scholarly journals Mechanical Stretch Kills Transformed Cancer Cells

2018 ◽  
Author(s):  
Ajay Tijore ◽  
Mingxi Yao ◽  
Yu-Hsiu Wang ◽  
Yasaman Nematbakhsh ◽  
Anushya Hariharan ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Calcium Influx ◽  
Mechanical Stretch ◽  
Cyclic Stretch ◽  
Transformed Cells ◽  
Normal Cells ◽  
Calcium Dependent ◽  
Cyclic Stretching ◽  
Protease Activation ◽  
Different Tissues

AbstractTransformed cancer cells differ from normal cells in several important features like anchorage independence, Warburg effect and mechanosensing. Consequently, transformed cancer cells develop an anaplastic morphology and respond aberrantly to external mechanical forces. Consistent with altered mechano-responsiveness, here we show that transformed cancer cells from many different tissues have reduced growth and become apoptotic upon cyclic stretch as do normal cells after the transformation. When matrix rigidity sensing is restored in transformed cancer cells, they survive and grow faster on soft surface upon cyclic stretch like normal cells but undergo anoikis without stretch by activation of death associated protein kinase1 (DAPK1). In contrast, stretch-dependent apoptosis (mechanoptosis) of transformed cells is driven by stretch-mediated calcium influx and calcium-dependent calpain 2 protease activation on both collagen and fibronectin matrices. Further, mechanosensitive calcium channel, Piezo1 is needed for mechanoptosis. Thus, cyclic stretching of transformed cells from different tissues activates apoptosis, whereas similar stretching of normal cells stimulates growth.

Classical Cancer Biology: Misconceptions and Limitations

2017 ◽  
Author(s):  
Abicumaran Uthamacumaran
Keyword(s):  
Cancer Cells ◽  
Cancer Biology ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Transformed Cells ◽  
Epigenetic Landscape ◽  
Normal Cells ◽  
Cancer Models ◽  
Stem Cell Division ◽  
Insight Into

Cancer is the co-evolution of cancer cells and their turbulent microenvironment, characterized by dynamical hyper-chaotic gene expression profiles. However, cancers should not be viewed as the result of random mutations and malfunctioning information processing systems. Rather, it is the selective advantages conferred by adaptive evolution of cellular biosystems. Although on a systemic scale, cancer is defined as a disease, on a cellular basis they outperform healthy (non-transformed cells) in terms of survival and reproductive success. Their enhanced longevity pathways, metastatic invasion, extended telomeres, dynamical morphogenesis, regenerative stem cell division and environment-specific metabolic cascades indicate they are adaptive evolutionary cell states that have surpassed the boundaries normal cells are confined to. Therefore, the paper presents a brief summary of currently existing classical cancer models in the field of mathematical biology and the misconceptions of cancer epimetabolomes to further advance cancer research beyond its current limits. Through an insight into the mathematical behaviors of cancer cells, a quantum adaptive epigenetic landscape is proposed to explain the selective evolutionary dominance of cancer cells.

Mechanical ventilation promotes lung tumor spread by modulation of cholesterol cell content

2021 ◽  
pp. 2101470
Author(s):  
Inés López-Alonso ◽  
Cecilia López-Martínez ◽  
Paula Martín-Vicente ◽  
Laura Amado-Rodríguez ◽  
Adrián González-López ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Cancer Cells ◽  
Lung Tumor ◽  
Mechanical Stretch ◽  
Lung Tumors ◽  
Cyclic Stretch ◽  
Tumor Spread ◽  
Static Conditions

Mechanical stretch of cancer cells can alter their invasiveness. During mechanical ventilation, lungs may be exposed to an increased amount of stretch, but the consequences on lung tumors have not been explored. To characterize the influence of mechanical ventilation on the behavior of lung tumors, invasiveness assays and transcriptomic analyses were performed in cancer cell lines cultured in static conditions or under cyclic stretch. Mice harbouring lung melanoma implants were submitted to mechanical ventilation and metastatic spread was assessed. Additional in vivo experiments were performed to determine the mechano-dependent specificity of the response. Incidence of metastases was studied in a cohort of lung cancer patients that received mechanical ventilation compared with a matched group of non-ventilated patients. Stretch increases invasiveness in melanoma B16F10luc2 and lung adenocarcinoma A549 cells. We identified a mechanosensitive upregulation of pathways involved in cholesterol processing in vitro, leading to an increase in PCSK9 and LDLR expression, a decrease in intracellular cholesterol and preservation of cell stiffness. A course of mechanical ventilation in mice harboring melanoma implants increased brain and kidney metastases two weeks later. Blockade of PCSK9 using a monoclonal antibody increased cell cholesterol and stiffness and decreased cell invasiveness in vitro and metastasis in vivo. In patients, mechanical ventilation increased PCSK9 abundance in lung tumors and the incidence of metastasis, thus decreasing survival. Our results suggest that mechanical stretch promote invasiveness of cancer cells, which may have clinically relevant consequences. Pharmacological manipulation of cholesterol endocytosis could be a novel therapeutic target in this setting.

scholarly journals Calcium signaling mediates a biphasic mechanoadaptive response of endothelial cells to cyclic mechanical stretch

2021 ◽  
pp. mbc.E21-03-0106
Author(s):  
Yekaterina A. Miroshnikova ◽  
Sandra Manet ◽  
Xinping Li ◽  
Sara A. Wickström ◽  
Eva Faurobert ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Vascular System ◽  
Calcium Influx ◽  
Mechanical Stretch ◽  
Mechanical Stimulus ◽  
Cyclic Stretch ◽  
Proteomic Profiling ◽  
Time Resolved ◽  
Mechanisms Of Adaptation ◽  
Actomyosin Cytoskeleton

The vascular system is precisely regulated to adjust blood flow to organismal demand, thereby guaranteeing adequate perfusion under varying physiological conditions. Mechanical forces, such as cyclic circumferential stretch, are among the critical stimuli that dynamically adjust vessel distribution and diameter, but the precise mechanisms of adaptation to changing forces are unclear. We find that endothelial monolayers respond to cyclic stretch by transient remodeling of the VE-Cadherin-based adherens junctions and the associated actomyosin cytoskeleton. Time-resolved proteomic profiling reveals that this remodeling is driven by calcium influx through the mechanosensitive Piezo1 channel, triggering Rho activation to increase actomyosin contraction. As the mechanical stimulus persists, calcium signaling is attenuated through transient downregulation of Piezo1 protein. At the same time, filamins are phosphorylated to increase monolayer stiffness, allowing mechanoadaptation to restore junctional integrity despite continuing exposure to stretch. Collectively, this study identifies a biphasic response to cyclic stretch, consisting of an initial, calcium driven junctional mechanoresponse, followed by mechanoadaptation facilitated by monolayer stiffening.

scholarly journals A Tale of Two States: Normal and Transformed, With and Without Rigidity Sensing

2019 ◽  
Vol 35 (1) ◽  
pp. 169-190 ◽  
Author(s):  
Michael Sheetz
Keyword(s):  
Wound Healing ◽  
Strong Correlation ◽  
Mechanical Characteristics ◽  
Cytoskeletal Proteins ◽  
Transformed Cells ◽  
Normal Cells ◽  
Rigidity Sensing ◽  
Tissue Healing ◽  
Probability Of Cancer ◽  
Different Tissues

For many years, major differences in morphology, motility, and mechanical characteristics have been observed between transformed cancer and normal cells. In this review, we consider these differences as linked to different states of normal and transformed cells that involve distinct mechanosensing and motility pathways. There is a strong correlation between repeated tissue healing and/or inflammation and the probability of cancer, both of which involve growth in adult tissues. Many factors are likely needed to enable growth, including the loss of rigidity sensing, but recent evidence indicates that microRNAs have important roles in causing the depletion of growth-suppressing proteins. One microRNA, miR-21, is overexpressed in many different tissues during both healing and cancer. Normal cells can become transformed by the depletion of cytoskeletal proteins that results in the loss of mechanosensing, particularly rigidity sensing. Conversely, the transformed state can be reversed by the expression of cytoskeletal proteins—without direct alteration of hormone receptor levels. In this review, we consider the different stereotypical forms of motility and mechanosensory systems. A major difference between normal and transformed cells involves a sensitivity of transformed cells to mechanical perturbations. Thus, understanding the different mechanical characteristics of transformed cells may enable new approaches to treating wound healing and cancer.

scholarly journals A primate virus generates transformed human cells by fusion

2005 ◽  
Vol 171 (3) ◽  
pp. 493-503 ◽  
Author(s):  
Dominik M. Duelli ◽  
Stephen Hearn ◽  
Michael P. Myers ◽  
Yuri Lazebnik
Keyword(s):  
Cancer Cells ◽  
Cell Fusion ◽  
Chromosome Segregation ◽  
Human Cells ◽  
Transformed Cells ◽  
Tumor Suppressor P53 ◽  
Epigenetic Variability ◽  
Normal Cells ◽  
Primate Virus ◽  
Prevailing View

Amodel that explains both the origin and sporadic nature of cancer argues that cancer cells are a chance result of events that cause genomic and epigenetic variability. The prevailing view is that these events are mutations that affect chromosome segregation or stability. However, genomic and epigenetic variability is also triggered by cell fusion, which is often caused by viruses. Yet, cells fused by viruses are considered harmless because they die. We provide evidence that a primate virus uses both viral and exosomal proteins involved in cell fusion to produce transformed proliferating human cells. Although normal cells indeed fail to proliferate after fusion, expression of an oncogene or a mutated tumor suppressor p53 in just one of the fusion partners is sufficient to produce heterogeneous progeny. We also show that this virus can produce viable oncogenically transformed cells by fusing cells that are otherwise destined to die. Therefore, we argue that viruses can contribute to carcinogenesis by fusing cells.

Molecular Studies on Novel Antitumor Bis 1,4-Dihydropyridine Derivatives Against Lung Carcinoma and their Limited Side Effects on Normal Melanocytes

2019 ◽  
Vol 18 (15) ◽  
pp. 2156-2168 ◽  
Author(s):  
Magda F. Mohamed ◽  
Nada S. Ibrahim ◽  
Ahmed H.M. Elwahy ◽  
Ismail A. Abdelhamid
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Cancer Cells ◽  
Cell Line ◽  
Lung Carcinoma ◽  
Carcinoma Cell ◽  
Normal Cells ◽  
Lung Carcinoma Cell Line ◽  
Molecular Studies ◽  
Dihydropyridine Derivatives

Background: Cancer is a complex genetic disease which is characterized by an abnormal cell growth, invasion and spreading to other parts of the body. There are several factors that lead to cancer by causing DNA damage and the impairment of its repair. Treatment of cancer using the chemotherapeutic drugs have adverse side effects such as toxicity as they lose their specificity toward cancer cells and affect also normal cells. Moreover, the cancer cells can resist the chemotherapeutic agents and make them ineffective. For these reasons, much attentions have been paid to develop new drugs with limited side effects on normal cells and to diminish cancer resistance to drug chemotherapy. Recently, some 1,4-dihydropyridine derivatives were reported to act as Multi-Drug Resistance (MDR) modulators that inhibit p-glycoprotein which is responsible for the inability of drugs to enter the cancer cells. Also 1,4-DHPs have antimutagenic properties against chemicals via modulating DNA repair when studied on drosophila. Objective: The objective of this study is the synthesis of bis 1,4-DHPs incorporating ester as well as ether linkages and evaluate the anticancer activity of new compounds for synergistic purpose. Different genetic tools were used in an attempt to know the mechanism of action of this compound against lung cancer. Method: An efficient one pot synthesis of bis 1,4-DHPs using 3-aminocrotononitrile and bis(aldehydes) has been developed. The cytotoxic effect against human cell lines MCF7, and A549 cell lines was evaluated. Results: All compounds exhibited better cytotoxicity toward lung carcinoma cells than breast cancer cells. With respect to lung carcinoma cell line (A549), compound 10 was the most active compound and the three other compounds 7, 8, and 9 showed comparable IC50 values. In case of breast cancer cell line (MCF7), the most active one was compound 7, while compound 8 recorded the least activity. Conclusion: we have developed an efficient method for the synthesis of novel bis 1,4-dihydropyridine derivatives incorporating ester or ether linkage. All compounds showed better cytotoxicity results against A549 than MCF7, so that lung carcinoma cell line was chosen to perform the molecular studies on it. The results showed that all compounds (7, 8, 9 and 10) caused cell cycle arrest at G1 phase. The molecular docking study on CDK2 confirmed the results of cell cycle assay which showed good binding energy between the compounds and the active site of enzyme indicating the inhibition of the enzyme.

scholarly journals Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yu-An Chen ◽  
Yong-Da Sie ◽  
Tsung-Yun Liu ◽  
Hsiang-Ling Kuo ◽  
Pei-Yi Chou ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cancer Cells ◽  
Room Temperature ◽  
Metastatic Cancer ◽  
Normal Cells ◽  
Tgfβ Receptor ◽  
Membrane Type ◽  
Cell Invasiveness ◽  
And Control ◽  
Metastatic Cancer Cells

AbstractMetastatic cancer cells are frequently deficient in WWOX protein or express dysfunctional WWOX (designated WWOXd). Here, we determined that functional WWOX-expressing (WWOXf) cells migrate collectively and expel the individually migrating WWOXd cells. For return, WWOXd cells induces apoptosis of WWOXf cells from a remote distance. Survival of WWOXd from the cell-to-cell encounter is due to activation of the survival IκBα/ERK/WWOX signaling. Mechanistically, cell surface epitope WWOX286-299 (repl) in WWOXf repels the invading WWOXd to undergo retrograde migration. However, when epitope WWOX7-21 (gre) is exposed, WWOXf greets WWOXd to migrate forward for merge. WWOX binds membrane type II TGFβ receptor (TβRII), and TβRII IgG-pretreated WWOXf greet WWOXd to migrate forward and merge with each other. In contrast, TβRII IgG-pretreated WWOXd loses recognition by WWOXf, and WWOXf mediates apoptosis of WWOXd. The observatons suggest that normal cells can be activated to attack metastatic cancer cells. WWOXd cells are less efficient in generating Ca2+ influx and undergo non-apoptotic explosion in response to UV irradiation in room temperature. WWOXf cells exhibit bubbling cell death and Ca2+ influx effectively caused by UV or apoptotic stress. Together, membrane WWOX/TβRII complex is needed for cell-to-cell recognition, maintaining the efficacy of Ca2+ influx, and control of cell invasiveness.

scholarly journals Quantum Dots as a Good Carriers of Unsymmetrical Bisacridines for Modulating Cellular Uptake and the Biological Response in Lung and Colon Cancer Cells

Nanomaterials ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 462 ◽  
Author(s):  
Joanna Pilch ◽  
Patrycja Kowalik ◽  
Piotr Bujak ◽  
Anna M. Nowicka ◽  
Ewa Augustin
Keyword(s):  
Quantum Dots ◽  
Cancer Cells ◽  
Cellular Uptake ◽  
Laser Scanning ◽  
Biological Response ◽  
Drug Carriers ◽  
Confocal Laser ◽  
Normal Cells ◽  
H460 Cells ◽  
Hct116 Cells

Nanotechnology-based drug delivery provides a promising area for improving the efficacy of cancer treatments. Therefore, we investigate the potential of using quantum dots (QDs) as drug carriers for antitumor unsymmetrical bisacridine derivatives (UAs) to cancer cells. We examine the influence of QD–UA hybrids on the cellular uptake, internalization (Confocal Laser Scanning Microscope), and the biological response (flow cytometry and light microscopy) in lung H460 and colon HCT116 cancer cells. We show the time-dependent cellular uptake of QD–UA hybrids, which were more efficiently retained inside the cells compared to UAs alone, especially in H460 cells, which could be due to multiple endocytosis pathways. In contrast, in HCT116 cells, the hybrids were taken up only by one endocytosis mechanism. Both UAs and their hybrids induced apoptosis in H460 and HCT116 cells (to a greater extent in H460). Cells which did not die underwent senescence more efficiently following QDs–UAs treatment, compared to UAs alone. Cellular senescence was not observed in HCT116 cells following treatment with both UAs and their hybrids. Importantly, QDgreen/red themselves did not provoke toxic responses in cancer or normal cells. In conclusion, QDs are good candidates for targeted UA delivery carriers to cancer cells while protecting normal cells from toxic drug activities.

scholarly journals The Exon Junction Complex Core Represses Cancer-Specific Mature mRNA Re-Splicing: A Potential Key Role in Terminating Splicing

2021 ◽  
Vol 22 (12) ◽  
pp. 6519
Author(s):  
Yuta Otani ◽  
Ken-ichi Fujita ◽  
Toshiki Kameyama ◽  
Akila Mayeda
Keyword(s):  
Cancer Cells ◽  
Control Factor ◽  
Exon Junction Complex ◽  
Core Component ◽  
Normal Cells ◽  
Knock Down ◽  
Exon Junction ◽  
Mature Mrna ◽  
Complex Core ◽  
Specific Mrna

Using TSG101 pre-mRNA, we previously discovered cancer-specific re-splicing of mature mRNA that generates aberrant transcripts/proteins. The fact that mRNA is aberrantly re-spliced in various cancer cells implies there must be an important mechanism to prevent deleterious re-splicing on the spliced mRNA in normal cells. We thus postulated that mRNA re-splicing is controlled by specific repressors, and we searched for repressor candidates by siRNA-based screening for mRNA re-splicing activity. We found that knock-down of EIF4A3, which is a core component of the exon junction complex (EJC), significantly promoted mRNA re-splicing. Remarkably, we could recapitulate cancer-specific mRNA re-splicing in normal cells by knock-down of any of the core EJC proteins, EIF4A3, MAGOH, or RBM8A (Y14), implicating the EJC core as the repressor of mRNA re-splicing often observed in cancer cells. We propose that the EJC core is a critical mRNA quality control factor to prevent over-splicing of mature mRNA.

scholarly journals CaV3.2 T-type calcium channels are involved in calcium-dependent secretion of neuroendocrine prostate cancer cells. VOLUME 283 (2008) PAGES 10162-10173

2008 ◽  
Vol 283 (28) ◽  
pp. 19872
Author(s):  
Florian Gackière ◽  
Gabriel Bidaux ◽  
Philippe Delcourt ◽  
Fabien Van Coppenolle ◽  
Maria Katsogiannou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Calcium Channels ◽  
Cancer Cells ◽  
Prostate Cancer Cells ◽  
Calcium Dependent ◽  
Neuroendocrine Prostate Cancer
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