Fibroblasts as Modulators of Local and Systemic Cancer Metabolism

Fibroblast activation is an accompanying feature of solid tumor progression, resembling a conserved host response to tissue damage. Cancer-associated fibroblasts (CAFs) comprise a heterogeneous and plastic population with increasingly appreciated roles in tumor growth, metastatic capacity, and response to therapy. Classical features of fibroblasts in a wound-healing response, including profound extracellular matrix production and cytokine release, are recapitulated in cancer. Emerging evidence suggests that fibroblastic cells in the microenvironments of solid tumors also critically modulate cellular metabolism in the neoplastic compartment through mechanisms including paracrine transfer of metabolites or non-cell-autonomous regulation of metabolic signaling pathways. These metabolic functions may represent common mechanisms by which fibroblasts stimulate growth of the regenerating epithelium during a wound-healing reaction, or may reflect unique co-evolution of cancer cells and surrounding stroma within the tumor microenvironment. Here we review the recent literature supporting an important role for CAFs in regulation of cancer cell metabolism, and relevant pathways that may serve as targets for therapeutic intervention.

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Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

Cancers ◽

10.3390/cancers13030396 ◽

2021 ◽

Vol 13 (3) ◽

pp. 396

Author(s):

Timon A. Bloedjes ◽

Guus de Wilde ◽

Jeroen E. J. Guikema

Keyword(s):

Multiple Myeloma ◽

Cell Metabolism ◽

Chromosomal Rearrangements ◽

Chromosomal Translocations ◽

Metabolic Effects ◽

Aberrant Expression ◽

Metabolic Functions ◽

Complex Chromosomal Rearrangements ◽

Cancer Cell Metabolism ◽

The Many

Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells.

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Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism

Redox Biology ◽

10.1016/j.redox.2017.04.018 ◽

2017 ◽

Vol 12 ◽

pp. 833-842 ◽

Cited By ~ 66

Author(s):

Balaraman Kalyanaraman

Keyword(s):

Cancer Cell ◽

Cancer Metabolism ◽

Cell Metabolism ◽

Cancer Cell Metabolism

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WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

Molecular and Cellular Biology ◽

10.1128/mcb.00992-14 ◽

2014 ◽

Vol 35 (1) ◽

pp. 2-10 ◽

Cited By ~ 83

Author(s):

Victoria Sherwood

Keyword(s):

Wnt Signaling ◽

Signaling Pathways ◽

Cancer Cell ◽

Cancer Metabolism ◽

Cell Metabolism ◽

Critical Role ◽

Oncogenic Signaling ◽

Cancer Cell Metabolism ◽

Oncogenic Signaling Pathways

WNT signaling was discovered in tumor models and has been recognized as a regulator of cancer development and progression for over 3 decades. Recent work has highlighted a critical role for WNT signaling in the metabolic homeostasis of mammals, where its misregulation has been heavily implicated in diabetes. While the majority of WNT metabolism research has focused on nontransformed tissues, the role of WNT in cancer metabolism remains underinvestigated. Cancer is also a metabolic disease where oncogenic signaling pathways regulate energy production and macromolecular synthesis to fuel rapidly proliferating tumors. This review highlights the emerging evidence for WNT signaling in the reprogramming of cancer cell metabolism and examines the role of these signaling pathways as mediators of tumor bioenergetics.

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Metabolic functions of macropinocytosis

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2018.0285 ◽

2018 ◽

Vol 374 (1765) ◽

pp. 20180285 ◽

Cited By ~ 10

Author(s):

Wilhelm Palm

Keyword(s):

Growth Factor ◽

Cancer Cells ◽

Nutrient Uptake ◽

Mammalian Cells ◽

Cancer Metabolism ◽

Cell Metabolism ◽

Extracellular Fluid ◽

Metabolic Functions ◽

Evolutionarily Conserved ◽

Growth Factor Signalling

Macropinocytosis is an evolutionarily conserved form of endocytosis that mediates non-selective uptake of extracellular fluid and the solutes contained therein. In mammalian cells, macropinocytosis is initiated by growth factor-mediated activation of the Ras and PI3-kinase signalling pathways. In malignant cells, oncogenic activation of growth factor signalling sustains macropinocytosis cell autonomously. Recent studies of cancer metabolism, discussed here, have begun to define a role for macropinocytosis as a nutrient uptake route. Macropinocytic cancer cells ingest macromolecules in bulk and break them down in the lysosome to support metabolism and macromolecular synthesis. Thereby, macropinocytosis allows cells to tap into the copious nutrient stores of extracellular macromolecules when canonical nutrients are scarce. These findings demonstrate that macropinocytosis promotes metabolic flexibility and resilience, which enables cancer cells to survive and grow in nutrient-poor environments. Implications for physiological roles of growth factor-stimulated macropinocytosis in cell metabolism and its relationship with other nutrient uptake pathways are considered. This article is part of the Theo Murphy meeting issue ‘Macropinocytosis’.

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Therapeutic Targeting of Cancer Cell Metabolism in Lymphoid Neoplasia

Blood ◽

10.1182/blood.v118.21.sci-27.sci-27 ◽

2011 ◽

Vol 118 (21) ◽

pp. SCI-27-SCI-27

Author(s):

Chi Van Dang

Keyword(s):

Cancer Metabolism ◽

Cell Metabolism ◽

Biomass Accumulation ◽

Tca Cycle ◽

Glutamine Metabolism ◽

Myc Oncogene ◽

Xenograft Growth ◽

The Tca Cycle ◽

Cancer Cell Metabolism ◽

The Warburg Effect

Abstract Abstract SCI-27 The MYC oncogene plays a pivotal role in human lymphoid neoplasias, specifically in lymphomas and acute leukemias, which are characterized by altered glucose metabolism, termed the Warburg effect. The Warburg effect or elevated conversion glucose to lactate by cancer cells has been a prevailing model of cancer metabolism. Since the 1980’s, genetic alterations of oncogenes and tumor suppressors have provided insights into tumorigenesis. However, whether metabolism contributes to tumorigenesis was highly debated. In 1997, we reported that the MYC oncogene product, the Myc transcription factor, regulates the lactate dehydrogenase A (LDHA)gene. Myc also activates many glycolytic enzymes, mitochondrial biogenesis, and glutamine metabolism by inducing glutaminase (GLS) and glutamine transporters, thereby providing not only ATP through the TCA cycle but also anapleurotic building blocks. Myc also induces biomass accumulation by stimulating ribosomal biogenesis. It stimulates the cell cycle machinery and DNA replication. Deregulated MYC in cancer results in enforced biomass accumulation, such that cell death occurs when bioenergetic demands exceed nutrient availability. In this regard, we have exploited this conceptual framework and targeted LDHA and GLS with small molecular inhibitors as proof-of- concept that altered cancer metabolism could be targeted for cancer therapy. Specifically, we documented that a drug-like inhibitor of LDHA could decreased tumor xenograft growth, providing evidence that metabolic therapy is feasible. We further found in a human Burkitt lymphoma model that Myc induces a genetic program that drives glutamine metabolism both under aerobic and hypoxic conditions. Inhibition of glutaminase, which converts glutamine to glutamate for its catabolism by the TCA cycle, by a drug-like molecule also diminished lymphoma xenograft growth in vivo. These studies indicate that targeting cancer cell metabolism could constitute a novel strategy to treat lymphoid neoplasias. Disclosures: Dang: Agios Pharmaceuticals, Inc.: Consultancy, Honoraria.

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Healing gone wrong: convergence of hemostatic pathways and liver fibrosis?

Clinical Science ◽

10.1042/cs20191102 ◽

2020 ◽

Vol 134 (16) ◽

pp. 2189-2201

Author(s):

Jessica P.E. Davis ◽

Stephen H. Caldwell

Keyword(s):

Wound Healing ◽

Liver Disease ◽

Hepatic Fibrosis ◽

Cell Activation ◽

Stellate Cell ◽

Factor Xa ◽

Clinical Trial Data ◽

Chronic Liver ◽

Healing Response ◽

Wound Healing Response

Abstract Fibrosis results from a disordered wound healing response within the liver with activated hepatic stellate cells laying down dense, collagen-rich extracellular matrix that eventually restricts liver hepatic synthetic function and causes increased sinusoidal resistance. The end result of progressive fibrosis, cirrhosis, is associated with significant morbidity and mortality as well as tremendous economic burden. Fibrosis can be conceptualized as an aberrant wound healing response analogous to a chronic ankle sprain that is driven by chronic liver injury commonly over decades. Two unique aspects of hepatic fibrosis – the chronic nature of insult required and the liver’s unique ability to regenerate – give an opportunity for pharmacologic intervention to stop or slow the pace of fibrosis in patients early in the course of their liver disease. Two potential biologic mechanisms link together hemostasis and fibrosis: focal parenchymal extinction and direct stellate cell activation by thrombin and Factor Xa. Available translational research further supports the role of thrombosis in fibrosis. In this review, we will summarize what is known about the convergence of hemostatic changes and hepatic fibrosis in chronic liver disease and present current preclinical and clinical data exploring the relationship between the two. We will also present clinical trial data that underscores the potential use of anticoagulant therapy as an antifibrotic factor in liver disease.

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