scholarly journals Regulation of Extracellular Matrix Production in Activated Fibroblasts: Roles of Amino Acid Metabolism in Collagen Synthesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Emily J. Kay ◽  
Grigorios Koulouras ◽  
Sara Zanivan
Keyword(s):  
Extracellular Matrix ◽  
Tumour Growth ◽  
Acid Metabolism ◽  
Tumour Progression ◽  
Tumour Microenvironment ◽  
Cancer Associated Fibroblasts ◽  
Secretory Phenotype ◽  
Matrix Production ◽  
Activated Fibroblasts ◽  
Translational Level

Cancer associated fibroblasts (CAFs) are a major component of the tumour microenvironment in most tumours, and are key mediators of the response to tissue damage caused by tumour growth and invasion, contributing to the observation that tumours behave as ‘wounds that do not heal’. CAFs have been shown to play a supporting role in all stages of tumour progression, and this is dependent on the highly secretory phenotype CAFs develop upon activation, of which extracellular matrix (ECM) production is a key element. A collagen rich, stromal ECM has been shown to influence tumour growth and metastasis, exclude immune cells and impede drug delivery, and is associated with poor prognosis in many cancers. CAFs also extensively remodel their metabolism to support cancer cells, however, it is becoming clear that metabolic rewiring also supports intrinsic functions of activated fibroblasts, such as increased ECM production. In this review, we summarise how fibroblasts metabolically regulate ECM production, focussing on collagen production, at the transcriptional, translational and post-translational level, and discuss how this can provide possible strategies for effectively targeting CAF activation and formation of a tumour-promoting stroma.

scholarly journals Metabolism in tumour-associated macrophages: a quid pro quo with the tumour microenvironment

2020 ◽  
Vol 29 (157) ◽  
pp. 200134
Author(s):  
Xiang Zheng ◽  
Siavash Mansouri ◽  
Annika Krager ◽  
Friedrich Grimminger ◽  
Werner Seeger ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Acid Metabolism ◽  
Environmental Changes ◽  
Tumour Progression ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Metabolic Reprogramming ◽  
High Plasticity ◽  
Functional Alteration

Lung cancer is the leading cause of death from cancer worldwide. Recent studies demonstrated that the tumour microenvironment (TME) is pivotal for tumour progression, providing multiple targeting opportunities for therapeutic strategies. As one of the most abundant stromal cell types in the TME, tumour-associated macrophages (TAMs) exhibit high plasticity. Malignant cells alter their metabolic profiles to adapt to the limited availability of oxygen and nutrients in the TME, resulting in functional alteration of TAMs. The metabolic features of TAMs are strongly associated with their functional plasticity, which further impacts metabolic profiling in the TME and contributes to tumourigenesis and progression. Here, we review the functional determination of the TME by TAM metabolic alterations, including glycolysis as well as fatty acid and amino acid metabolism, which in turn are influenced by environmental changes. Additionally, we discuss metabolic reprogramming of TAMs to a tumouricidal phenotype as a potential antitumoural therapeutic strategy.

scholarly journals Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ute Jungwirth ◽  
Antoinette van Weverwijk ◽  
Rachel J. Evans ◽  
Liam Jenkins ◽  
David Vicente ◽  
...  
Keyword(s):  
Normal Mouse ◽  
Tumour Growth ◽  
Tumour Microenvironment ◽  
Phenotypic Heterogeneity ◽  
Cancer Associated Fibroblasts ◽  
Cancer Associated Fibroblast ◽  
Functional Characterisation ◽  
Genetic Deletion ◽  
Insight Into

AbstractProfiling studies have revealed considerable phenotypic heterogeneity in cancer-associated fibroblasts (CAFs) present within the tumour microenvironment, however, functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations. Here we show that genetic deletion of the Endo180 (MRC2) receptor, predominantly expressed by a population of matrix-remodelling CAFs, profoundly limits tumour growth and metastasis; effects that can be recapitulated in 3D co-culture assays. This impairment results from a CAF-intrinsic contractility defect and reduced CAF viability, which coupled with the lack of phenotype in the normal mouse, demonstrates that upregulated Endo180 expression by a specific, potentially targetable CAF subset is required to generate a supportive tumour microenvironment. Further, characterisation of a tumour subline selected via serial in vivo passage for its ability to overcome these stromal defects provides important insight into, how tumour cells adapt to a non-activated stroma in the early stages of metastatic colonisation.

scholarly journals Metabolic control of tumour extracellular matrix production in cancer-associated fibroblasts

2020 ◽  
Author(s):  
Emily J Kay ◽  
Karla Paterson ◽  
David Sumpton ◽  
Ekaterina Stepanova ◽  
Claudia Boldrini ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Metabolic Control ◽  
Pyruvate Dehydrogenase ◽  
Tumour Progression ◽  
Pyruvate Dehydrogenase Complex ◽  
Epigenetic Reprogramming ◽  
Pyruvate Dehydrogenase Kinase ◽  
Cancer Associated Fibroblasts ◽  
Histone Acetyl Transferase ◽  
Cancer Aggressiveness

AbstractThe extracellular matrix (ECM) is the central driver of the desmoplastic reaction that fosters cancer aggressiveness. Cancer associated fibroblasts (CAFs) are the major source of ECM in tumours, thus being the optimal target to limit deposition of pro-tumourigenic ECM to oppose cancer. CAFs are metabolically active cells, however, how they support the biosynthetic requirements of producing ECM, and whether this can be targeted to influence tumour progression has not been investigated. We found that the pyruvate dehydrogenase kinase 2 (PDK2), a major inhibitor of the pyruvate dehydrogenase complex (PDC), is highly downregulated in CAFs and in the tumour stroma, when compared to normal fibroblasts. As consequence, PDC is more activated and generates acetyl-CoA, which elicits an epigenetic reprogramming through the histone acetyl transferase P300/CBP. This epigenetic reprogramming drives increased ECM production through increasing transcription of collagen genes and proline synthesis. We found that increased proline availability is necessary to support the biosynthetic requirements that follow the epigenetic reprogramming, for the translation of collagen to make abundant ECM. Targeting the rate-limiting enzyme for proline synthesis, pyrroline-5-carboxylate reductase 1 (PYCR1), in CAFs was sufficient to limit collagen deposition and hamper tumour growth. In conclusion, ECM production in CAFs is under strict metabolic control, and our results warrant considering targeting proline synthesis to normalise ECM production in tumours and possibly other diseases involving collagen production, such as fibrosis.

Anti-neoplastic action of aspirin against a T-cell lymphoma involves an alteration in the tumour microenvironment and regulation of tumour cell survival

2011 ◽  
Vol 32 (1) ◽  
pp. 91-104 ◽  
Author(s):  
Anjani Kumar ◽  
Naveen Kumar Vishvakarma ◽  
Abhishek Tyagi ◽  
Alok Chandra Bharti ◽  
Sukh Mahendra Singh
Keyword(s):  
T Cell ◽  
Growth Factor ◽  
Cell Survival ◽  
Tumour Cell ◽  
Tumour Growth ◽  
Cell Lymphoma ◽  
Tumour Progression ◽  
Tumour Microenvironment ◽  
T Cell Lymphoma ◽  
Tumour Bearing

The present study explores the potential of the anti-neoplastic action of aspirin in a transplantable murine tumour model of a spontaneously originated T-cell lymphoma designated as Dalton's lymphoma. The antitumour action of aspirin administered to tumour-bearing mice through oral and/or intraperitoneal (intratumoral) routes was measured via estimation of survival of tumour-bearing mice, tumour cell viability, tumour progression and changes in the tumour microenvironment. Intratumour administration of aspirin examined to assess its therapeutic potential resulted in retardation of tumour progression in tumour-bearing mice. Oral administration of aspirin to mice as a prophylactic measure prior to tumour transplantation further primed the anti-neoplastic action of aspirin administered at the tumour site. The anti-neoplastic action of aspirin was associated with a decline in tumour cell survival, augmented induction of apoptosis and nuclear shrinkage. Tumour cells of aspirin-treated mice were found arrested in G0/G1 phase of the cell cycle and showed nuclear localization of cyclin B1. Intratumoral administration of aspirin was accompanied by alterations in the biophysical, biochemical and immunological composition of the tumour microenvironment with respect to pH, level of dissolved O2, glucose, lactate, nitric oxide, IFNγ (interferon γ), IL-4 (interleukin-4), IL-6 and IL-10, whereas the TGF-β (tumour growth factor-β) level was unaltered. Tumour cells obtained from aspirin-treated tumour-bearing mice demonstrated an altered expression of pH regulators monocarboxylate transporter-1 and V-ATPase along with alteration in the level of cell survival regulatory molecules such as survivin, vascular endothelial growth factor, heat-shock protein 70, glucose transporter-1, SOCS-5 (suppressor of cytokine signalling-5), HIF-1α (hypoxia-inducible factor-1α) and PUMA (p53 up-regulated modulator of apoptosis). The study demonstrates a possible indirect involvement of the tumour microenvironment in addition to a direct but limited anti-neoplastic action of aspirin in the retardation of tumour growth.

scholarly journals Cancer-Associated Fibroblasts: Implications for Cancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3526
Author(s):  
Ana Maia ◽  
Stefan Wiemann
Keyword(s):  
Patient Outcome ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Tumour Progression ◽  
Therapy Response ◽  
Tumour Microenvironment ◽  
Response To Therapy ◽  
Cancer Associated Fibroblasts ◽  
Cell Type

Tumour cells do not exist as an isolated entity. Instead, they are surrounded by and closely interact with cells of the environment they are emerged in. The tumour microenvironment (TME) is not static and several factors, including cancer cells and therapies, have been described to modulate several of its components. Fibroblasts are key elements of the TME with the capacity to influence tumour progression, invasion and response to therapy, which makes them attractive targets in cancer treatment. In this review, we focus on fibroblasts and their numerous roles in the TME with a special attention to recent findings describing their heterogeneity and role in therapy response. Furthermore, we explore how different therapies can impact these cells and their communication with cancer cells. Finally, we highlight potential strategies targeting this cell type that can be employed for improving patient outcome.

scholarly journals Diet, lipids, and antitumor immunity

2022 ◽  
Author(s):  
Hannah Prendeville ◽  
Lydia Lynch
Keyword(s):  
Lipid Metabolism ◽  
Tumour Growth ◽  
Therapeutic Potential ◽  
Tumour Progression ◽  
Tumour Microenvironment ◽  
Dietary Lipids ◽  
Metabolic Adaptation ◽  
Cancer Therapies ◽  
Lipid Uptake ◽  
The Relationship

AbstractTumour growth and dissemination is largely dependent on nutrient availability. It has recently emerged that the tumour microenvironment is rich in a diverse array of lipids that increase in abundance with tumour progression and play a role in promoting tumour growth and metastasis. Here, we describe the pro-tumorigenic roles of lipid uptake, metabolism and synthesis and detail the therapeutic potential of targeting lipid metabolism in cancer. Additionally, we highlight new insights into the distinct immunosuppressive effects of lipids in the tumour microenvironment. Lipids threaten an anti-tumour environment whereby metabolic adaptation to lipid metabolism is linked to immune dysfunction. Finally, we describe the differential effects of commondietary lipids on cancer growth which may uncover a role for specific dietary regimens in association with traditional cancer therapies. Understanding the relationship between dietary lipids, tumour, and immune cells is important in the context of obesity which may reveal a possibility to harness the diet in the treatment of cancers.

scholarly journals Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis

2020 ◽  
Author(s):  
Ute Jungwirth ◽  
Antoinette van Weverwijk ◽  
Liam Jenkins ◽  
John Alexander ◽  
David Vicente ◽  
...  
Keyword(s):  
Normal Mouse ◽  
Tumour Growth ◽  
Tumour Microenvironment ◽  
Phenotypic Heterogeneity ◽  
Cancer Associated Fibroblasts ◽  
Cancer Associated Fibroblast ◽  
Functional Characterisation ◽  
Genetic Deletion ◽  
Insight Into

AbstractProfiling studies have revealed considerable phenotypic heterogeneity in cancer-associated fibroblasts (CAFs) present within the tumour microenvironment, however, functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations. Here we show that genetic deletion of the Endo180 (MRC2) receptor, predominantly expressed by a population of matrix-remodelling CAFs, profoundly limits tumour growth and metastasis; effects that can be recapitulated in 3D co-culture assays. This impairment results from a CAF-intrinsic contractility defect and reduced CAF viability which, coupled with the lack of phenotype in the normal mouse, demonstrates that upregulated Endo180 expression by a specific, potentially targetable CAF subset is required to generate a supportive tumour microenvironment. Further, characterisation of a tumour subline selected via serial in vivo passage for its ability to overcome these stromal defects provides important insight into how tumour cells adapt to a non-activated stroma in the early stages of metastatic colonisation.

Ethanolic Extract of Algerian Propolis and Galangin Decreased Murine Melanoma Tumor Progression in Mice

2016 ◽  
Vol 16 (9) ◽  
pp. 1172-1183 ◽  
Author(s):  
Lamia Benguedouar ◽  
Mesbah Lahouel ◽  
Sophie C. Gangloff ◽  
Anne Durlach ◽  
Florent Grange ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Tumour Progression ◽  
Ethanolic Extract ◽  
Complementary Therapy ◽  
Melanoma Cells ◽  
Biological Properties ◽  
Therapeutic Treatment ◽  
Melanoma Tumor ◽  
Ki 67

Melanoma is the more dangerous skin cancer, and metastatic melanoma still carries poor prognosis. Despite recent therapeutic advances, prolonged survival remains rare and research is still required. Propolis extracts from many countries have attracted a great deal of attention for their biological properties. We here investigated the ability of an ethanolic extract of Algerian propolis (EEP) to control melanoma tumour growth when given to mice bearing B16F1melanoma tumour either as preventive or as therapeutic treatment. EEP given after tumour occurrence increased mice survival (+30%) and reduced tumour growth (-75%). This was associated with a decrease of the Mitotic Index (-75%) and of Ki-67 (-50%) expression. When given either before or both before and after tumour occurrence, EEP reduced tumour growth but without prolonging mice life. Isolation of B16F1 melanoma cells from resected tumour showed that preventive and curative EEP treatments reduced invasiveness by 55% and 40% respectively compared to control. Galangin, one of the most abundant flavonoids in propolis, significantly reduced the number of melanoma cells in vitro and induced autophagy/apoptosis dose dependently. In conclusion, we showed that EEP reduced melanoma tumour progression/dissemination and could extend mice lifespan when used as therapeutic treatment. Then, EEP may help patients with melanoma when used as a complementary therapy to classical treatment for which autophagy is not contraindicated.

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.

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