scholarly journals Surviving Stress with the Tumour Microenvironment: Understanding Complex Cell - Cell Interactions

2021 ◽  
Author(s):  
Rebecca Dawson
Keyword(s):  
Mitochondrial Dna ◽  
Stress Response ◽  
Metabolic Stress ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Cellular Interactions ◽  
Cellular Survival ◽  
Potential Part ◽  
4T1 Breast Cancer ◽  
Chemokine Signalling

<p><b>Each year more than 18 million people are diagnosed with cancer. Stress survival plays a key role in tumour resistance which is a leading cause of cancer deaths. Understanding how cells respond to stress is key to understanding and treating cancer. Within a tumour, cells interact with many other cell types in the surrounding tumour microenvironment. The tumour microenvironment acts to both assist and resist tumorigenesis and metastasis depending on these cellular interactions.</b></p> <p>Rho Zero cells are cells that contain no mitochondrial DNA and therefore lack a functional electron transport chain and rely on glycolysis for energy metabolism, these cells require supplementation to survive in cell culture. When deprived of essential supplementation rho zero cells exhibit severe metabolic stress. Yet when implanted into mice they form tumours after a 2-3 week delay. After this they contain new mitochondrial DNA acquired from the tumour microenvironment.</p> <p>This thesis explored how cells under stress interact with a model tumour microenvironment and exploit normal cellular processes for continued survival. Using confocal microscopy, IncuCyte microscopic videography, and MinION sequencing techniques we have established that rho zero cells under metabolic stress in a co-culture environment uptake mitochondrial DNA from the surrounding microenvironment and that this cell survival is contact associated. Nars1 was identified as a potential signal from the rho zero cells to the tumour microenvironment when placed under metabolic stress. This identified Nars1 as potential part of a novel stress response mechanism for severe metabolic stress. I then investigated if these findings could be replicated in cisplatin and doxorubicin treated wild type cells. While contact dependant survival was implied in the doxorubicin treated cells no Nars1 signal was found. However, an up-regulation of Cxcl5 and Cxcl1 was identified as a commonly up-regulated transcript between the rho zero and both chemotherapy treatments in 4T1 breast cancer implicating a conserved chemokine signalling response to stress.</p> <p>Together these results illustrate the importance of chemokine signalling in complex cellular interactions as part of a cellular survival stress response.</p>

scholarly journals Surviving Stress with the Tumour Microenvironment: Understanding Complex Cell - Cell Interactions

2021 ◽  
Author(s):  
Rebecca Dawson
Keyword(s):  
Mitochondrial Dna ◽  
Stress Response ◽  
Metabolic Stress ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Cellular Interactions ◽  
Cellular Survival ◽  
Potential Part ◽  
4T1 Breast Cancer ◽  
Chemokine Signalling

<p><b>Each year more than 18 million people are diagnosed with cancer. Stress survival plays a key role in tumour resistance which is a leading cause of cancer deaths. Understanding how cells respond to stress is key to understanding and treating cancer. Within a tumour, cells interact with many other cell types in the surrounding tumour microenvironment. The tumour microenvironment acts to both assist and resist tumorigenesis and metastasis depending on these cellular interactions.</b></p> <p>Rho Zero cells are cells that contain no mitochondrial DNA and therefore lack a functional electron transport chain and rely on glycolysis for energy metabolism, these cells require supplementation to survive in cell culture. When deprived of essential supplementation rho zero cells exhibit severe metabolic stress. Yet when implanted into mice they form tumours after a 2-3 week delay. After this they contain new mitochondrial DNA acquired from the tumour microenvironment.</p> <p>This thesis explored how cells under stress interact with a model tumour microenvironment and exploit normal cellular processes for continued survival. Using confocal microscopy, IncuCyte microscopic videography, and MinION sequencing techniques we have established that rho zero cells under metabolic stress in a co-culture environment uptake mitochondrial DNA from the surrounding microenvironment and that this cell survival is contact associated. Nars1 was identified as a potential signal from the rho zero cells to the tumour microenvironment when placed under metabolic stress. This identified Nars1 as potential part of a novel stress response mechanism for severe metabolic stress. I then investigated if these findings could be replicated in cisplatin and doxorubicin treated wild type cells. While contact dependant survival was implied in the doxorubicin treated cells no Nars1 signal was found. However, an up-regulation of Cxcl5 and Cxcl1 was identified as a commonly up-regulated transcript between the rho zero and both chemotherapy treatments in 4T1 breast cancer implicating a conserved chemokine signalling response to stress.</p> <p>Together these results illustrate the importance of chemokine signalling in complex cellular interactions as part of a cellular survival stress response.</p>

scholarly journals Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism

2020 ◽  
Vol 22 (1) ◽  
pp. 141
Author(s):  
George Anderson
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Glycogen Synthase ◽  
Tumour Progression ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Future Research ◽  
Acetyl Coa ◽  
Dynamic Interactions ◽  
Aryl Hydrocarbon ◽  
Metabolic Interactions

This article reviews the dynamic interactions of the tumour microenvironment, highlighting the roles of acetyl-CoA and melatonergic pathway regulation in determining the interactions between oxidative phosphorylation (OXPHOS) and glycolysis across the array of cells forming the tumour microenvironment. Many of the factors associated with tumour progression and immune resistance, such as yin yang (YY)1 and glycogen synthase kinase (GSK)3β, regulate acetyl-CoA and the melatonergic pathway, thereby having significant impacts on the dynamic interactions of the different types of cells present in the tumour microenvironment. The association of the aryl hydrocarbon receptor (AhR) with immune suppression in the tumour microenvironment may be mediated by the AhR-induced cytochrome P450 (CYP)1b1-driven ‘backward’ conversion of melatonin to its immediate precursor N-acetylserotonin (NAS). NAS within tumours and released from tumour microenvironment cells activates the brain-derived neurotrophic factor (BDNF) receptor, TrkB, thereby increasing the survival and proliferation of cancer stem-like cells. Acetyl-CoA is a crucial co-substrate for initiation of the melatonergic pathway, as well as co-ordinating the interactions of OXPHOS and glycolysis in all cells of the tumour microenvironment. This provides a model of the tumour microenvironment that emphasises the roles of acetyl-CoA and the melatonergic pathway in shaping the dynamic intercellular metabolic interactions of the various cells within the tumour microenvironment. The potentiation of YY1 and GSK3β by O-GlcNAcylation will drive changes in metabolism in tumours and tumour microenvironment cells in association with their regulation of the melatonergic pathway. The emphasis on metabolic interactions across cell types in the tumour microenvironment provides novel future research and treatment directions.

scholarly journals Mitochondrial DNA Heteroplasmy as an Informational Reservoir Dynamically Linked to Metabolic and Immunological Processes Associated with COVID-19 Neurological Disorders

2021 ◽  
Author(s):  
George B. Stefano ◽  
Richard M. Kream
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Neurological Disorders ◽  
Nuclear Dna ◽  
Mitochondrial Dynamics ◽  
Cell Types ◽  
Tissue Specific ◽  
Copy Numbers ◽  
The Central Nervous System ◽  
Mitochondrial Dna Heteroplasmy

AbstractMitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.

scholarly journals Therapeutic Targeting of the Tumour Microenvironment in Metastatic Colorectal Cancer

2021 ◽  
Vol 22 (4) ◽  
pp. 2067
Author(s):  
Rhynelle S. Dmello ◽  
Sarah Q. To ◽  
Ashwini L. Chand
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapy ◽  
Liver Metastasis ◽  
Metastatic Colorectal Cancer ◽  
Tumour Microenvironment ◽  
Tumour Cells ◽  
Cellular Interactions ◽  
Circulating Tumour Cells ◽  
Therapeutic Targeting ◽  
Colorectal Cancer Patients

Liver metastasis is the primary contributor to the death of patients with colorectal cancer. Despite the overall success of current treatments including targeted therapy, chemotherapy, and immunotherapy combinations in colorectal cancer patients, the prognosis of patients with liver metastasis remains poor. Recent studies have highlighted the importance of the tumour microenvironment and the crosstalk within that determines the fate of circulating tumour cells in distant organs. Understanding the interactions between liver resident cells and tumour cells colonising the liver opens new therapeutic windows for the successful treatment of metastatic colorectal cancer. Here we discuss critical cellular interactions within the tumour microenvironment in primary tumours and in liver metastases that highlight potential therapeutic targets. We also discuss recent therapeutic advances for the treatment of metastatic colorectal cancer.

Abstract 415: Cardioprotective Effects of Interleukin-15 in Immortalized Human Ventricular Cardiomyocytes

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Marin Jane McBride ◽  
Kristina Durham ◽  
Bernardo L Trigatti
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Interleukin 2 ◽  
Cell Types ◽  
Human Cardiomyocytes ◽  
Er Stress Response ◽  
Distinct Cell ◽  
Receptor Chain ◽  
Interleukin 15 ◽  
Receptor Beta

Interleukin-15 (IL-15) is a pleotropic cytokine that has a profound effect on the proliferation, survival and differentiation of many distinct cell types. The IL-15 receptor complex has 3 subunits: the unique receptor chain IL-15 receptor alpha (IL-15Rα), and two receptor chains shared with interleukin-2 (IL-2) and/or other cytokines, referred to as IL-2 receptor beta (IL-2Rβ) and IL-2 receptor gamma/gamma common chain (IL-2Rγ/γc), respectively. To our knowledge, this is the first study to examine the effects of IL-15 in immortalized human cardiomyocytes. Data collected by RT-PCR shows mRNA expression of IL-15Rα, IL-2Rβ and IL-2 Rγ/γc in these cells. Additionally, western blotting for IL-15Rα, IL-2Rβ and IL-2 Rγ/γc confirms the presence of all three IL-15 receptors. Early experiments examining the effect of IL-15 on cardiomyocyte cell survival show a statistically significant protective effect of IL-15 on the survival of cells exposed to tunicamycin, a pharamacological endoplasmic reticulum (ER) stress inducing agent. These findings suggest that IL-15 signaling may be an important cardioprotective pathway that is involved in the cardiac ER stress response. As ER stress is a major component of multiple different cardiac pathologies, such as myocardial infarction, heart failure and diabetes, uncovering the molecular mechanism by which IL-15 protects the heart will allow for deeper understanding of the cardiac ER stress response.

scholarly journals Mitochondrial DNA in the tumour microenvironment activates neutrophils and is associated with worse outcomes in patients with advanced epithelial ovarian cancer

2018 ◽  
Vol 120 (2) ◽  
pp. 207-217 ◽  
Author(s):  
Kelly L. Singel ◽  
Kassondra S. Grzankowski ◽  
A. N. M. Nazmul H. Khan ◽  
Melissa J. Grimm ◽  
Anthony C. D’Auria ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mitochondrial Dna ◽  
Epithelial Ovarian Cancer ◽  
Tumour Microenvironment ◽  
Advanced Epithelial Ovarian Cancer

Differential sensitivity of AS-30D rat hepatoma cells and normal hepatocytes to anoxic cell damage

1992 ◽  
Vol 262 (6) ◽  
pp. C1384-C1387 ◽  
Author(s):  
C. E. Kobryn ◽  
G. Fiskum
Keyword(s):  
Tumor Cells ◽  
Cell Damage ◽  
Metabolic Stress ◽  
Metastatic Potential ◽  
Cell Types ◽  
Hepatoma Cells ◽  
Differential Sensitivity ◽  
Trypan Blue Exclusion ◽  
Lactate Dehydrogenase Release

A substantial fraction of cells present within hard tumors experience extremely hypoxic and hypoglycemic conditions that can lead to phenotypic alterations such as increased metastatic potential and chemotherapeutic drug resistance. Little is known regarding the influence of anoxic aglycemia on tumor cell energy metabolism and viability, and no direct comparisons have been made between the effects of this form of metabolic stress on tumor cells and their tissue of origin. In this study, the effects of in vitro aglycemic incubation under N2 (with or without iodoacetate) on trypan blue exclusion, lactate dehydrogenase release, cell surface blebbing, ATP levels, and mitochondrial respiratory capacity of rat AS-30D ascites hepatoma cells and normal hepatocytes were measured. Under anoxic-aglycemic conditions, the period of incubation during which 50% viability was lost was 2 h for hepatocytes and 6-8 h for AS-30D cells. In contrast, the rate of anoxia-induced loss of ATP was comparable for the two cell types, and mitochondrial damage was actually accelerated in the tumor cells. These findings suggest that tumor cells are more resistant to anoxic cell death because of their greater ability to withstand deenergization and subcellular injury.

scholarly journals Spatial deconvolution of HER2-positive breast cancer delineates tumor-associated cell type interactions

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alma Andersson ◽  
Ludvig Larsson ◽  
Linnea Stenbeck ◽  
Fredrik Salmén ◽  
Anna Ehinger ◽  
...  
Keyword(s):  
Spatial Information ◽  
Cell Types ◽  
Interferon Response ◽  
Type I ◽  
Cellular Interactions ◽  
Her2 Positive ◽  
High Resolution Map ◽  
Functional Relevance ◽  
Macrophage Subset ◽  
Treatment And Diagnosis

AbstractIn the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra- and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. By integration with single cell data, we spatially map tumor-associated cell types to find tertiary lymphoid-like structures, and a type I interferon response overlapping with regions of T-cell and macrophage subset colocalization. We construct a predictive model to infer presence of tertiary lymphoid-like structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define a high resolution map of cellular interactions in tumors and provide tools generalizing across tissues and diseases.

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