scholarly journals Cytocapsular tubes and networks function as physical superdefence freeway systems conducting conventional cancer drug pan-resistant tumor metastasis

2022 ◽  
Author(s):  
Tingfang Yi ◽  
Gerhard Wagner
Keyword(s):  
Drug Resistance ◽  
Drug Development ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Tumor Metastasis ◽  
Cancer Drug ◽  
Clinical Cancer ◽  
Cancer Drug Resistance ◽  
Cancer Tissues

Cancer drug pan-resistant tumor metastasis (cdp-rtm) is a major source of cancer lethality. Cytocapsular tubes (CCTs) and their networks are physical membrane-enclosed freeway systems for cancer cell dissemination across tissues and organs in vivo. Whether cytocapsular tube superlarge biomembranes function as superdenfence and conduct cdp-rtm is unknown. It is also unknown whether conventional cancer drug development methods, including cancer cell line derived xenograft (CDX) and patient cancer cell derived xenograft (PDX), generate cytocapsular tubes (CCTs). It is also unclear whether xenografts can be created that contain CCTs for efficient cancer drug development. Here, we investigated CCT functions related to cancer drug resistance, CCTs in CDX and PDX and CCT xenograft (CCTX). Using clinical cancer tissues, we discovered that CCTs potently shielded against multiple chemotherapy treatments with diverse conventional cancer drugs. Next, our quantitative analyses show that CCT biomembrane drug barriers significantly increase cancer drug resistance by 6.6-folds to14-folds. We found that conventional CDX and PDX animal models do not generate CCTs in these xenografts. By mimicking in vivo cancer cell environments for cancer patient cancer cell culturing, we have successfully isolated CH-5high/CH-6high subpopulations of patient breast cancer cells and pancreas cancer cells that are propertied with cytocapsular tube generation capacities and engender large quantities of CCTs in mouse xenografts. Biochemical and immunohistochemistry analyses demonstrated that CCTs in these xenografts are similar to those in clinical cancer tissues. In summary, our research has identified that CCTs and networks function as physical superdefence freeway systems conducting conventional cancer drug pan-resistant tumor metastasis, and developed a CCTX platform for highly efficient cancer drug development, which pave avenues for more efficient development of effective and precise cancer drugs for tumor cure at both personal and broad-spectrum levels.

scholarly journals MiR-9-3p regulates the biological functions and drug resistance of gemcitabine-treated breast cancer cells and affects tumor growth through targeting MTDH

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Yike Wang ◽  
Lifeng Dong ◽  
Fang Wan ◽  
Fangfang Chen ◽  
Dianlei Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Biological Functions ◽  
Qrt Pcr ◽  
Treated Breast ◽  
Cancer Tissues ◽  
Treated Breast Cancer

AbstractThis study explored the role of MTDH in regulating the sensitivity of breast cancer cell lines to gemcitabine (Gem) and the potential miRNAs targeting MTDH. The expression of MTDH in cancer tissues and cells was detected by immunohistochemical staining or qRT-PCR. The target genes for MTDH were predicted by bioinformatics and further confirmed by dual-luciferase reporter assay and qRT-PCR. Cancer cells were transfected with siMTDH, MTDH, miR-9-3p inhibitor, or mimics and treated by Gem, then CCK-8, colony formation assay, tube formation assay, flow cytometry, wound healing assay, and Transwell were performed to explore the effects of MTDH, miR-9-3p, and Gem on cancer cell growth, apoptosis, migration, and invasion. Expressions of VEGF, p53, cleaved caspase-3, MMP-2, MMP-9, E-Cadherin, N-Cadherin, and Vimentin were determined by Western blot. MTDH was high-expressed in cancer tissues and cells, and the cells with high-expressed MTDH were less sensitive to Gem, while silencing MTDH expression significantly promoted the effect of Gem on inducing apoptosis, inhibiting cell migration, invasion, and growth, and on regulating protein expressions of cancer cells. Moreover, miR-9-3p had a targeted binding relationship with MTDH, and overexpressed miR-9-3p greatly promoted the toxic effects of Gem on cancer cells and expressions of apoptosis-related proteins, whereas overexpressed MTDH partially reversed such effects of overexpressed miR-9-3p. The study proved that miR-9-3p regulates biological functions, drug resistance, and the growth of Gem-treated breast cancer cells through targeting MTDH.

PEAK1 promotes invasion and metastasis and confers drug resistance in breast cancer

2021 ◽  
Author(s):  
xingang wang ◽  
YAN ZHENG ◽  
YU WANG
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Multi Drug Resistance ◽  
Cancer Tissues

Abstract Background and AimsPseudopodium-enriched atypical kinase 1 (PEAK1) has reported to be upregulated in human malignancies and related with poor prognosis. Enhanced PEAK1 expression facilitates tumor cell survival, invasion, metastasis and chemoresistance. However, the role of PEAK1 in breast cancer is not clear. Here, we investigated the PEAK1 expression in breast cancer and analyzed its relation with clinicopathological status and chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated the role of PEAK1 on breast cancer cells in vitro and in vivo. MethodsImmunohistochemistry (IHC) was performed in 112 surgical resected breast cancer tissues. The associations between clinicopathological status, multi-drug resistance and PEAK1 expression were determined. Effect of PEAK1 overexpression or down-expression on proliferation, colony formation, invasion, migration, metastasis and Doxorubicin sensitivity in the MCF-7 cells in vitro and in vivo was detected. ResultsPEAK1 was overexpressed in breast cancer tissues and NAC -resistant breast cancer tissues. High PEAK1 expression was related with tumor size, high tumor grade, T stage, LN metastasis, recurrence, Ki-67 expression, Her-2 expression and multi-drug resistance. Targeting PEAK1 inhibited cell growth, invasion, metastasis and reversed chemoresistance to Doxorubicin in breast cancer cells in vitro and in vivo. ConclusionHigh PEAK1 expression was associated with invasion, metastasis and chemoresistance of breast cancers. Furthermore, targeting PEAK1 could inhibit cell growth and metastasis, and reverse chemoresistance in breast cancer cells, which provides an effective treatment strategies for breast cancer.

scholarly journals The role of photodynamic therapy in overcoming cancer drug resistance

2015 ◽  
Vol 14 (8) ◽  
pp. 1476-1491 ◽  
Author(s):  
Bryan Q. Spring ◽  
Imran Rizvi ◽  
Nan Xu ◽  
Tayyaba Hasan
Keyword(s):  
Drug Resistance ◽  
Photodynamic Therapy ◽  
Cancer Cells ◽  
Cancer Drug ◽  
Cancer Drug Resistance

This perspective highlights unique mechanisms of photodynamic therapy (PDT) that can be utilized to overcome classical drug resistance and re-sensitize resistant cancer cells for standard therapies.

MicroRNA-296-5p Promotes Cell Invasion and Drug Resistance by Targeting Bcl2-Related Ovarian Killer, Leading to a Poor Prognosis in Pancreatic Cancer

Digestion ◽  
2019 ◽  
Vol 101 (6) ◽  
pp. 794-806 ◽  
Author(s):  
Jun Okazaki ◽  
Toshihito Tanahashi ◽  
Yasushi Sato ◽  
Jinsei Miyoshi ◽  
Tadahiko Nakagawa ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Poor Prognosis ◽  
Cancer Cell Lines ◽  
Pancreatic Cancer Cells ◽  
Cancer Tissues

<b><i>Background/Aims:</i></b> Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive invasion, early metastasis, and resistance to chemotherapy, leading to a poor prognosis. To clarify the molecular mechanism of these malignant characteristics, we performed a genome-wide microRNA (miRNA) array analysis utilizing micro-cancer tissues from patients with unresectable PDAC (stage IV), obtained by endoscopic ultrasound-fine needle aspiration (EUS-FNA). <b><i>Methods:</i></b> The expression profiles of 2,042 miRNAs were determined using micro-cancer tissues from 13 patients with unresectable PDAC obtained by EUS-FNA. The relationship between individual miRNA levels and overall survival (OS) was analyzed. Possible target genes for miRNAs were bioinformatically analyzed using the online database miRDB. Pancreatic cancer cell lines PANC-1, MIA PaCa-2, and PK-8 were transfected with miRNA mimic or small interfering RNA, and cell invasion, epithelial-mesenchymal transition (EMT), and apoptosis markers were examined. miRNA and mRNA expressions were examined by quantitative polymerase chain reaction. <b><i>Results:</i></b> Of 2,042 miRNAs, the 10 that exhibited the lowest correlation coefficient (<i>p</i> ≤ 0.005) between miRNA expression level and OS among the patients were identified. The miRDB and expression analysis in cancer cell lines for the 10 miRNAs identified miR-296-5p and miR-1207-5p as biomarkers predictive of shorter survival (<i>p</i> &#x3c; 0.0005). Bioinformative target gene analysis and transfection experiments with miRNA mimics showed that <i>Bcl2-related</i> <i>ovarian</i> <i>killer</i> (<i>BOK</i>), a pro-apoptotic gene, is a target for miR296-5p in pancreatic cancer cells; transfection of miR-296-5p mimic into PANC-1, MIA PaCa-2, and PK-8 cells resulted in significant suppression of <i>BOK</i> mRNA and protein expression. These transfectants showed significantly higher invasion capability compared with control cells, and knock down of <i>BOK</i> in pancreatic cancer cells similarly enhanced invasion capability. Transfectants of miR-296-5p mimic also exhibited aberrant expression of EMT markers, including vimentin and N-cadherin. Moreover, these transfectants showed a significantly lower apoptosis rate in response to 5-fluorouracil and gemcitabine with a decrease of <i>BOK</i> expression, suggesting a role of miR-296-5p in drug resistance. <b><i>Conclusion:</i></b> These results suggest that miR-296-5p is a useful biomarker for a poor prognosis in patients with PDAC, and that the miR-296-5p/BOK signaling axis plays an important role in cell invasion, drug resistance, and EMT in PDACs.

Analysis of the differences in the Expression of mRNAs and miRNAs Asso-ciated with Drug Resistance in Endometrial Cancer Cells Treated with Salinomycin

2020 ◽  
Vol 21 ◽  
Author(s):  
Piotr Januszyk ◽  
Krzysztof Januszyk ◽  
Magdalena Wierzbik-Strońska ◽  
Dariusz Boroń ◽  
Beniamin Grabarek
Keyword(s):  
Drug Resistance ◽  
Endometrial Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Cancer Cell Line ◽  
Control Culture ◽  
New Drugs ◽  
Cancer Drug ◽  
Cancer Drug Resistance ◽  
Expression Of Genes

Background: It is important to understand the molecular mechanisms involved in cancer drug resistance and to study the activity of new drugs, e.g. salinomycin. Objective: The purpose of the study was to analyze changes in the expression of genes associated with drug resistance in the Ishikawa endometrial cancer cell line when treated with salinomycin. In addition, changes in the level of miRNA potentially regulating these mRNAs were evaluated. Results: The following was observed about the number of mRNAs differentiating the cell culture exposed to the drug compared to a control culture: H-12 vs C - 9 mRNAs, H_24 vs C – 6 mRNAs, H_48 vs C - 1 mRNA. It was noted that 4 of the 9 differentiating mRNAs were characteristic for 12 hours of exposure to the salinomycin and they correspond to the following genes: TUFT1, ABCB1, MTMR11, MX2. After 24 hours, 2 mRNAs were characteristic for this time of incubation cells with salinomycin: TUFT1, MYD88 and after 48 hours, SLC30A5 could also be observed. The highest differences in expression were indicated for TUFT1, MTMR11, SLC30A5. The highest influence probability was determined between TUFT1 and hsamiR-3188 (FC + 2.48), MTMR11and has-miR-16 (FC -1.74), and between SLC30A5 and hsa-miR-30d (FC -2.01). Materials and Methods: Endometrial cancer cells were treated with 1 µM of salinomycin for 12, 24 and 48 hour periods. Untreated cells were a control culture. The molecular analysis consists of mRNA and miRNA microarray analysis and the RTqPCR technique. Conclusions: Salinomycin induces changes in the activity of mRNA and miRNA participating in drug resistance, however the observed changes in character are an expected result of anti-cancer treatment.

scholarly journals Sensitization of Drug Resistant Cancer Cells: A Matter of Combination Therapy

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 483 ◽  
Author(s):  
Meghan Leary ◽  
Sarah Heerboth ◽  
Karolina Lapinska ◽  
Sibaji Sarkar
Keyword(s):  
Drug Resistance ◽  
Combination Therapy ◽  
Cancer Cells ◽  
Progenitor Cells ◽  
Rational Design ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Combination Therapies ◽  
Cancer Drug Resistance ◽  
Rational Development

Cancer drug resistance is an enormous problem. It is responsible for most relapses in cancer patients following apparent remission after successful therapy. Understanding cancer relapse requires an understanding of the processes underlying cancer drug resistance. This article discusses the causes of cancer drug resistance, the current combination therapies, and the problems with the combination therapies. The rational design of combination therapy is warranted to improve the efficacy. These processes must be addressed by finding ways to sensitize the drug-resistant cancers cells to chemotherapy, and to prevent formation of drug resistant cancer cells. It is also necessary to prevent the formation of cancer progenitor cells by epigenetic mechanisms, as cancer progenitor cells are insensitive to standard therapies. In this article, we emphasize the role for the rational development of combination therapy, including epigenetic drugs, in achieving these goals.

scholarly journals PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner

2018 ◽  
Vol 50 (6) ◽  
pp. 2108-2123 ◽  
Author(s):  
Ruifang Gao ◽  
Yanhua Liu ◽  
Dan Li ◽  
Jing Xun ◽  
Wei Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Tumor Metastasis ◽  
Dependent Manner ◽  
Fructose 2

Background/Aims: The bi-functional enzyme 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase-4 (PFKFB4) is highly expressed in many types of cancer and its requirement for tumor survival has been demonstrated in glioma, lung, and prostate cancers. However, whether PFKFB4 plays a role in the tumor metastasis remains uncertain. This study explores the role of PFKFB4 in tumor metastasis and its underlying mechanisms in breast cancer cells. Methods: The expression of PFKFB4 was first analyzed using the Cancer Genome Atlas (TCGA) dataset, and confirmed by immunohistochemical staining of tissue microarray and breast cancer tissues from patient samples. Gain- and loss-of- function approaches were used to investigate the effects of PFKFB4 on breast cancer cell migration in vitro. Orthotopic xenograft model and experimental metastasis model were used to assess the effects of PFKFB4 on breast cancer cell metastasis in vivo. ELISA and immunofluorescence staining were used to examine HA production. Quantitative RT-PCR and western blotting were used to explore the mRNA and protein levels of HAS2, respectively. Results: We found that PFKFB4 enhances the migration/invasiveness of breast cancer cells in vitro as well as in vivo. Notably, the effects of PFKFB4 on migration are mediated by induction of HAS2 expression and HA production. Moreover, PFKFB4-induced HAS2 up-regulation depends upon the activation of p38 signaling. Conclusion: PFKFB4 promotes the metastasis of breast cancer cells via induction of HAS2 expression and HA production in a p38-dependent manner. Therefore, the PFKFB4/p38/HAS2 signaling pathway may serve as a potential therapeutic target for metastatic breast cancer.

scholarly journals Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance

2011 ◽  
Vol 108 (46) ◽  
pp. 18708-18713 ◽  
Author(s):  
J.-P. Gillet ◽  
A. M. Calcagno ◽  
S. Varma ◽  
M. Marino ◽  
L. J. Green ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Cancer Drug ◽  
Cancer Drug Resistance ◽  
Anti Cancer

scholarly journals Modeling adaptive drug resistance of colorectal cancer and therapeutic interventions with tumor spheroids

2021 ◽  
pp. 153537022110141
Author(s):  
Astha Lamichhane ◽  
Pradip Shahi Thakuri ◽  
Pouria Rafsanjani Nejad ◽  
Hossein Tavana
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Tumor Biology ◽  
Three Dimensional ◽  
Therapeutic Interventions ◽  
Cancer Drug ◽  
Tumor Spheroids ◽  
Major Barrier ◽  
Cancer Drug Discovery ◽  
Cancer Drug Resistance

Drug resistance is a major barrier against successful treatments of cancer patients. Various intrinsic mechanisms and adaptive responses of tumor cells to cancer drugs often lead to failure of treatments and tumor relapse. Understanding mechanisms of cancer drug resistance is critical to develop effective treatments with sustained anti-tumor effects. Three-dimensional cultures of cancer cells known as spheroids present a biologically relevant model of avascular tumors and have been increasingly incorporated in tumor biology and cancer drug discovery studies. In this review, we discuss several recent studies from our group that utilized colorectal tumor spheroids to investigate responses of cancer cells to cytotoxic and molecularly targeted drugs and uncover mechanisms of drug resistance. We highlight our findings from both short-term, one-time treatments and long-term, cyclic treatments of tumor spheroids and discuss mechanisms of adaptation of cancer cells to the treatments. Guided by mechanisms of resistance, we demonstrate the feasibility of designing specific drug combinations to effectively block growth and resistance of cancer cells in spheroid cultures. Finally, we conclude with our perspectives on the utility of three-dimensional tumor models and their shortcomings and advantages for phenotypic and mechanistic studies of cancer drug resistance.

scholarly journals Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

2021 ◽  
Vol 14 (5) ◽  
pp. 470
Author(s):  
Nirmala Tilija Pun ◽  
Chul-Ho Jeong
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Drug Repurposing ◽  
Synergistic Action ◽  
Cancer Drug ◽  
Cancer Cell Proliferation ◽  
Cancer Drug Resistance ◽  
Anti Cancer

Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., the use of old drugs for new therapeutic indications), which is an economical, safe, and efficacious approach as it is emerged from clinical drug development or may even be marketed with a well-established safety profile and optimal dosing. Statins are inhibitors of HMG-CoA reductase in cholesterol biosynthesis and are used in the treatment of hypercholesterolemia, atherosclerosis, and obesity. As cholesterol is linked to the initiation and progression of cancer, statins have been extensively used in cancer therapy with a concept of drug repurposing. Many studies including in vitro and in vivo have shown that statin has been used as monotherapy to inhibit cancer cell proliferation and induce apoptosis. Moreover, it has been used as a combination therapy to mediate synergistic action to overcome anti-cancer drug resistance as well. In this review, the recent explorations are done in vitro, in vivo, and clinical trials to address the action of statin either single or in combination with anti-cancer drugs to improve the chemotherapy of the cancers were discussed. Here, we discussed the emergence of statin as a lipid-lowering drug; its use to inhibit cancer cell proliferation and induction of apoptosis as a monotherapy; and its use in combination with anti-cancer drugs for its synergistic action to overcome anti-cancer drug resistance. Furthermore, we discuss the clinical trials of statins and the current possibilities and limitations of preclinical and clinical investigations.

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