scholarly journals The impact of the spatial heterogeneity of resistant cells and fibroblasts on treatment response

2021 ◽  
Author(s):  
Masud M.A ◽  
Jae-Young Kim ◽  
Cheol-Ho Pan ◽  
Eunjung Kim
Keyword(s):  
Cancer Cell ◽  
Spatial Competition ◽  
Adaptive Strategy ◽  
Maximum Tolerated Dose ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Continuous Therapy ◽  
The Impact ◽  
Adaptive Therapy ◽  
Resistant Cells

A long-standing practice in the treatment of cancer is that of hitting hard with the maximum tolerated dose to eradicate tumors. This continuous therapy, however, selects for resistant cells, leading to the failure of the treatment. A different type of treatment strategy, adaptive therapy, has recently been shown to have a degree of success in both preclinical xenograft experiments and clinical trials. Adaptive therapy is used to maintain a tumor's volume by exploiting the competition between drug-sensitive and drug-resistant cells with minimum effective drug doses or timed drug holidays. To further understand the role of competition in the outcomes of adaptive therapy, we developed a 2D on-lattice agent-based model. Our simulations show that the superiority of the adaptive strategy over continuous therapy depends on the local competition shaped by the spatial distribution of resistant cells. Cancer cell migration and increased carrying capacity accelerate the progression of the tumor under both types of treatments by reducing the spatial competition. Intratumor competition can also be affected by fibroblasts, which produce microenvironmental factors that promote cancer cell growth. Our simulations show that the spatial architecture of fibroblasts modulates the benefits of adaptive therapy. Finally, as a proof of concept, we simulated the outcomes of adaptive therapy in multiple metastatic sites composed of different spatial distributions of fibroblasts and drug-resistant cell populations.

scholarly journals Understanding the potential benefits of adaptive therapy for metastatic melanoma

2020 ◽  
Author(s):  
Eunjung Kim ◽  
Joel S. Brown ◽  
Zeynep Eroglu ◽  
Alexander R.A. Anderson
Keyword(s):  
Mathematical Models ◽  
Underlying Mechanism ◽  
Resistant Cell ◽  
Phenotypic Switching ◽  
Patient Specific ◽  
Optimal Timing ◽  
Initial Population ◽  
Continuous Therapy ◽  
Adaptive Therapy ◽  
Resistant Cells

AbstractAdaptive therapy is an evolution-based treatment approach that aims to maintain tumor volume by employing minimum effective drug doses or timed drug holidays. For successful adaptive therapy outcomes, it is critical to find the optimal timing of treatment switch points. Mathematical models are ideal tools to facilitate adaptive therapy dosing and switch time points. We developed two different mathematical models to examine interactions between drug-sensitive and resistant cells in a tumor. The first model assumes genetically fixed drug-sensitive and resistant populations that compete for limited resources. Resistant cell growth is inhibited by sensitive cells. The second model considers phenotypic switching between drug-sensitive and resistant cells. We calibrated each model to fit melanoma patient biomarker changes over time and predicted patient-specific adaptive therapy schedules. Overall, the models predict that adaptive therapy would have delayed time to progression by 6-25 months compared to continuous therapy with dose rates of 6%-74% relative to continuous therapy. We identified predictive factors driving the clinical time gained by adaptive therapy. The first model predicts 6-20 months gained from continuous therapy when the initial population of sensitive cells is large enough, and when the sensitive cells have a large competitive effect on resistant cells. The second model predicts 20-25 months gained from continuous therapy when the switching rate from resistant to sensitive cells is high and the growth rate of sensitive cells is low. This study highlights that there is a range of potential patient specific benefits of adaptive therapy, depending on the underlying mechanism of resistance, and identifies tumor specific parameters that modulate this benefit.

scholarly journals Turnover modulates the need for a cost of resistance in adaptive therapy

2020 ◽  
Author(s):  
Maximilian Strobl ◽  
Jeffrey West ◽  
Yannick Viossat ◽  
Mehdi Damaghi ◽  
Mark Robertson-Tessi ◽  
...  
Keyword(s):  
Carrying Capacity ◽  
Selection Criterion ◽  
Standard Of Care ◽  
Therapy Resistance ◽  
Resistant Cell ◽  
Necessary Condition ◽  
Continuous Therapy ◽  
Cost Of Resistance ◽  
The Impact ◽  
Adaptive Therapy

Abstract“Control and conquer” - this is the philosophy behind adaptive therapy, which seeks to exploit intra-tumoural competition to avoid, or at least, delay the emergence of therapy resistance in cancer. Motivated by promising results from theoretical, experimental and, most recently, a clinical study in prostate cancer, there is an increasing interest in extending this approach to other cancers. As such, it is urgent to understand the characteristics of a cancer which determine whether it will respond well to adaptive therapy, or not. A plausible candidate for such a selection criterion is the fitness cost of resistance. In this paper, we study a simple competition model between sensitive & resistant cell populations to investigate whether the presence of a cost is a necessary condition for adaptive therapy to extend the time to progression beyond that of a standard-of-care continuous therapy. We find that for tumours close to their environmental carrying capacity such a cost of resistance is not required. However, for tumours growing far from carrying capacity, a cost may be required to see meaningful gains. Notably, we show that in such cases it is important to consider the cell turnover in the tumour and we discuss its role in modulating the impact of a cost of resistance. Overall, our work helps to clarify under which circumstances adaptive therapy may be beneficial, and suggests that turnover may play an unexpectedly important role in the decision making process.

scholarly journals The Ribosomal Protein L28 Gene Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Yi Shi ◽  
Xiaojiang Wang ◽  
Qiong Zhu ◽  
Gang Chen
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Hepg2 Cells ◽  
Cell Model ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Resistant Gene ◽  
Key Genes ◽  
Resistant Cells

Abstract Background: Sorafenib is the first molecular-targeted drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its treatment efficiency decreases after a short period of time because of the development of drug resistance. This study investigates the role of key genes in regulating sorafenib-resistance in hepatocellular carcinoma and elucidates the mechanism of drug resistance. Methods: The HCC HepG2 cells were used to generate a sorafenib-resistant cell model by culturing the cells in gradually increasing concentration of sorafenib. RNA microarray was applied to profile gene expression and screen key genes associated with sorafenib resistance. Specific targets were knockdown in sorafenib-resistant HepG2 cells for functional studies. The HCC model was established in ACI rats using Morris hepatoma3924A cells to validate selected genes associated with sorafenib resistance in vivo. Results: The HepG2 sorafenib-resistant cell model was successfully established. The IC50 of sorafenib was 9.988mM in HepG2 sorafenib-resistant cells. A total of 35 up-regulated genes were detected by expression profile chip. High-content screening technology was used and a potential drug-resistant gene RPL28 was filtered out. After knocking down of RPL28 in HepG2 sorafenib-resistant cells, the results of cell proliferation and apoptosis illustrated that RPL28 is the key drug-resistant gene in the cells. Furthermore, it was found that both RNA and protein expression of RPL28 increased in HepG2 sorafenib-resistant specimens of Morris Hepatoma rats. In addition, the expression of functional proteins Ki-67 increased in sorafenib-resistant cells. Conclusion: Our study suggested that RPL28 was a key gene for sorafenib resistance in HCC both in vitro and in vivo.

scholarly journals Exosomal miR-331 from Chemoresistant Osteosarcoma Cells induced Chemoresistance through Autophagy

2021 ◽  
Author(s):  
Aiqing Zhao ◽  
Yanbin Zhao ◽  
Wanlin Liu ◽  
Wei Feng ◽  
Wenhua Xing ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Rt Pcr ◽  
Chemotherapeutic Resistance ◽  
Acquire Drug Resistance ◽  
And Migration ◽  
Drug Resistant Cell ◽  
Resistant Cells

Abstract BackgroundOsteosarcoma (OS) is a highly malignant tumor. Improving chemotherapeutic resistance is very important to improve the survival rate of OS. Exosomes and microRNAs (MiRNA) play important roles in the mechanism of chemotherapeutic resistance transmission. More and more researches focus the mechanism of miRNAs carried by exosomes in the transmission of chemotherapeutic resistance of OS. This study focused on exploring the mechanism of exosomal miR-331 in the transmission of chemoresistance in OS.MethodsWe cultured OS drug-resistant cells and extracted exosomes of these cells. The secretion and uptake of exosomes in OS drug-resistant cells and OS cells (OSCs) were confirmed by fluorescence tracking assay and transwell experiments. The differential expression of microRNA-331 (miR-331) in exosomes of OS resistant and OS cells was investigated by RT-PCR. The effects of drug-resistant exosomes on proliferation and migration of OS cells were determined by MTT assay and scratches assay. MDC staining, RT-PCR, and Western blot were used to detect the role of autophagy which regulated by drug-resistant cell-derived exosom-miR-331.ResultsWe found that the expression difference of miR-331 between MG63/CDDP and MG63 was the most significant. Drug resistant OSCs secreted exosomes and were ingested by OSCs, which then promoted OSCs to acquire drug resistance. In addition, exosomes secreted by drug-resistant OSCs promote drug resistance by carrying miRNAs. Interestingly, inhibition of miRNA resulted in reduced drug resistance transmission of exosomes. Finally, we found that the exosomes secreted by drug-resistant OSCs could induce autophagy of OSCs by carrying miR-331, thus making OSCs acquire drug resistance. Inhibition of miR-331 can effectively improve drug resistance of OSCs.ConclusionsChemoresistant OSCs-derived exosomes promote the transmission of drug resistance by carrying miR-331 and inducing autophagy. Inhibition of miR-331 could effectively alleviate drug resistance of OSCs.

scholarly journals Spatial heterogeneity and evolutionary dynamics modulate time to recurrence in continuous and adaptive cancer therapies

2017 ◽  
Author(s):  
Jill A. Gallaher ◽  
Pedro M. Enriquez-Navas ◽  
Kimberly A. Luddy ◽  
Robert A. Gatenby ◽  
Alexander R. A. Anderson
Keyword(s):  
Evolutionary Dynamics ◽  
Spatial Competition ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Continuous Treatment ◽  
Evolutionary Strategies ◽  
Tumor Control ◽  
Wide Range ◽  
Dose Modulation ◽  
Resistant Cells

AbstractTreatment of advanced cancers has benefited from new agents that supplement or bypass conventional therapies. However, even effective therapies fail as cancer cells deploy a wide range of resistance strategies. We propose that evolutionary dynamics ultimately determine survival and proliferation of resistant cells, therefore evolutionary strategies should be used with conventional therapies to delay or prevent resistance. Using an agent-based framework to model spatial competition among sensitive and resistant populations, we apply anti-proliferative drug treatments to varying ratios of sensitive and resistant cells. We compare a continuous maximum tolerated dose schedule with an adaptive schedule aimed at tumor control through competition between sensitive and resistant cells. We find that continuous treatment cures mostly sensitive tumors, but with any resistant cells, recurrence is inevitable. We identify two adaptive strategies that control heterogeneous tumors: dose modulation controls most tumors with less drug, while a more vacation-oriented schedule can control more invasive tumors.

scholarly journals Generating Paclitaxel-Resistant in Cervical Cancer HeLa Cell Line

2020 ◽  
Vol 11 (2) ◽  
pp. 90
Author(s):  
Muhammad Hasan Bashari ◽  
Fachreza Aryo Damara ◽  
Isna Nisrina Hardani ◽  
Gita Widya Pradini ◽  
Tenny Putri ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Line ◽  
Hela Cells ◽  
Molecular Mechanisms ◽  
Inhibitory Concentration ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Resistant Cells

Cervical cancer is one of the most leading causes of women death. Currently, paclitaxel is still one of the main therapeutic regimens for cervical cancer patients. However, some patients developed to be paclitaxel-resistant. Hence, studies to find out the novel strategies to resolve this problem are important. Generating resistant cancer cell lines can be utilized as the potent tool to evaluate the efficacy of any therapeutic agent toward cancer drug-resistant problems. Current studies describing the methods to establish chemoresistance are lacking. Moreover, study in Indonesia conducting chemoresistance in cell line is limited. This study was aimed to elaborate the characteristics of HeLa cells during generation of paclitaxel-resistant cervical cancer cells. The parental HeLa cells were exposed to an escalating concentration of paclitaxel for a long time period. Subsequently, cells were divided into two groups for the evaluation of resistance characteristics. The values of inhibitory concentration 50 (IC50) and inhibitory concentration 90 (IC90) were analyzed using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Our data showed that the longer exposing periods of paclitaxel, the higher IC50 and IC90 values of HeLa cells are. IC90 of paclitaxel in HeLa Pac RB was increased from 69 pM, 440 pM, 2,561 pM and 10,337 pM on 0th, 1st, 2nd, 3rd and 4th months, respectively. Interestingly, the resistant cells were recovered to be paclitaxel-sensitive when they were not being continuously exposed to paclitaxel. In addition, the paclitaxel resistant cells become less sensitive against 5-FU but not doxorubicin, cisplatin and etoposide. We were able to generate cervical cancer HeLa paclitaxel-resistant cell line. These cell line could potentially be utilized for further studies in order to understand the molecular mechanisms of drug resistance in cervical cancer and as a tool for cancer drug discovery.Keywords: cervical cancer, drug resistant cell line, paclitaxel resistant cells, stepwise escalating concentration.

scholarly journals The Significance of MicroRNAs Expression in Regulation of Extracellular Matrix and Other Drug Resistant Genes in Drug Resistant Ovarian Cancer Cell Lines

2020 ◽  
Vol 21 (7) ◽  
pp. 2619 ◽  
Author(s):  
Dominika Kazmierczak ◽  
Karol Jopek ◽  
Karolina Sterzynska ◽  
Barbara Ginter-Matuszewska ◽  
Michal Nowicki ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Extracellular Matrix ◽  
Drug Resistance ◽  
Cell Line ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Drug Resistant ◽  
Resistant Genes

Ovarian cancer rates the highest mortality among all gynecological malignancies. The main reason for high mortality is the development of drug resistance. It can be related to increased expression of drug transporters and increased expression of extracellular matrix (ECM) proteins. Our foremost aim was to exhibit alterations in the miRNA expression levels in cisplatin (CIS), paclitaxel (PAC), doxorubicin (DOX), and topotecan (TOP)—resistant variants of the W1 sensitive ovarian cancer cell line—using miRNA microarray. The second goal was to identify miRNAs responsible for the regulation of drug-resistant genes. According to our observation, alterations in the expression of 40 miRNAs were present. We could observe that, in at least one drug-resistant cell line, the expression of 21 miRNAs was upregulated and that of 19 miRNAs was downregulated. We identified target genes for 22 miRNAs. Target analysis showed that miRNA regulates key genes responsible for drug resistance. Among others, we observed regulation of the ATP-binding cassette subfamily B member 1 gene (ABCB1) in the paclitaxel-resistant cell line by miR-363 and regulation of the collagen type III alpha 1 chain gene (COL3A1) in the topotekan-resistant cell line by miR-29a.

scholarly journals Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Zicong Gao ◽  
Xingxing Han ◽  
Yuying Zhu ◽  
He Zhang ◽  
Ran Tian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Resistant Cell ◽  
Breast Cancer Progression ◽  
Drug Resistant ◽  
Drug Resistant Cell ◽  
Resistant Cells

AbstractTumor metastasis induced by drug resistance is a major challenge in successful cancer treatment. Nevertheless, the mechanisms underlying the pro-invasive and metastatic ability of drug resistance remain elusive. Exosome-mediated intercellular communications between cancer cells and stromal cells in tumor microenvironment are required for cancer initiation and progression. Recent reports have shown that communications between cancer cells also promote tumor aggression. However, little attention has been regarded on this aspect. Herein, we demonstrated that drug-resistant cell-derived exosomes promoted the invasion of sensitive breast cancer cells. Quantitative proteomic analysis showed that EphA2 was rich in exosomes from drug-resistant cells. Exosomal EphA2 conferred the invasive/metastatic phenotype transfer from drug-resistant cells to sensitive cells. Moreover, exosomal EphA2 activated ERK1/2 signaling through the ligand Ephrin A1-dependent reverse pathway rather than the forward pathway, thereby promoting breast cancer progression. Our findings indicate the key functional role of exosomal EphA2 in the transmission of aggressive phenotype between cancer cells that do not rely on direct cell–cell contact. Our study also suggests that the increase of EphA2 in drug-resistant cell-derived exosomes may be an important mechanism of chemotherapy/drug resistance-induced breast cancer progression.

scholarly journals The Profile of MicroRNA Expression and Potential Role in the Regulation of Drug-Resistant Genes in Cisplatin- and Paclitaxel-Resistant Ovarian Cancer Cell Lines

2022 ◽  
Vol 23 (1) ◽  
pp. 526
Author(s):  
Dominika Kazmierczak ◽  
Karol Jopek ◽  
Karolina Sterzynska ◽  
Michal Nowicki ◽  
Marcin Rucinski ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Cell Lines ◽  
Cancer Cell ◽  
Resistance Genes ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cell Line ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Resistant Genes

Ovarian cancer is the most lethal gynecological malignancy. The high mortality results from late diagnosis and the development of drug resistance. Drug resistance results from changes in the expression of different drug-resistance genes that may be regulated miRNA. The main aim of our study was to detect changes in miRNA expression levels in two cisplatin (CIS) and two paclitaxel (PAC)—resistant variants of the A2780 drug-sensitive ovarian cancer cell line—by miRNA microarray. The next goal was to identify miRNAs responsible for the regulation of drug-resistance genes. We observed changes in the expression of 46 miRNA that may be related to drug resistance. The overexpression of miR-125b-5p, miR-99a-5p, miR-296-3p, and miR-887-3p and downregulation of miR-218-5p, miR-221-3p, and miR-222-3p was observed in both CIS-resistant cell lines. In both PAC-resistant cell lines, we observed the upregulation of miR-221-3p, miR-222-3p, and miR-4485, and decreased expression of miR-551b-3p, miR-551b-5p, and miR-218-5p. Analysis of targets suggest that expression of important drug-resistant genes like protein Tyrosine Phosphatase Receptor Type K (PTPRK), receptor tyrosine kinase—EPHA7, Semaphorin 3A (SEMA3A), or the ATP-binding cassette subfamily B member 1 gene (ABCB1) can be regulated by miRNA.

scholarly journals Misregulation of translation drives prostate cancer drug resistance

2021 ◽  
Author(s):  
Emeline I. J. Lelong ◽  
France Hélène Joncas ◽  
Pauline Adjibade ◽  
Valerie ST.-Sauveur Grenier ◽  
Jean-Philippe Lambert ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Cell Line ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Cancer Drug ◽  
Biological Processes ◽  
Drug Resistant ◽  
Cancer Resistance ◽  
Resistant Cells

ABSTRACTEmerging evidence associates translation factors and regulators to tumorigenesis. Recent advances in our ability to perform global translatome analyses indicate that our understanding of translational changes in cancer resistance is still limited. Here, we characterize global translational changes that occur during the acquisition of prostate cancer (PCa) drug resistance. We generated a patient derived xenograft (PDX) model created from PCa cells to recapitulate key features of resistant PCa progression. From an enzalutamide-sensitive patient derived cell line (VCaP), we generated a castration resistant cell line (VCaPCRPC) and an enzalutamide resistant cell line (VCaPER). We performed Total and polyribosome-bound RNA sequencing and mass spectroscopy from both VCaPCRPC and VCaPER to reveal their respective translatomes. We found that in drug-resistant cells, RNAs associated to ribosomes were enriched for nuclear RNA and DNA binding related biological processes, whereas RNAs that are less associated showed enrichment for processes such as cell membrane and cell-cell junction related biological processes. These results were corroborated by mass spectrometry and suggest that translation is indeed affected during drug resistance. Furthermore, our analysis revealed enrichment of long non-coding RNAs associated to ribosomes, which may suggest aberrant translation or translation of novel peptides that can be considered as new biomarkers. Our findings thus point towards novel therapeutic avenues that may target drug-resistant cells.

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