Cancer Cells
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2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shigeyuki Magi ◽  
Sewon Ki ◽  
Masao Ukai ◽  
Elisa Domínguez-Hüttinger ◽  
Atsuhiko T Naito ◽  
...  

AbstractCancer cells acquire drug resistance through the following stages: nonresistant, pre-resistant, and resistant. Although the molecular mechanism of drug resistance is well investigated, the process of drug resistance acquisition remains largely unknown. Here we elucidate the molecular mechanisms underlying the process of drug resistance acquisition by sequential analysis of gene expression patterns in tamoxifen-treated breast cancer cells. Single-cell RNA-sequencing indicates that tamoxifen-resistant cells can be subgrouped into two, one showing altered gene expression related to metabolic regulation and another showing high expression levels of adhesion-related molecules and histone-modifying enzymes. Pseudotime analysis showed a cell transition trajectory to the two resistant subgroups that stem from a shared pre-resistant state. An ordinary differential equation model based on the trajectory fitted well with the experimental results of cell growth. Based on the established model, it was predicted and experimentally validated that inhibition of transition to both resistant subtypes would prevent the appearance of tamoxifen resistance.


2021 ◽  
Vol 12 ◽  
Author(s):  
Dongfeng Sun ◽  
Qingfa Chen ◽  
Zhibo Gai ◽  
Fengxia Zhang ◽  
Xiaoqing Yang ◽  
...  

Esophageal cancer is the ninth most common malignancy worldwide, ranking sixth in mortality. Platinum-based chemotherapy is commonly used for treating locally advanced esophageal cancer, yet it is ineffective in a large portion of patients. There is a need for reliable molecular markers with direct clinical application for a prospective selection of patients who can benefit from chemotherapy and patients in whom toxicity is likely to outweigh the benefit. The cytotoxic activity of platinum derivatives largely depends on the uptake and accumulation into cells, primarily by organic cation transporters (OCTs). The aim of the study was to investigate the impact of OCT expression on the clinical outcome of patients with esophageal cancer treated with oxaliplatin. Twenty patients with esophageal squamous cell carcinoma (SCC) were prospectively enrolled and surgical specimens used for screening OCT expression level by western blotting and/or immunostaining, and for culture of cancer cells. Sixty-seven patients with SCC who received oxaliplatin and for whom follow-up was available were retrospectively assessed for organic cation/carnitine transporter 2 (OCTN2) expression by real time RT-PCR and immunostaining. OCTN2 staining was also performed in 22 esophageal adenocarcinomas. OCTN2 function in patient-derived cancer cells was evaluated by assessing L-carnitine uptake and sensitivity to oxaliplatin. The impact of OCTN2 on oxaliplatin activity was also assessed in HEK293 cells overexpressing OCTN2. OCTN2 expression was higher in tumor than in normal tissues. In patient-derived cancer cells and HEK293 cells, the expression of OCTN2 sensitized to oxaliplatin. Patients treated with oxaliplatin who had high OCTN2 level in the tumor tissue had a reduced risk of recurrence and a longer survival time than those with low expression of OCTN2 in tumor tissue. In conclusion, OCTN2 is expressed in esophageal cancer and it is likely to contribute to the accumulation and cytotoxic activity of oxaliplatin in patients with esophageal carcinoma treated with oxaliplatin.


2021 ◽  
Vol 12 ◽  
Author(s):  
Navneet Kumar ◽  
Chandi C. Mandal

Cholesterol has been reported to be accumulated in cancer cells. The metabolic dysregulation of the cholesterol is associated with tumor development and progression. The cholesterol-lowering drugs have been found to be involved in the prevention and treatment of various cancers. Akt, a serine/threonine kinase, can modulate the role of several downstream proteins involved in cell proliferation, migration, invasion, metabolism, and apoptosis. Since its involvement in several signaling pathways, its dysregulation is commonly reported in several cancers. Thus, targeting Akt could be an effective approach for cancer prevention and therapy. Cholesterol-lowering drugs have been found to affect the expression of Akt, and its activation in the cancer cells and thus have shown anticancer activity in different type of cancers. These drugs act on various signaling pathways such as PTEN/Akt, PI3k/Akt, Akt/NF-κB, Akt/FOXO1, Akt/mTOR, etc., which will be discussed in this article. This review article will discuss the significance of cholesterol in cancer cells, cholesterol-lowering drugs, the role of Akt in cancer cells, and the effects of cholesterol-lowering drugs on Akt in the prevention of therapy resistance and metastasis.


2021 ◽  
Author(s):  
JIachi Ma ◽  
Chensong Zhang ◽  
Wanqing Liang ◽  
Lei Li ◽  
Jun Du ◽  
...  

Abstract Background: To investigate the effect of polyunsaturated fatty acids ω-3 and ω-6 and their metabolites prostaglandin PGE2 and PGE3 on the proliferation, invasion and neovascularization of gastric cancer.Methods: RT-PCR and ELISA were used to detect the gene and protein expression of COX-1 and COX-2 in gastric cancer cell lines, respectively. The effects of ω-3, ω-6, PFG2 and PEG3 on the proliferation, invasion and neovascularization of gastric cancer cells were detected by cell proliferation, invasion and neovascularization assay in vitro. COX-2 siRNA was synthesized by short gene interfering RNA (siRNA) technique and transfected into gastric cancer cells, and the expression of COX-2 protein in gastric cancer cell lines was detected again by Western blot. The effects of COX-2 gene silencing on proliferation, invasion and neovascularization of gastric cancer cells were detected by WST-1 assay, transwell chamber assay and gastric cancer neovascularization assay, respectively.Results: COX-2 was only expressed in MKN74 and MKN45 cell lines, while COX-1 was expressed in four gastric cancer cell lines. In gastric cancer cell lines with positive COX-2 expression, ω-6 and PEG2 could significantly enhance the proliferation, invasion and neovascularization of gastric cancer cells, and after transfection with COX-2 siRNA, the effects of ω-6 and PEG2 on enhancing the proliferation, invasion and neovascularization of gastric cancer cells were significantly attenuated; ω-3 and PEG3 could inhibit the proliferation, invasion and neovascularization of gastric cancer cells. In gastric cancer cell lines with negative COX-2 expression, ω-6 and PEG2 had no significant effect on the proliferation, invasion and neovascularization of gastric cancer; ω-3 and PEG3 could significantly inhibit the proliferation, invasion and neovascularization of gastric cancer.Conclusion: ω-6 PUFAs reinforce the metastatic potential energy of gastric cancer cells via COX-2/PGE2; ω-3 PUFAs inhibit the metastatic potential energy of gastric cancer via COX-1/PGE3.


2021 ◽  
Author(s):  
Roni F Rayes ◽  
Marnie G Wilson ◽  
Stephen D Gowing ◽  
France Bourdeau ◽  
Betty Giannias ◽  
...  

Background: Lung cancer is a leading cause of death partially due to high recurrence rates after surgical resection. Clinical data suggest that post-operative infections may increase the risk of recurrence. Our previous work indicated that increased adhesion of circulating tumors in the context of infection is partially responsible for this phenotype. However, cancer metastasis is a multi-step process, and it is likely that other events following tumor adhesion also play a role. Methods: In vivo intrasplenic injection of murine lung cancer cells into wild type (WT) and Toll-like receptor 4 knockout (TLR4-/-) mice followed by cecal-ligation and puncture (CLP) as a model of post-operative infection or sham surgery were used. H&E staining and immunohistochemistry analysis of Ki67+ cells in the livers of those mice were performed. In vitro proliferation assays were performed on human lung cancer cells using combinations of TLR blockade. Results: We found a 5-fold increase in hepatic metastases in WT CLP mice compared to WT sham mice. TLR4-/- CLP mice had a significant decreased tumor burden compared to WT CLP mice. This indicated an important mechanistic role for the TLR4-initiated host response to gram negative infection post-tumor cell adhesion. By analyzing the livers of those mice, we observed an increase in proliferation of tumor micrometastases in vivo in WT CLP mice as compared to WT sham mice. Here again, CLP TLR4 -/- mice had significantly fewer replicating micrometastases than CLP WT mice. Indeed, we found that direct stimulation of lung cancer cells with heat-inactivated E.Coli resulted in increased proliferation of tumor growth in vitro. These effects were partially abrogated by tumor TLR4 blockade; combined TLR2, 4 and 5 blockades led to a more prominent decrease. Conditioned media from bronchoalveolar epithelial cells treated with lipopolysaccharide lead to increased lung cancer proliferation; these changes were reversed with TLR blockade, indicating that the host response to infection is TLR mediated. Conclusions: Overall, these results imply a more complex mechanistic role of post-operative infection in metastasis. From a clinical standpoint, this evidence strengthens the case for the use of TLR blockade as a potential therapeutic target in the prevention of metastasis.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiromasa Tanaka ◽  
Yugo Hosoi ◽  
Kenji Ishikawa ◽  
Jun Yoshitake ◽  
Takahiro Shibata ◽  
...  

AbstractLow-temperature plasma is being widely used in the various fields of life science, such as medicine and agriculture. Plasma-activated solutions have been proposed as potential cancer therapeutic reagents. We previously reported that plasma-activated Ringer’s lactate solution exhibited selective cancer-killing effects, and that the plasma-treated L-sodium lactate in the solution was an anti-tumor factor; however, the components that are generated through the interactions between plasma and L-sodium lactate and the components responsible for the selective killing of cancer cells remain unidentified. In this study, we quantified several major chemical products, such as pyruvate, formate, and acetate, in plasma-activated L-sodium lactate solution by nuclear magnetic resonance analysis. We further identified novel chemical products, such as glyoxylate and 2,3-dimethyltartrate, in the solution by direct infusion-electrospray ionization with tandem mass spectrometry analysis. We found that 2,3-dimethyltartrate exhibited cytotoxic effects in glioblastoma cells, but not in normal astrocytes. These findings shed light on the identities of the components that are responsible for the selective cytotoxic effect of plasma-activated solutions on cancer cells, and provide useful data for the potential development of cancer treatments using plasma-activated L-sodium lactate solution.


2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yuki Sunagawa ◽  
Masamichi Hayashi ◽  
Suguru Yamada ◽  
Hiroshi Tanabe ◽  
Keisuke Kurimoto ◽  
...  

Abstract Background Pancreatic cancer is one of the lethal cancers among solid malignancies. Pathological diagnosis of surgical margins is sometimes unreliable due to tissue shrinkage, invisible field cancerization and skipped lesions like tumor budding. As a result, tumor recurrences sometimes occur even from the pathologically negative surgical margins. Methods We applied molecular surgical margin (MSM) analysis by tissue imprinting procedure to improve the detection sensitivity of tiny cancerous cells on the surgical specimen surface after pancreatoduodenectomy. Surgical specimens were collected from 45 pancreatic cancer cases who received subtotal stomach preserving pancreatoduodenectomy at Nagoya University Hospital during 2017–2019. Quantitative methylation-specific PCR (QMSP) of the original methylation marker panel (CD1D, KCNK12, PAX5) were performed and analyzed with postoperative survival outcomes. Results Among 45 tumors, 26 cases (58%) were QMSP-positive for CD1D, 25 (56%) for KCNK12 and 27 (60%) for PAX5. Among the 38 tumors in which at least one of the three markers was positive, CD1D-positive cancer cells, KCNK12-positive cancer cells, and PAX5-positive cancer cells were detected at the surgical margin in 8 cases, 7 cases and 10 cases, respectively. Consequently, a total of 17 patients had at least one marker detected at the surgical margin by QMSP, and these patients were defined as MSM-positive. They were associated with significantly poor recurrence-free survival (p = 0.002) and overall survival (p = 0.005) than MSM-negative patients. Multivariable analysis showed that MSM-positive was the only significant independent factor for worse recurrence-free survival (hazard ratio: 3.522, 95% confidence interval: 1.352–9.179, p = 0.010). On the other hand, a significant proportion of MSM-negative cases were found to have received neoadjuvant chemotherapy (p = 0.019). Conclusion Pancreatic cancer-specific methylation marker panel was established to perform MSM analysis. MSM-positive status might represent microscopically undetectable cancer cells on the surgical margin and might influence the postoperative long-term outcomes.


Author(s):  
Ying Zhong ◽  
Naveen Kumar Bejjanki ◽  
Xiangwan Miao ◽  
Huanhuan Weng ◽  
Quanming Li ◽  
...  

Chemotherapy for the treatment of nasopharyngeal carcinoma (NPC) is usually associated with many side effects; therefore, its treatment options have not yet been completely resolved. Improving distribution to the targeted tumor region and enhancing the cellular uptake of drugs can efficiently alleviate the above adverse medical effects. Near-infrared (NIR) laser light-mediated photothermal therapy (PTT) and photodynamic therapy (PDT) are promising strategies for cancer treatment. In the present study, we developed an efficient multifunctional nanocluster with enhanced targeting and aggregation efficiency for PTT and PDT that is composed of a biocompatible folic acid (FA), indocyanine green (ICG) and 2-cyanobenzothiazole (CBT)-functionalized peptide labeled with an aldehyde sodium alginate-modified magnetic iron oxide nanoparticle (ASA-MNP)-based nanocarrier. FA can bind to folate receptors on cancer cell membranes to enhance nanocluster uptake. CBT-modified peptide can react with glutathione (GSH), which is typically present at higher levels in cancer cells, to form intracellular aggregates and increase the local concentration of the nanodrug. In in vitro studies, these nanodrugs displayed the desired uptake capacity by NPC cells and the ability to suppress the growth of cancer cells under laser irradiation. Animal studies validated that these nanodrugs are safe and nontoxic, efficiently accumulate in NPC tumor sites following injection via the caudal vein, and shows superior inhibition of tumor growth in a tumor-bearing mouse model upon near-infrared laser irradiation. The results indicate the potential application of the multifunctional nanoparticles (NPs), which can be used as a new method for the treatment of folate receptor-positive NPC.


Aging ◽  
2021 ◽  
Author(s):  
Tharcisio Citrangulo Tortelli Jr. ◽  
Rodrigo Esaki Tamura ◽  
Mara de Souza Junqueira ◽  
Janio da Silva Mororó ◽  
Silvina Odete Bustos ◽  
...  

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