Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment

Tumors consist of a wide variety of cells, including immune cells, that affect tumor progression. Macrophages are abundant innate immune cells in the tumor microenvironment (TME) and are crucial in regulating tumorigenicity. Specific metabolic conditions in the TME can alter the phenotype of tumor-associated macrophages (TAMs) in a direction that supports their pro-tumor functions. One of these conditions is the accumulation of metabolites, also known as oncometabolites. Interactions of oncometabolites with TAMs can promote a pro-tumorigenic phenotype, thereby sustaining cancer cell growth and decreasing the chance of eradication. This review focuses on the metabolic cancer-macrophage crosstalk in the TME. We discuss how cancer cell metabolism and oncometabolites affect macrophage phenotype and function, and conversely how macrophage metabolism can impact tumor progression. Lastly, we propose tumor-secreted exosome-mediated metabolic signaling as a potential factor in tumorigenesis. Insight in these processes may contribute to the development of novel cancer therapies.

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Purinergic P2X7 Receptor: A Cation Channel Sensitive to Tumor Microenvironment

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892814666190116122256 ◽

2019 ◽

Vol 14 (1) ◽

pp. 32-38 ◽

Cited By ~ 5

Author(s):

Giorgia Scarpellino ◽

Tullio Genova ◽

Luca Munaron

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

P2x7 Receptor ◽

Purinergic Receptor ◽

Purinergic Signalling ◽

Cancer Therapies ◽

Cell Functions ◽

Anti Cancer ◽

Purinergic P2x7 Receptor ◽

And Function

Background: Purinergic signalling is involved in several physiological and pathophysiological processes. P2X7 Receptor (P2X7R) is a calcium-permeable ion channel that is gaining interest as a potential therapeutic target for the treatment of different diseases including inflammation, pain, psychiatric disorders and cancer. P2X7R is ubiquitously expressed and sensitive to high ATP levels, usually found in tumor microenvironment. P2X7R regulates several cell functions, from migration to cell death, but its selective contribution to tumor progression remains controversial.Objective:Current review was conducted to check involvement of P2X7R use in cancer treatment.Methods:We review the most recent patents focused on the use of P2X7R in the treatment of cancer.Results:P2X7R is an intriguing purinergic receptor that plays different roles in tumor progression.Conclusion:Powerful strategies able to selectively interfere with its expression and function should reveal helpful in the development of new anti-cancer therapies.

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When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen

International Journal of Cell Biology ◽

10.1155/2011/470597 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 16

Author(s):

Katrin Schlie ◽

Jaeline E. Spowart ◽

Luke R. K. Hughson ◽

Katelin N. Townsend ◽

Julian J. Lum

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Patient Treatment ◽

Low Oxygen ◽

Tumor Environment ◽

And Function ◽

The Impact

Hypoxia is a signature feature of growing tumors. This cellular state creates an inhospitable condition that impedes the growth and function of all cells within the immediate and surrounding tumor microenvironment. To adapt to hypoxia, cells activate autophagy and undergo a metabolic shift increasing the cellular dependency on anaerobic metabolism. Autophagy upregulation in cancer cells liberates nutrients, decreases the buildup of reactive oxygen species, and aids in the clearance of misfolded proteins. Together, these features impart a survival advantage for cancer cells in the tumor microenvironment. This observation has led to intense research efforts focused on developing autophagy-modulating drugs for cancer patient treatment. However, other cells that infiltrate the tumor environment such as immune cells also encounter hypoxia likely resulting in hypoxia-induced autophagy. In light of the fact that autophagy is crucial for immune cell proliferation as well as their effector functions such as antigen presentation and T cell-mediated killing of tumor cells, anticancer treatment strategies based on autophagy modulation will need to consider the impact of autophagy on the immune system.

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Interstitial flow promotes macrophage polarization toward an M2 phenotype

Molecular Biology of the Cell ◽

10.1091/mbc.e18-03-0164 ◽

2018 ◽

Vol 29 (16) ◽

pp. 1927-1940 ◽

Cited By ~ 22

Author(s):

Ran Li ◽

Jean Carlos Serrano ◽

Hao Xing ◽

Tara A. Lee ◽

Hesham Azizgolshani ◽

...

Keyword(s):

Fluid Flow ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Cancer Cell ◽

Interstitial Fluid ◽

Macrophage Polarization ◽

Interstitial Flow ◽

Interstitial Fluid Flow ◽

M2 Polarization ◽

Tumor Tissues

Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored. Here, we used three-dimensional biomimetic models to reveal that macrophages can sense and respond to pathophysiological levels of interstitial fluid flow reported in tumors (∼3 µm/s). Specifically, interstitial flow (IF) polarizes macrophages toward an M2-like phenotype via integrin/Src-mediated mechanotransduction pathways involving STAT3/6. Consistent with this flow-induced M2 polarization, macrophages treated with IF migrate faster and have an enhanced ability to promote cancer cell migration. Moreover, IF directs macrophages to migrate against the flow. Since IF emanates from the tumor to the surrounding stromal tissues, our results suggest that IF could not only induce M2 polarization of macrophages but also recruit these M2 macrophages toward the tumor masses, contributing to cancer cell invasion and tumor progression. Collectively, our study reveals that IF could be a critical regulator of tumor immune environment.

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The Neglected Liaison: Targeting Cancer Cell Metabolic Reprogramming Modifies the Composition of Non-Malignant Populations of the Tumor Microenvironment

Cancers ◽

10.3390/cancers13215447 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5447

Author(s):

Maria Iorio ◽

Nikkitha Umesh Ganesh ◽

Monica De Luise ◽

Anna Maria Porcelli ◽

Giuseppe Gasparre ◽

...

Keyword(s):

Complex System ◽

Clinical Trials ◽

Cancer Cell ◽

Immune Cells ◽

Cell Metabolism ◽

Metabolic Reprogramming ◽

Preclinical Studies ◽

Tumor Mass ◽

Cancer Cell Metabolism ◽

Target Cancer

Metabolic reprogramming is a well-known hallmark of cancer, whereby the development of drugs that target cancer cell metabolism is gaining momentum. However, when establishing preclinical studies and clinical trials, it is often neglected that a tumor mass is a complex system in which cancer cells coexist and interact with several types of microenvironment populations, including endothelial cells, fibroblasts and immune cells. We are just starting to understand how such populations are affected by the metabolic changes occurring in a transformed cell and little is known

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Author response: Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

10.7554/elife.10250.022 ◽

2015 ◽

Author(s):

Hongyun Zhao ◽

Lifeng Yang ◽

Joelle Baddour ◽

Abhinav Achreja ◽

Vincent Bernard ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Cell ◽

Cell Metabolism ◽

Author Response ◽

Cancer Cell Metabolism

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RASSF1A Suppresses Estrogen-Dependent Breast Cancer Cell Growth through Inhibition of the Yes-Associated Protein 1 (YAP1), Inhibition of the Forkhead Box Protein M1 (FOXM1), and Activation of Forkhead Box Transcription Factor 3A (FOXO3A)

Cancers ◽

10.3390/cancers12092689 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2689

Author(s):

Sven Roßwag ◽

Gitta Thiede ◽

Jonathan P. Sleeman ◽

Sonja Thaler

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Cell Growth ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Cell Growth ◽

Breast Cancer Cell Growth ◽

Forkhead Box ◽

Cancer Initiation ◽

And Function

The estrogen receptor alpha (ERα) is expressed by the majority of breast cancers and plays an important role in breast cancer development and tumor outgrowth. Although ERα is well known to be a specific and efficient therapeutic target, the molecular mechanisms that are responsible for the control of ERα expression and function in the context of breast cancer initiation and progression are complex and not completely elucidated. In previous work, we have demonstrated that the tumor suppressor RASSF1A inhibits ERα expression and function in ERα-positive breast cancer cells through an AKT-dependent mechanism. Transcriptional activators such as forkhead box protein M1 (FOXM1) and forkhead transcription factor 3A (FOXO3A) and signaling pathways such as the Hippo pathway are also known to modulate ERα expression and activity. Here we report that RASSF1A acts as an inhibitor of ERα-driven breast cancer cell growth through a complex, hierarchically organized network that initially involves suppression of the Hippo effector Yes-associated protein 1 (YAP1), which is followed by inhibition of AKT1 activity, increased FOXO3A activity as well as a blockade of FOXM1 and ERα expression. Together our findings provide important new mechanistic insights into how the loss of RASSF1A contributes to ERα+ breast cancer initiation and progression.

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Impact of the Tumor Microenvironment on Tumor Heterogeneity and Consequences for Cancer Cell Plasticity and Stemness

Cancers ◽

10.3390/cancers12123716 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3716

Author(s):

Ralf Hass ◽

Juliane von der Ohe ◽

Hendrik Ungefroren

Keyword(s):

Tumor Microenvironment ◽

Cancer Cell ◽

Tumor Heterogeneity ◽

Cancer Therapies ◽

Epigenetic Alterations ◽

Cell Plasticity ◽

Cellular Phenotypes ◽

Therapy Success ◽

Physical And Chemical

Tumor heterogeneity is considered the major cause of treatment failure in current cancer therapies. This feature of solid tumors is not only the result of clonal outgrowth of cells with genetic mutations, but also of epigenetic alterations induced by physical and chemical signals from the tumor microenvironment (TME). Besides fibroblasts, endothelial and immune cells, mesenchymal stroma/stem-like cells (MSCs) and tumor-associated macrophages (TAMs) intimately crosstalk with cancer cells and can exhibit both anti- and pro-tumorigenic effects. MSCs can alter cancer cellular phenotypes to increase cancer cell plasticity, eventually resulting in the generation of cancer stem cells (CSCs). The shift between different phenotypic states (phenotype switching) of CSCs is controlled via both genetic programs, such as epithelial-mesenchymal transdifferentiation or retrodifferentiation, and epigenetic alterations triggered by signals from the TME, like hypoxia, spatial heterogeneity or stromal cell-derived chemokines. Finally, we highlight the role of spontaneous cancer cell fusion with various types of stromal cells. i.e., MSCs in shaping CSC plasticity. A better understanding of cell plasticity and phenotype shifting in CSCs is a prerequisite for exploiting this phenomenon to reduce tumor heterogeneity, thereby improving the chance for therapy success.

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Tumor-Associated Neutrophils and Macrophages—Heterogenous but Not Chaotic

Frontiers in Immunology ◽

10.3389/fimmu.2020.553967 ◽

2020 ◽

Vol 11 ◽

Author(s):

Ling Wu ◽

Xiang H.-F. Zhang

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Cancer Cells ◽

Immune Cells ◽

Mutual Influence ◽

Therapeutic Resistance ◽

Tumor Associated Macrophages ◽

Tumor Associated Neutrophils ◽

Shed Light ◽

Lines Of Evidence

Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) have been extensively studied. Their pleotropic roles were observed in multiple steps of tumor progression and metastasis, and sometimes appeared to be inconsistent across different studies. In this review, we collectively discussed many lines of evidence supporting the mutual influence between cancer cells and TAMs/TANs. We focused on how direct interactions among these cells dictate co-evolution involving not only clonal competition of cancer cells, but also landscape shift of the entire tumor microenvironment (TME). This co-evolution may take distinct paths and contribute to the heterogeneity of cancer cells and immune cells across different tumors. A more in-depth understanding of the cancer-TAM/TAN co-evolution will shed light on the development of TME that mediates metastasis and therapeutic resistance.

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The Immune Endocannabinoid System of the Tumor Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms21238929 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8929

Author(s):

Melanie Kienzl ◽

Julia Kargl ◽

Rudolf Schicho

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Immune Cells ◽

Cannabinoid Receptors ◽

Immune Cell ◽

Tumor Development ◽

Endocannabinoid System ◽

Cell Functions ◽

In Vitro Effects

Leukocytes are part of the tumor microenvironment (TME) and are critical determinants of tumor progression. Because of the immunoregulatory properties of cannabinoids, the endocannabinoid system (ECS) may have an important role in shaping the TME. Members of the ECS, an entity that consists of cannabinoid receptors, endocannabinoids and their synthesizing/degrading enzymes, have been associated with both tumor growth and rejection. Immune cells express cannabinoid receptors and produce endocannabinoids, thereby forming an “immune endocannabinoid system”. Although in vitro effects of exogenous cannabinoids on immune cells are well described, the role of the ECS in the TME, and hence in tumor development and immunotherapy, is still elusive. This review/opinion discusses the possibility that the “immune endocannabinoid system” can fundamentally influence tumor progression. The widespread influence of cannabinoids on immune cell functions makes the members of the ECS an interesting target that could support immunotherapy.

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Immunometabolism at the Nexus of Cancer Therapeutic Efficacy and Resistance

Frontiers in Immunology ◽

10.3389/fimmu.2021.657293 ◽

2021 ◽

Vol 12 ◽

Author(s):

Javier Traba ◽

Michael N. Sack ◽

Thomas A. Waldmann ◽

Olga M. Anton

Keyword(s):

Immune System ◽

Immune Cells ◽

Immune Cell ◽

Cell Metabolism ◽

Immune Surveillance ◽

Antitumor Effects ◽

Cancer Management ◽

Immunosuppressive Tumor Microenvironment ◽

And Function ◽

Main Effects

Constitutive activity of the immune surveillance system detects and kills cancerous cells, although many cancers have developed strategies to avoid detection and to resist their destruction. Cancer immunotherapy entails the manipulation of components of the endogenous immune system as targeted approaches to control and destroy cancer cells. Since one of the major limitations for the antitumor activity of immune cells is the immunosuppressive tumor microenvironment (TME), boosting the immune system to overcome the inhibition provided by the TME is a critical component of oncotherapeutics. In this article, we discuss the main effects of the TME on the metabolism and function of immune cells, and review emerging strategies to potentiate immune cell metabolism to promote antitumor effects either as monotherapeutics or in combination with conventional chemotherapy to optimize cancer management.

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