chemotherapeutic Drugs ◽  
Slow Growing ◽  
Personalized Chemotherapy

Abstract Background: Cancer cells are different from normal healthy cells even though they reside within the same tissue and adapt to others. This intra-tumoral heterogeneity is the reason for chemo-resistance, and the emergence of one or more clones, which are resistant to chemotherapeutic drugs, causing clonal outgrowth to form recurrent cancer mass. The need for personalized chemotherapy is increasing because of the tumor heterogeneity and diverse mechanism of chemotherapy resistance. The recent accumulation of extensive evidence for the existence of cancer stem cells strengthens the cancer stem cell hypothesis for chemotherapy resistance and relapse. The development of a primary culture of cancer cells is essential for functional analysis like the sensitivity of chemotherapeutic drugs and the evaluation of the characteristics of cancer stem cells. Methods: We used a clonal cylinder to establish sub-clones originated from a single cell. Twenty-two sub-clones were successfully established, and eleven clones were selected according to their growth rate and analyzed. The sub-clones with low expression of BRAF, MEK2, and ERK, but not EGFR or KRAS, showed a correlation with the doubling time. We grouped the sub-clones as the fast-growing group and the slow-growing group of the HT29 cell line. Three out of five slow-growing sub-clones showed resistance to oxaliplatin treatment. All oxaliplatin-resistant sub-clones overexpressed ABCC2, and no relevance was found with ABCB1 and ABCG2. Active efflux of the drug by ABCC2, but not by ABCB1 or ABCG2, was confirmed with the inhibitor study using each specific inhibitor. The viability of resistant sub-clones decreased after the MK571 treatment, but other clones were not responsive. CD44 expression in oxaliplatin-resistant sub-clones was higher than that of sensitive clones. Conclusions: This study provides definite evidence of heterogeneity using a cancer cell line. Based on our studies, it appears that intra-tumoral heterogeneity of human cancer tissue is responsible for the development of chemotherapy resistance in cancer. These sub-clones are an excellent model for testing efficacy of anti-cancer drug candidates for advanced cancer therapy. The experimental design and concept of this study could be applied to personalized chemotherapy.

Gadolinium Oxide Nanoparticles Enhance the Cytotoxicity of Chemotherapeutic Drugs by Blocking Autophagic Flux in Human Ovarian Cancer Cells

2020 ◽  
Vol 16 ◽  
Author(s):  
Zhixiong Xie ◽  
Tianyu Zhang ◽  
Cheng Zhong
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Hela Cells ◽  
Late Stage ◽  
Ovarian Cancer Cells ◽  
Oxide Nanoparticles ◽  
Autophagic Flux ◽  
Human Ovarian Cancer ◽  
Chemotherapeutic Drugs ◽  
Chemotherapy Drugs

Background: During chemotherapy, drugs can damage cancer cells’ DNA and cytomembrane structure, and then induce cell death. However, autophagy can increase the chemotherapy resistance of cancer cells, reducing the effect of chemotherapy. Objective: To block the autophagic flux in cancer cells, it is vital to enhance the anti-cancer efficacy of chemotherapy drugs; for this purpose, we test the gadolinium oxide nanoparticles (Gd2O3 NPs)’ effect on autophagy. Methods: The cytotoxicity of Gd2O3 NPs on HeLa cells was evaluated by a (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Then, monodasylcadaverine staining, immunofluorescence, immunoblot and apoptosis assay were conducted to evaluate the effect of Gd2O3 NPs on autophagy and efficacy of chemotherapy drugs in human ovarian cancer cells. Results: We found that Gd2O3 NPs, which have great potential for use as a contrast agent in magnetic resonance imaging, could block the late stage of autophagic flux in a dose-dependent manner and then cause autophagosome accumulation in HeLa cells. When co-treated with 8 μg/mL Gd2O3 NPs and 5 μg/mL cisplatin, the number of dead HeLa cells increased by about 20% compared with cisplatin alone. We observed the same phenomenon in cisplatin-resistant COC1/DDP cells. Conclusion: We conclude that Gd2O3 NPs can block the late stage of autophagic flux and enhance the cytotoxicity of chemotherapeutic drugs in human ovarian cancer cells. Thus, the nanoparticles have significant potential for use in both diagnosis and therapy of solid tumor.

scholarly journals Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 325
Author(s):  
Carolina Venturoli ◽  
Ilaria Piga ◽  
Matteo Curtarello ◽  
Martina Verza ◽  
Giovanni Esposito ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Pyruvate Dehydrogenase ◽  
Metabolic Pathways ◽  
Negative Impact ◽  
Digital Pathology ◽  
Pyruvate Dehydrogenase Kinase ◽  
Ovarian Cancer Cells ◽  
Pyruvate Dehydrogenase Kinase 1

Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors, we investigated effects of PDK1 silencing on growth, angiogenesis and metabolic features of tumor xenografts formed by highly glycolytic OC316 and OVCAR3 ovarian cancer cells. Notably, at variance with the moderate antiproliferative effects observed in vitro, we found a dramatic negative impact of PDK1 silencing on tumor growth. These findings were associated with reduced angiogenesis and increased necrosis in the OC316 and OVCAR3 tumor models, respectively. Analysis of viable tumor areas uncovered increased proliferation as well as increased apoptosis in PDK1-silenced OVCAR3 tumors. Moreover, RNA profiling disclosed increased glucose catabolic pathways—comprising both oxidative phosphorylation and glycolysis—in PDK1-silenced OVCAR3 tumors, in line with the high mitotic activity detected in the viable rim of these tumors. Altogether, our findings add new evidence in support of a link between tumor metabolism and angiogenesis and remark on the importance of investigating net effects of modulations of metabolic pathways in the context of the tumor microenvironment.

scholarly journals Phytochemicals Block Glucose Utilization and Lipid Synthesis to Counteract Metabolic Reprogramming in Cancer Cells

2021 ◽  
Vol 11 (3) ◽  
pp. 1259
Author(s):  
Qiong Wu ◽  
Bo Zhao ◽  
Guangchao Sui ◽  
Jinming Shi
Keyword(s):  
Cancer Cells ◽  
Metabolic Pathways ◽  
De Novo ◽  
Aerobic Glycolysis ◽  
Structural Characteristics ◽  
Natural Compounds ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Anticancer Activities ◽  
Substrate Analogs

Aberrant metabolism is one of the hallmarks of cancers. The contributions of dysregulated metabolism to cancer development, such as tumor cell survival, metastasis and drug resistance, have been extensively characterized. “Reprogrammed” metabolic pathways in cancer cells are mainly represented by excessive glucose consumption and hyperactive de novo lipogenesis. Natural compounds with anticancer activities are constantly being demonstrated to target metabolic processes, such as glucose transport, aerobic glycolysis, fatty acid synthesis and desaturation. However, their molecular targets and underlying anticancer mechanisms remain largely unclear or controversial. Mounting evidence indicated that these natural compounds could modulate the expression of key regulatory enzymes in various metabolic pathways at transcriptional and translational levels. Meanwhile, natural compounds could also inhibit the activities of these enzymes by acting as substrate analogs or altering their protein conformations. The actions of natural compounds in the crosstalk between metabolism modulation and cancer cell destiny have become increasingly attractive. In this review, we summarize the activities of natural small molecules in inhibiting key enzymes of metabolic pathways. We illustrate the structural characteristics of these compounds at the molecular level as either inhibitor of various enzymes or regulators of metabolic pathways in cancer cells. Our ultimate goal is to both facilitate the clinical application of natural compounds in cancer therapies and promote the development of novel anticancer therapeutics.

scholarly journals GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 816
Author(s):  
Stephen L. Abrams ◽  
Shaw M. Akula ◽  
Akshaya K. Meher ◽  
Linda S. Steelman ◽  
Agnieszka Gizak ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signal Transduction ◽  
Cancer Cells ◽  
Mitochondrial Respiration ◽  
Breast Cancer Cells ◽  
Chemotherapeutic Drugs ◽  
Pancreatic Cancers ◽  
Signal Transduction Inhibitors ◽  
Gsk 3Β ◽  
Mcf 7

Glycogen synthase kinase-3 (GSK-3) is a regulator of signaling pathways. KRas is frequently mutated in pancreatic cancers. The growth of certain pancreatic cancers is KRas-dependent and can be suppressed by GSK-3 inhibitors, documenting a link between KRas and GSK-3. To further elucidate the roles of GSK-3β in drug-resistance, we transfected KRas-dependent MIA-PaCa-2 pancreatic cells with wild-type (WT) and kinase-dead (KD) forms of GSK-3β. Transfection of MIA-PaCa-2 cells with WT-GSK-3β increased their resistance to various chemotherapeutic drugs and certain small molecule inhibitors. Transfection of cells with KD-GSK-3β often increased therapeutic sensitivity. An exception was observed with cells transfected with WT-GSK-3β and sensitivity to the BCL2/BCLXL ABT737 inhibitor. WT-GSK-3β reduced glycolytic capacity of the cells but did not affect the basal glycolysis and mitochondrial respiration. KD-GSK-3β decreased both basal glycolysis and glycolytic capacity and reduced mitochondrial respiration in MIA-PaCa-2 cells. As a comparison, the effects of GSK-3 on MCF-7 breast cancer cells, which have mutant PIK3CA, were examined. KD-GSK-3β increased the resistance of MCF-7 cells to chemotherapeutic drugs and certain signal transduction inhibitors. Thus, altering the levels of GSK-3β can have dramatic effects on sensitivity to drugs and signal transduction inhibitors which may be influenced by the background of the tumor.

scholarly journals Mitochondrial Transfer in Cancer: A Comprehensive Review

2021 ◽  
Vol 22 (6) ◽  
pp. 3245
Author(s):  
Luca X. Zampieri ◽  
Catarina Silva-Almeida ◽  
Justin D. Rondeau ◽  
Pierre Sonveaux
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Metabolic Pathways ◽  
Current Knowledge ◽  
Cancer Cell Proliferation ◽  
Tunneling Nanotubes ◽  
Comprehensive Review ◽  
Cancer Cell Death ◽  
Mitochondrial Transfer ◽  
Metabolic Activities

Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer.

scholarly journals MASKING ANTI-PHAGOCYTIC SIGNAL OF TUMOR BY PRO-PHAGOCYTIC SIGNAL-A KEY TO IMMUREMENT OF CANCER CELL

2016 ◽  
Vol 8 (9) ◽  
pp. 323
Author(s):  
Madheswaran Suresh ◽  
Malarvizhi Gurusamy ◽  
Natarajan Sudhakar
Keyword(s):  
Breast Cancer ◽  
Immune System ◽  
Breast Carcinoma ◽  
Cell Surface ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Immune Surveillance ◽  
Phagocytic Cell ◽  
Surveillance Mechanism

<p>Immune surveillance is a mechanism where cells and tissues are watched constantly by ever alerted immune system. Most incipient cancer cells are recognized and eliminated by the immune surveillance mechanism, but still tumors have the ability to evade immune surveillance and immunological killing. One greater arm that tumor use to evade immune surveillance, is by expressing anti-phagocytic signal (CD47). Here we present a provocative hypothesis where cancer cells are removed alive by phagocytic cell (DC). That in turn will elicit effective and higher immunogenic condition. All this could be possible by addition pro-phagocytic signal (PtdSer) over cancer cell surface (Breast Cancer), that mask the presence of anti-phagocytic signal (CD47). In other words, adding eat me signal (PtdSer) over the breast cancer cell surface that mask the presence of don’t eat me signal or anti-phagocytic signal present in breast cancer cell surface. This could be possible by using bi-specific antibody, conjugated to PEG-modified liposomes, which carry (PtdSer) pro-phagocytic signal (or) eat me signal, which target both CD47 and EGFRVIII on breast carcinoma. The simultaneous masking of anti-phagocytic signal, and adding of pro–phagocytic signal over cancer cell, will enhance the phagocytic clearance of live tumor cell and elicit immunological killing.</p>

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