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Cells
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Metabolic Interactions in Tumor Microenvironment (TME)
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Metabolic Interactions in Tumor Microenvironment (TME)

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 23543

Special Issue Editor

Dr. Roberta Pastorelli

E-Mail Website
Guest Editor
Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
Interests: mass spectrometry-based proteomics and metabolomics; metabolic reprogramming; proteins and metabolites signatures in human diseases; biomarkers

Special Issue Information

Dear Colleagues,

 

Metabolic reprogramming is now well established as one of the hallmarks of cancer. While early studies focused mainly on the metabolic processes within a cancer cell (e.g., driven by oncogenic lesions, an epigenetic state), recent approaches also consider the impact of metabolic cross-talk between different cell types within the tumor.

 

The interaction of cancer cells with stromal and infiltrating immune cells appears to have a tremendous impact on disease progression, patient survival and therapy efficacy.

 

The network of stromal, immune, and malignant cells creates a complex tumor microenvironment (TME), which consists of mechanical stimuli, non-malignant cell-cancer cell interactions, soluble signals, and the extracellular matrix.

 

Indeed, metabolic coupling between cancer and stromal cells is known to provide essential nutrients that support cancer cell growth and survival. As such, environmental nutrient availability acts as a regulator of cancer cell metabolism. Only recently, it has been shown that nutrient differences between standard cell culture,  primary cell culture, and animal tumor models can drive substantial changes in cancer cell metabolism that alter the response of cancer cells to metabolically targeted drugs.

Recent insights from immunometabolism research indicate that most immune cells employ specific metabolic reprogramming mechanisms to bioenergetically adapt while polarizing into various activation/effector states and reveal that tumor cells can utilize different metabolic strategies for immune evasion (e.g., metabolic competition, excessive secretion of by-products metabolites), creating a hostile metabolic environment for immune cells.

 

Although our understanding of cancer metabolic rewiring has considerably progressed, much remains to be learned on the heterocellular interactions that shape the metabolic nature of the TME to support tumor growth and evade immune destruction.

 

Furthermore, the complex nature of heterocellular communication within tumors warrants a reconsideration of the models being used to study tumor metabolism, in order to understand and therapeutically target cancer cell metabolism.

 

From this perspective, the purpose of this Special Issue is to gather reports (reviews and research articles) on the remodeling of the TME that leads to pathophysiologic interactions that are influenced and shaped by metabolism. Novel approaches for targeting metabolic activities in TME may hold additional promise by synergizing with existing targeted therapies in eliminating cancer cells.

 

We hope that this Special Issue will serve as a platform for the exchange of new ideas and that will be of help in elucidating the metabolic role of the TME and associated therapeutic vulnerabilities. 

Dr. Roberta Pastorelli
Guest Editor

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Keywords

  • tumor microenvironment (TME)
  • cancer cell metabolism
  • immunometabolism
  • inflammation
  • metabolites
  • tumor–stroma metabolic interactions
  • models for TME studies
  • targeting the TME

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Published Papers (5 papers)

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Research

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17 pages, 2040 KiB  
Article
Inhibition of Metabolism as a Therapeutic Option for Tamoxifen-Resistant Breast Cancer Cells
by Friederike Steifensand, Julia Gallwas, Gerd Bauerschmitz and Carsten Gründker
Cells 2021, 10(9), 2398; https://doi.org/10.3390/cells10092398 - 12 Sep 2021
Cited by 9 | Viewed by 3421
Abstract
Cancer cells have an increased need for glucose and, despite aerobic conditions, obtain their energy through aerobic oxidation and lactate fermentation, instead of aerobic oxidation alone. Glutamine is an essential amino acid in the human body. Glutaminolysis and glycolysis are crucial for cancer [...] Read more.
Cancer cells have an increased need for glucose and, despite aerobic conditions, obtain their energy through aerobic oxidation and lactate fermentation, instead of aerobic oxidation alone. Glutamine is an essential amino acid in the human body. Glutaminolysis and glycolysis are crucial for cancer cell survival. In the therapy of estrogen receptor α (ERα)-positive breast cancer (BC), the focus lies on hormone sensitivity targeting therapy with selective estrogen receptor modulators (SERMs) such as 4-hydroxytamoxifen (4-OHT), although this therapy is partially limited by the development of resistance. Therefore, further targets for therapy improvement of ERα-positive BC with secondary 4-OHT resistance are needed. Hence, increased glucose requirement and upregulated glutaminolysis in BC cells could be used. We have established sublines of ERα-positive MCF7 and T47D BC cells, which were developed to be resistant to 4-OHT. Further, glycolysis inhibitor 2-Deoxy-D-Glucose (2-DG) and glutaminase inhibitor CB-839 were analyzed. Co-treatments using 4-OHT and CB-839, 2-DG and CB-839, or 4-OHT, 2-DG and CB-839, respectively, showed significantly stronger inhibitory effects on viability compared to single treatments. It could be shown that tamoxifen-resistant BC cell lines, compared to the non-resistant cell lines, exhibited a stronger reducing effect on cell viability under co-treatments. In addition, the tamoxifen-resistant BC cell lines showed increased expression of proto-oncogene c-Myc compared to the parental cell lines. This could be reduced depending on the treatment. Suppression of c-Myc expression using specific siRNA completely abolished resistance to 4OH-tamoxifen. In summary, our data suggest that combined treatments affecting the metabolism of BC are suitable depending on the cellularity and resistance status. In addition, the anti-metabolic treatments affected the expression of the proto-oncogene c-Myc, a key player in the regulation of cancer cell metabolism. Full article
(This article belongs to the Special Issue Metabolic Interactions in Tumor Microenvironment (TME))
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13 pages, 1625 KiB  
Article
Treatment with Cyclic AMP Activators Reduces Glioblastoma Growth and Invasion as Assessed by Two-Photon Microscopy
by Krista Minéia Wartchow, Benjamin Schmid, Philipp Tripal, Andreas Stadlbauer, Michael Buchfelder, Carlos-Alberto Gonçalves and Andrea Kleindienst
Cells 2021, 10(3), 556; https://doi.org/10.3390/cells10030556 - 4 Mar 2021
Cited by 5 | Viewed by 2510
Abstract
(1) Background: Despite progress in surgery and radio-chemotherapy of glioblastoma (GB), the prognosis remains very poor. GB cells exhibit a preference for hypoxia to maintain their tumor-forming capacity. Enhancing oxidative phosphorylation—known as the anti-Warburg effect—with cyclic AMP activators has been demonstrated to drive [...] Read more.
(1) Background: Despite progress in surgery and radio-chemotherapy of glioblastoma (GB), the prognosis remains very poor. GB cells exhibit a preference for hypoxia to maintain their tumor-forming capacity. Enhancing oxidative phosphorylation—known as the anti-Warburg effect—with cyclic AMP activators has been demonstrated to drive GB cells from proliferation to differentiation thereby reducing tumor growth in a cell culture approach. Here we re-evaluate this treatment in a more clinically relevant model. (2) Methods: The effect of treatment with dibutyryl cyclic AMP (dbcAMP, 1 mM) and the cAMP activator forskolin (50µM) was assessed in a GB cell line (U87GFP+, 104 cells) co-cultured with mouse organotypic brain slices providing architecture and biochemical properties of normal brain tissue. Cell viability was determined by propidium-iodide, and gross metabolic effects were excluded in the extracellular medium. Tumor growth was quantified in terms of area, volume, and invasion at the start of culture, 48 h, 7 days, and 14 days after treatment. (3) Results: The tumor area was significantly reduced following dbcAMP or forskolin treatment (F2,249 = 5.968, p = 0.0029). 3D volumetric quantification utilizing two-photon fluorescence microscopy revealed that the treated tumors maintained a spheric shape while the untreated controls exhibited the GB typical invasive growth pattern. (4) Conclusions: Our data demonstrate that treatment with a cAMP analog/activator reduces GB growth and invasion. Full article
(This article belongs to the Special Issue Metabolic Interactions in Tumor Microenvironment (TME))
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Review

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22 pages, 2801 KiB  
Review
Metabolic Implications of Immune Checkpoint Proteins in Cancer
by Elizabeth R. Stirling, Steven M. Bronson, Jessica D. Mackert, Katherine L. Cook, Pierre L. Triozzi and David R. Soto-Pantoja
Cells 2022, 11(1), 179; https://doi.org/10.3390/cells11010179 - 5 Jan 2022
Cited by 20 | Viewed by 5790
Abstract
Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous [...] Read more.
Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response. Full article
(This article belongs to the Special Issue Metabolic Interactions in Tumor Microenvironment (TME))
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34 pages, 2984 KiB  
Review
A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment
by Francesca Hofer, Gianna Di Sario, Chiara Musiu, Silvia Sartoris, Francesco De Sanctis and Stefano Ugel
Cells 2021, 10(10), 2700; https://doi.org/10.3390/cells10102700 - 9 Oct 2021
Cited by 30 | Viewed by 4829
Abstract
Myeloid-derived suppressor cells (MDSCs) constitute a plastic and heterogeneous cell population among immune cells within the tumour microenvironment (TME) that support cancer progression and resistance to therapy. During tumour progression, cancer cells modify their metabolism to sustain an increased energy demand to cope [...] Read more.
Myeloid-derived suppressor cells (MDSCs) constitute a plastic and heterogeneous cell population among immune cells within the tumour microenvironment (TME) that support cancer progression and resistance to therapy. During tumour progression, cancer cells modify their metabolism to sustain an increased energy demand to cope with uncontrolled cell proliferation and differentiation. This metabolic reprogramming of cancer establishes competition for nutrients between tumour cells and leukocytes and most importantly, among tumour-infiltrating immune cells. Thus, MDSCs that have emerged as one of the most decisive immune regulators of TME exhibit an increase in glycolysis and fatty acid metabolism and also an upregulation of enzymes that catabolise essential metabolites. This complex metabolic network is not only crucial for MDSC survival and accumulation in the TME but also for enhancing immunosuppressive functions toward immune effectors. In this review, we discuss recent progress in the field of MDSC-associated metabolic pathways that could facilitate therapeutic targeting of these cells during cancer progression. Full article
(This article belongs to the Special Issue Metabolic Interactions in Tumor Microenvironment (TME))
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22 pages, 2109 KiB  
Review
HPV and Other Microbiota; Who’s Good and Who’s Bad: Effects of the Microbial Environment on the Development of Cervical Cancer—A Non-Systematic Review
by Matthias Läsche, Horst Urban, Julia Gallwas and Carsten Gründker
Cells 2021, 10(3), 714; https://doi.org/10.3390/cells10030714 - 23 Mar 2021
Cited by 14 | Viewed by 5665
Abstract
Cervical cancer is responsible for around 5% of all human cancers worldwide. It develops almost exclusively from an unsolved, persistent infection of the squamocolumnar transformation zone between the endo- and ecto-cervix with various high-risk (HR) human papillomaviruses (HPVs). The decisive turning point on [...] Read more.
Cervical cancer is responsible for around 5% of all human cancers worldwide. It develops almost exclusively from an unsolved, persistent infection of the squamocolumnar transformation zone between the endo- and ecto-cervix with various high-risk (HR) human papillomaviruses (HPVs). The decisive turning point on the way to persistent HPV infection and malignant transformation is an immune system weakened by pathobionts and oxidative stress and an injury to the cervical mucosa, often caused by sexual activities. Through these injury and healing processes, HPV viruses, hijacking activated keratinocytes, move into the basal layers of the cervical epithelium and then continue their development towards the distal prickle cell layer (Stratum spinosum). The microbial microenvironment of the cervical tissue determines the tissue homeostasis and the integrity of the protective mucous layer through the maintenance of a healthy immune and metabolic signalling. Pathological microorganisms and the resulting dysbiosis disturb this signalling. Thus, pathological inflammatory reactions occur, which manifest the HPV infection. About 90% of all women contract an HPV infection in the course of their lives. In about 10% of cases, the virus persists and cervical intra-epithelial neoplasia (CIN) develops. Approximately 1% of women with a high-risk HPV infection incur a cervical carcinoma after 10 to 20 years. In this non-systematic review article, we summarise how the sexually and microbial mediated pathogenesis of the cervix proceeds through aberrant immune and metabolism signalling via CIN to cervical carcinoma. We show how both the virus and the cancer benefit from the same changes in the immune and metabolic environment. Full article
(This article belongs to the Special Issue Metabolic Interactions in Tumor Microenvironment (TME))
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