Cell signalling pathways

2016 ◽  
pp. 23-30
Author(s):  
Stefan Knapp
Keyword(s):  
Tumour Growth ◽  
Cell Signalling ◽  
Tumour Microenvironment ◽  
The Body ◽  
Cellular Growth ◽  
Regulatory Mechanisms ◽  
Signalling Pathways ◽  
Tissue Remodelling ◽  
Cellular Replication ◽  
Key Pathways

Development and progression of cancer is driven by dysfunctional signalling pathways that promote tumour growth and invasion. The combined effect of a variety of deregulated key pathways leads to the acquisition of capabilities in cancer that are tightly controlled in normal cells. These altered cellular properties strongly promote cancer cell proliferation and the evasion of cellular growth suppression mechanisms and apoptosis. Cancer-specific alterations in signalling pathways also overcome limitations of cellular replication potential. In late-stage cancers, communication of cancer cells with the tumour microenvironment leads to tissue remodelling and reprogramming, including the formation of new blood vessels and the spread of tumour cells in the body. These complex cellular changes are controlled by a myriad of cellular signalling pathways. The chapter reviews the principal regulatory mechanisms that control key cancer signalling pathways, particularly focusing on pathways that have been successfully targeted in cancer therapy.

scholarly journals Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323363
Author(s):  
Ester Pagano ◽  
Joshua E Elias ◽  
Georg Schneditz ◽  
Svetlana Saveljeva ◽  
Lorraine M Holland ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumour Growth ◽  
Tumour Microenvironment ◽  
Tube Formation ◽  
Tissue Remodelling ◽  
Colon Cancers ◽  
Inflammatory Bowel ◽  
Ion Pumping ◽  
G Protein Coupled

ObjectivePrimary sclerosing cholangitis (PSC) is in 70% of cases associated with inflammatory bowel disease. The hypermorphic T108M variant of the orphan G protein-coupled receptor GPR35 increases risk for PSC and ulcerative colitis (UC), conditions strongly predisposing for inflammation-associated liver and colon cancer. Lack of GPR35 reduces tumour numbers in mouse models of spontaneous and colitis associated cancer. The tumour microenvironment substantially determines tumour growth, and tumour-associated macrophages are crucial for neovascularisation. We aim to understand the role of the GPR35 pathway in the tumour microenvironment of spontaneous and colitis-associated colon cancers.DesignMice lacking GPR35 on their macrophages underwent models of spontaneous colon cancer or colitis-associated cancer. The role of tumour-associated macrophages was then assessed in biochemical and functional assays.ResultsHere, we show that GPR35 on macrophages is a potent amplifier of tumour growth by stimulating neoangiogenesis and tumour tissue remodelling. Deletion of Gpr35 in macrophages profoundly reduces tumour growth in inflammation-associated and spontaneous tumour models caused by mutant tumour suppressor adenomatous polyposis coli. Neoangiogenesis and matrix metalloproteinase activity is promoted by GPR35 via Na/K-ATPase-dependent ion pumping and Src activation, and is selectively inhibited by a GPR35-specific pepducin. Supernatants from human inducible-pluripotent-stem-cell derived macrophages carrying the UC and PSC risk variant stimulate tube formation by enhancing the release of angiogenic factors.ConclusionsActivation of the GPR35 pathway promotes tumour growth via two separate routes, by directly augmenting proliferation in epithelial cells that express the receptor, and by coordinating macrophages’ ability to create a tumour-permissive environment.

scholarly journals Intersection of Brain Development and Paediatric Diffuse Midline Gliomas: Potential Role of Microenvironment in Tumour Growth

2018 ◽  
Vol 8 (11) ◽  
pp. 200 ◽  
Author(s):  
Katie Loveson ◽  
Helen Fillmore
Keyword(s):  
Tumour Growth ◽  
Median Overall Survival ◽  
Tumour Microenvironment ◽  
Diffuse Intrinsic Pontine Glioma ◽  
The Body ◽  
Paediatric Brain Tumour ◽  
Molecular Aberrations ◽  
The Brain ◽  
Complex Organ

Diffuse intrinsic pontine glioma (DIPG) is a devastating and incurable paediatric brain tumour with a median overall survival of 9 months. Until recently, DIPGs were treated similarly to adult gliomas, but due to the advancement in molecular and imaging technologies, our understanding of these tumours has increased dramatically. While extensive research is being undertaken to determine the function of the molecular aberrations in DIPG, there are significant gaps in understanding the biology and the influence of the tumour microenvironment on DIPG growth, specifically in regards to the developing pons. The precise orchestration and co-ordination of the development of the brain, the most complex organ in the body, is still not fully understood. Herein, we present a brief overview of brainstem development, discuss the developing microenvironment in terms of DIPG growth, and provide a basis for the need for studies focused on bridging pontine development and DIPG microenvironment. Conducting investigations in the context of a developing brain will lead to a better understanding of the role of the tumour microenvironment and will help lead to identification of drivers of tumour growth and therapeutic resistance.

scholarly journals Targeting obesity-related dysfunction in hormonally driven cancers

2021 ◽  
Author(s):  
Maria M. Rubinstein ◽  
Kristy A. Brown ◽  
Neil M. Iyengar
Keyword(s):  
Cell Signalling ◽  
Treatment Resistance ◽  
Tumour Microenvironment ◽  
Subsequent Increase ◽  
Treatment And Prevention ◽  
Cancer Pathogenesis ◽  
Diet And Exercise ◽  
Systemic Factors ◽  
Tumour Vascularity ◽  
Obesity And Cancer

AbstractObesity is a risk factor for at least 13 different types of cancer, many of which are hormonally driven, and is associated with increased cancer incidence and morbidity. Adult obesity rates are steadily increasing and a subsequent increase in cancer burden is anticipated. Obesity-related dysfunction can contribute to cancer pathogenesis and treatment resistance through various mechanisms, including those mediated by insulin, leptin, adipokine, and aromatase signalling pathways, particularly in women. Furthermore, adiposity-related changes can influence tumour vascularity and inflammation in the tumour microenvironment, which can support tumour development and growth. Trials investigating non-pharmacological approaches to target the mechanisms driving obesity-mediated cancer pathogenesis are emerging and are necessary to better appreciate the interplay between malignancy, adiposity, diet and exercise. Diet, exercise and bariatric surgery are potential strategies to reverse the cancer-promoting effects of obesity; trials of these interventions should be conducted in a scientifically rigorous manner with dose escalation and appropriate selection of tumour phenotypes and have cancer-related clinical and mechanistic endpoints. We are only beginning to understand the mechanisms by which obesity effects cell signalling and systemic factors that contribute to oncogenesis. As the rates of obesity and cancer increase, we must promote the development of non-pharmacological lifestyle trials for the treatment and prevention of malignancy.

scholarly journals Strategies for the Development of pH-Responsive Synthetic Polypeptides and Polymer-Peptide Hybrids: Recent Advancements

Polymers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 624
Author(s):  
Cintya Dharmayanti ◽  
Todd A. Gillam ◽  
Manuela Klingler-Hoffmann ◽  
Hugo Albrecht ◽  
Anton Blencowe
Keyword(s):  
Functional Groups ◽  
Hybrid Materials ◽  
Tumour Microenvironment ◽  
The Body ◽  
Supramolecular Interactions ◽  
Biological Interactions ◽  
Ph Responsive ◽  
Form Complex ◽  
Synthetic Polypeptides ◽  
External Stimuli

Synthetic polypeptides and polymer-peptide hybrid materials have been successfully implemented in an array of biomedical applications owing to their biocompatibility, biodegradability and ability to mimic natural proteins. In addition, these materials have the capacity to form complex supramolecular structures, facilitate specific biological interactions, and incorporate a diverse selection of functional groups that can be used as the basis for further synthetic modification. Like conventional synthetic polymers, polypeptide-based materials can be designed to respond to external stimuli (e.g., light and temperature) or changes in the environmental conditions (e.g., redox reactions and pH). In particular, pH-responsive polypeptide-based systems represent an interesting avenue for the preparation of novel drug delivery systems that can exploit physiological or pathological pH variations within the body, such as those that arise in the extracellular tumour microenvironment, intracellularly within endosomes/lysosomes, or during tissue inflammation. Here, we review the significant progress made in advancing pH-responsive polypeptides and polymer-peptide hybrid materials during the last five years, with a particular emphasis on the manipulation of ionisable functional groups, pH-labile linkages, pH-sensitive changes to secondary structure, and supramolecular interactions.

scholarly journals Neuroprotective and anti-ageing role of leptin

2012 ◽  
Vol 49 (3) ◽  
pp. R149-R156 ◽  
Author(s):  
Jaume Folch ◽  
Ignacio Pedrós ◽  
Iván Patraca ◽  
Francesc Sureda ◽  
Fèlix Junyent ◽  
...  
Keyword(s):  
Cognitive Process ◽  
Memory Loss ◽  
The Body ◽  
Physiological Effects ◽  
Systematic Exploration ◽  
Major Interest ◽  
Long Form ◽  
Key Pathways ◽  
Primary Risk Factor

Leptin (Lep), an adipose-derived hormone, exerts very important functions in the body mainly on energy storage and availability. The physiological effects of Lep controlling the body weight and suppressing appetite are mediated by the long form of Lep receptor in the hypothalamus. Lep receptor activates several downstream molecules involved in key pathways related to cell survival such as STAT3, PI3K, MAPK, AMPK, CDK5 and GSK3β. Collectively, these pathways act in a coordinated manner and form a network that is fully involved in Lep physiological response. Although the major interest in Lep is related to its role in the regulation of energy balance, and since resistance to Lep affects is the primary risk factor for obesity, the interest on their effects on brain cognition and neuroprotection is increasing. Thus, Lep and Lep mimetic compounds now await and deserve systematic exploration as the orchestrator of protective responses in the nervous system. Moreover, Lep might promote the activation of a cognitive process that may retard or even partially reverse selected aspects of Alzheimer's disease or ageing memory loss.

scholarly journals Clostridial Spores for Cancer Therapy: Targeting Solid Tumour Microenvironment

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Brittany Umer ◽  
David Good ◽  
Jozef Anné ◽  
Wei Duan ◽  
Ming Q. Wei
Keyword(s):  
Cancer Therapy ◽  
Solid Tumour ◽  
Early Stage ◽  
Treatment Options ◽  
Anaerobic Bacteria ◽  
Past Research ◽  
Tumour Microenvironment ◽  
The Body ◽  
Solid Tumours ◽  
Current Status

Solid tumour accounts for 90% of all cancers. The current treatment approach for most solid tumours is surgery, however it is limited to early stage tumours. Other treatment options such as chemotherapy and radiotherapy are non-selective, thus causing damage to both healthy and cancerous tissue. Past research has focused on understanding tumour cells themselves, and conventional wisdom has aimed at targeting these cells directly. Recent research has shifted towards understanding the tumour microenvironment and it’s differences from that of healthy cells/tissues in the body and then to exploit these differences for treatmeat of the tumour. One such approach is utilizing anaerobic bacteria. Several strains of bacteria have been shown to selectively colonize in solid tumours, making them valuable tools for selective tumour targeting and destruction. Amongst them, the anaerobicClostridiumhas shown great potential in penetration and colonization of the hypoxic and necrotic areas of the tumour microenvironment, causing significant oncolysis as well as enabling the delivery of therapeutics directly to the tumourin situ. Various strategies utilizingClostridiumare currently being investigated, and represent a novel area of emerging cancer therapy. This review provides an update review of tumour microenvironment as well as summary of the progresses and current status of Clostridial spore-based cancer therapies.

scholarly journals Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer

Gut ◽  
2018 ◽  
Vol 68 (4) ◽  
pp. 693-707 ◽  
Author(s):  
Delphine Goehrig ◽  
Jérémy Nigri ◽  
Rémi Samain ◽  
Zhichong Wu ◽  
Paola Cappello ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumour Growth ◽  
Matrix Protein ◽  
Immune Escape ◽  
Interaction Mechanism ◽  
Tumour Microenvironment ◽  
Extracellular Matrix Protein ◽  
Ductal Adenocarcinoma ◽  
The Impact

ObjectivePancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer.DesignWe performed studies with p48-Cre;KrasG12D, pdx1-Cre;KrasG12D;Ink4a/Arffl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy.ResultsWe identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment.ConclusionsOur data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer.

scholarly journals A chemo-mechano-biological formulation for the effects of biochemical alterations on arterial mechanics: the role of molecular transport and multiscale tissue remodelling

2017 ◽  
Vol 14 (136) ◽  
pp. 20170615 ◽  
Author(s):  
Michele Marino ◽  
Giuseppe Pontrelli ◽  
Giuseppe Vairo ◽  
Peter Wriggers
Keyword(s):  
Arterial Compliance ◽  
Cell Signalling ◽  
Molecular Transport ◽  
Protective Role ◽  
Tissue Remodelling ◽  
Arterial Mechanics ◽  
Biochemical Alterations ◽  
Hierarchical Arrangement ◽  
Healing Phase

This paper presents a chemo-mechano-biological framework for arterial physiopathology. The model accounts for the fine remodelling in the multiscale hierarchical arrangement of tissue constituents and for the diffusion of molecular species involved in cell–cell signalling pathways. Effects in terms of alterations in arterial compliance are obtained. A simple instructive example is introduced. Although oversimplified with respect to realistic case studies, the proposed application mimics the biochemical activity of matrix metalloproteinases, transforming growth factors beta and interleukins on tissue remodelling. Effects of macrophage infiltration, of intimal thickening and of a healing phase are investigated, highlighting the corresponding influence on arterial compliance. The obtained results show that the present approach is able to capture changes in arterial mechanics as a consequence of the alterations in tissue biochemical environment and cellular activity, as well as to incorporate the protective role of both autoimmune responses and pharmacological treatments.

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