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Pharmacologic Targeting of the Tumor Microenvironment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 62722

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Special Issue Editor

Dr. Peter C. Hart

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Guest Editor

College of Pharmacy, Roosevelt University, 1400 N Roosevelt Blvd, Schaumburg, IL 60173, USA
Interests: tumor microenvironment; cell–cell signaling; cell metabolism; hypoxia; oxidative stress; drug repurposing; ovarian cancer; breast cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Progress in our understanding of the complex composition of the tumor microenvironment has revealed the critical influence of stromal cells (e.g., fibroblasts, adipocytes, endothelial cells) in the ability of tumors to rapidly grow and metastasize to secondary tissues. Recent research has identified novel signaling mechanisms by which tumor–stroma interactions, in part due to signals emanating from stromal cells, facilitate key mechanisms involved in tumor cell proliferation, clonogenicity, migration, adhesion, and invasion. These interactions potentially provide a new set of therapeutic liabilities to target pharmacologically, to refine clinical strategies, and ultimately to improve patient outcomes. Here, in this Special Issue on “Pharmacologic Targeting of the Tumor Microenvironment”, we shall discuss the ability of repurposed and novel compounds to modulate tumor–stroma interactions with a focus on the efficacy of pharmacologic agents to impede bidirectional signaling mechanisms required for tumor development and metastatic progression.

This issue of the International Journal of Molecular Sciences is open to both original research articles and review articles focusing on advances in preclinical evaluation of pharmacologic approaches to modulate the tumor microenvironment in order to inhibit cancer progression.

Dr. Peter C. Hart
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

tumor microenvironment
stroma
fibroblast
adipocyte
leukocyte
endothelial cell
metastasis

Published Papers (14 papers)

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Research

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17 pages, 5366 KiB

Open AccessArticle

Combined Radionuclide Therapy and Immunotherapy for Treatment of Triple Negative Breast Cancer

by Alyssa Vito, Stephanie Rathmann, Natalie Mercanti, Nader El-Sayes, Karen Mossman and John Valliant

Int. J. Mol. Sci. 2021, 22(9), 4843; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094843 - 03 May 2021

Cited by 8 | Viewed by 4124

Abstract

Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with poor clinical outcomes and limited therapeutic options. Immune checkpoint blockade (CP) has surged to the forefront of cancer therapies with widespread clinical success in a variety of cancer types. However, the percentage of TNBC patients that benefit from CP as a monotherapy is low, and clinical trials have shown the need for combined therapeutic modalities. Specifically, there has been interest in combining CP therapy with radiation therapy where clinical studies primarily with external beam have suggested their therapeutic synergy, contributing to the development of anti-tumor immunity. Here, we have developed a therapeutic platform combining radionuclide therapy (RT) and immunotherapy utilizing a radiolabeled biomolecule and CP in an E0771 murine TNBC tumor model. Survival studies show that while neither monotherapy is able to improve therapeutic outcomes, the combination of RT + CP extended overall survival. Histologic analysis showed that RT + CP increased necrotic tissue within the tumor and decreased levels of F4/80+ macrophages. Flow cytometry analysis of the peripheral blood also showed that RT + CP suppressed macrophages and myeloid-derived suppressive cells, both of which actively contribute to immune escape and tumor relapse. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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13 pages, 5483 KiB

Open AccessArticle

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

by Yu-Hung Lee, Ching-Fang Yu, Ying-Chieh Yang, Ji-Hong Hong and Chi-Shiun Chiang

Int. J. Mol. Sci. 2021, 22(4), 2091; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042091 - 19 Feb 2021

Cited by 12 | Viewed by 2331

Abstract

The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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17 pages, 4541 KiB

Open AccessArticle

In-Depth Immune-Oncology Studies of the Tumor Microenvironment in a Humanized Melanoma Mouse Model

by Jonathan Schupp, Arne Christians, Niklas Zimmer, Lukas Gleue, Helmut Jonuleit, Mark Helm and Andrea Tuettenberg

Int. J. Mol. Sci. 2021, 22(3), 1011; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031011 - 20 Jan 2021

Cited by 6 | Viewed by 4972

Abstract

The presence and interaction of immune cells in the tumor microenvironment is of significant importance and has a great impact on disease progression and response to therapy. Hence, their identification is of high interest for prognosis and treatment decisions. Besides detailed phenotypic analyses of immune, as well as tumor cells, spatial analyses is an important parameter in the complex interplay of neoplastic and immune cells—especially when moving into focus efforts to develop and validate new therapeutic strategies. Ex vivo analysis of tumor samples by immunohistochemistry staining methods conserves spatial information is restricted to single markers, while flow cytometry (disrupting tissue into single cell suspensions) provides access to markers in larger numbers. Nevertheless, this comes at the cost of scarifying morphological information regarding tissue localization and cell–cell contacts. Further detrimental effects incurred by, for example, tissue digestion include staining artifacts. Consequently, ongoing efforts are directed towards methods that preserve, completely or in part, spatial information, while increasing the number of markers that can potentially be interrogated to the level of conventional flow cytometric methods. Progression in multiplex immunohistochemistry in the last ten years overcame the limitation to 1–2 markers in classical staining methods using DAB with counter stains or even pure chemical staining methods. In this study, we compared the multiplex method Chipcytometry to flow cytometry and classical IHC-P using DAB and hematoxylin. Chipcytometry uses frozen or paraffin-embedded tissue sections stained with readily available commercial fluorophore-labeled antibodies in repetitive cycles of staining and bleaching. The iterative staining approach enables sequential analysis of a virtually unlimited number of markers on the same sample, thereby identifying immune cell subpopulations in the tumor microenvironment in the present study in a humanized mouse melanoma model. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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15 pages, 3352 KiB

Open AccessArticle

Impact of the Stroma on the Biological Characteristics of the Parenchyma in Oral Squamous Cell Carcinoma

by Kiyofumi Takabatake, Hotaka Kawai, Haruka Omori, Shan Qiusheng, May Wathone Oo, Shintaro Sukegawa, Keisuke Nakano, Hidetsugu Tsujigiwa and Hitoshi Nagatsuka

Int. J. Mol. Sci. 2020, 21(20), 7714; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207714 - 18 Oct 2020

Cited by 10 | Viewed by 3949

Abstract

Solid tumors consist of the tumor parenchyma and stroma. The standard concept of oncology is that the tumor parenchyma regulates the tumor stroma and promotes tumor progression, and that the tumor parenchyma represents the tumor itself and defines the biological characteristics of the tumor tissue. Thus, the tumor stroma plays a pivotal role in assisting tumor parenchymal growth and invasiveness and is regarded as a supporter of the tumor parenchyma. The tumor parenchyma and stroma interact with each other. However, the influence of the stroma on the parenchyma is not clear. Therefore, in this study, we investigated the effect of the stroma on the parenchyma in oral squamous cell carcinoma (OSCC). We isolated tumor stroma from two types of OSCCs with different invasiveness (endophytic type OSCC (ED-st) and exophytic type OSCC (EX-st)) and examined the effect of the stroma on the parenchyma in terms of proliferation, invasion, and morphology by co-culturing and co-transplanting the OSCC cell line (HSC-2) with the two types of stroma. Both types of stroma were partially positive for alpha-smooth muscle actin. The tumor stroma increased the proliferation and invasion of tumor cells and altered the morphology of tumor cells in vitro and in vivo. ED-st exerted a greater effect on the tumor parenchyma in proliferation and invasion than EX-st. Morphological analysis showed that ED-st changed the morphology of HSC-2 cells to the invasive type of OSCC, and EX-st altered the morphology of HSC-2 cells to verrucous OSCC. This study suggests that the tumor stroma influences the biological characteristics of the parenchyma and that the origin of the stroma is strongly associated with the biological characteristics of the tumor. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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Review

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27 pages, 5201 KiB

Open AccessReview

The Role of EREG/EGFR Pathway in Tumor Progression

by Wan-Li Cheng, Po-Hao Feng, Kang-Yun Lee, Kuan-Yuan Chen, Wei-Lun Sun, Nguyen Van Hiep, Ching-Shan Luo and Sheng-Ming Wu

Int. J. Mol. Sci. 2021, 22(23), 12828; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312828 - 27 Nov 2021

Cited by 54 | Viewed by 8722

Abstract

Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal cancer (CRC). Epiregulin (EREG) is one of the EGFR ligands and is low expressed in most normal tissues. Elevated EREG in various cancers mainly activates EGFR signaling pathways and promotes cancer progression. Notably, a higher EREG expression level in CRC with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) is related to better efficacy of therapeutic treatment. By contrast, the resistance of anti-EGFR therapy in CRC was driven by low EREG expression, aberrant genetic mutation and signal pathway alterations. Additionally, EREG overexpression in non-small cell lung cancer (NSCLC) is anticipated to be a therapeutic target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that EREG derived from macrophages promotes NSCLC cell resistance to EGFR-TKI treatment. The emerging events of EREG-mediated tumor promotion signals are generated by autocrine and paracrine loops that arise from tumor epithelial cells, fibroblasts, and macrophages in the tumor microenvironment (TME). The TME is a crucial element for the development of various cancer types and drug resistance. The regulation of EREG/EGFR pathways depends on distinct oncogenic driver mutations and cell contexts that allows specific pharmacological targeting alone or combinational treatment for tailored therapy. Novel strategies targeting EREG/EGFR, tumor-associated macrophages, and alternative activation oncoproteins are under development or undergoing clinical trials. In this review, we summarize the clinical outcomes of EREG expression and the interaction of this ligand in the TME. The EREG/EGFR pathway may be a potential target and may be combined with other driver mutation targets to combat specific cancers. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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12 pages, 793 KiB

Open AccessReview

Role of Energy Metabolism in the Progression of Neuroblastoma

by Monika Sakowicz-Burkiewicz, Tadeusz Pawełczyk and Marlena Zyśk

Int. J. Mol. Sci. 2021, 22(21), 11421; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111421 - 22 Oct 2021

Cited by 5 | Viewed by 2174

Abstract

Neuroblastoma is a common childhood cancer possessing a significant risk of death. This solid tumor manifests variable clinical behaviors ranging from spontaneous regression to widespread metastatic disease. The lack of promising treatments calls for new research approaches which can enhance the understanding of the molecular background of neuroblastoma. The high proliferation of malignant neuroblastoma cells requires efficient energy metabolism. Thus, we focus our attention on energy pathways and their role in neuroblastoma tumorigenesis. Recent studies suggest that neuroblastoma-driven extracellular vesicles stimulate tumorigenesis inside the recipient cells. Furthermore, proteomic studies have demonstrated extracellular vesicles (EVs) to cargo metabolic enzymes needed to build up a fully operative energy metabolism network. The majority of EV-derived enzymes comes from glycolysis, while other metabolic enzymes have a fatty acid β-oxidation and tricarboxylic acid cycle origin. The previously mentioned glycolysis has been shown to play a primary role in neuroblastoma energy metabolism. Therefore, another way to modify the energy metabolism in neuroblastoma is linked with genetic alterations resulting in the decreased activity of some tricarboxylic acid cycle enzymes and enhanced glycolysis. This metabolic shift enables malignant cells to cope with increasing metabolic stress, nutrition breakdown and an upregulated proliferation ratio. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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30 pages, 1473 KiB

Open AccessReview

The Tumor Proteolytic Landscape: A Challenging Frontier in Cancer Diagnosis and Therapy

by Matej Vizovisek, Dragana Ristanovic, Stefano Menghini, Michael G. Christiansen and Simone Schuerle

Int. J. Mol. Sci. 2021, 22(5), 2514; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052514 - 03 Mar 2021

Cited by 35 | Viewed by 5658

Abstract

In recent decades, dysregulation of proteases and atypical proteolysis have become increasingly recognized as important hallmarks of cancer, driving community-wide efforts to explore the proteolytic landscape of oncologic disease. With more than 100 proteases currently associated with different aspects of cancer development and progression, there is a clear impetus to harness their potential in the context of oncology. Advances in the protease field have yielded technologies enabling sensitive protease detection in various settings, paving the way towards diagnostic profiling of disease-related protease activity patterns. Methods including activity-based probes and substrates, antibodies, and various nanosystems that generate reporter signals, i.e., for PET or MRI, after interaction with the target protease have shown potential for clinical translation. Nevertheless, these technologies are costly, not easily multiplexed, and require advanced imaging technologies. While the current clinical applications of protease-responsive technologies in oncologic settings are still limited, emerging technologies and protease sensors are poised to enable comprehensive exploration of the tumor proteolytic landscape as a diagnostic and therapeutic frontier. This review aims to give an overview of the most relevant classes of proteases as indicators for tumor diagnosis, current approaches to detect and monitor their activity in vivo, and associated therapeutic applications. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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16 pages, 1398 KiB

Open AccessReview

Oncolytic Virotherapy and Microenvironment in Multiple Myeloma

by Valentina Marchica, Federica Costa, Gaetano Donofrio and Nicola Giuliani

Int. J. Mol. Sci. 2021, 22(5), 2259; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052259 - 24 Feb 2021

Cited by 1 | Viewed by 2744

Abstract

Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of bone marrow (BM) clonal plasma cells, which are strictly dependent on the microenvironment. Despite the improvement of MM survival with the use of new drugs, MM patients still relapse and become always refractory to the treatment. The development of new therapeutic strategies targeting both tumor and microenvironment cells are necessary. Oncolytic virotherapy represent a promising approach in cancer treatment due to tumor-specific oncolysis and activation of the immune system. Different types of human viruses were checked in preclinical MM models, and the use of several viruses are currently investigated in clinical trials in MM patients. More recently, the use of alternative non-human viruses has been also highlighted in preclinical studies. This strategy could avoid the antiviral immune response of the patients against human viruses due to vaccination or natural infections, which could invalid the efficiency of virotherapy approach. In this review, we explored the effects of the main oncolytic viruses, which act through both direct and indirect mechanisms targeting myeloma and microenvironment cells inducing an anti-MM response. The efficacy of the oncolytic virus-therapy in combination with other anti-MM drugs targeting the microenvironment has been also discussed. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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37 pages, 2005 KiB

Open AccessReview

Therapeutic Targeting of MicroRNAs in the Tumor Microenvironment

by Rebecca Raue, Ann-Christin Frank, Shahzad Nawaz Syed and Bernhard Brüne

Int. J. Mol. Sci. 2021, 22(4), 2210; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042210 - 23 Feb 2021

Cited by 27 | Viewed by 5426

Abstract

The tumor-microenvironment (TME) is an amalgamation of various factors derived from malignant cells and infiltrating host cells, including cells of the immune system. One of the important factors of the TME is microRNAs (miRs) that regulate target gene expression at a post transcriptional level. MiRs have been found to be dysregulated in tumor as well as in stromal cells and they emerged as important regulators of tumorigenesis. In fact, miRs regulate almost all hallmarks of cancer, thus making them attractive tools and targets for novel anti-tumoral treatment strategies. Tumor to stroma cell cross-propagation of miRs to regulate protumoral functions has been a salient feature of the TME. MiRs can either act as tumor suppressors or oncogenes (oncomiRs) and both miR mimics as well as miR inhibitors (antimiRs) have been used in preclinical trials to alter cancer and stromal cell phenotypes. Owing to their cascading ability to regulate upstream target genes and their chemical nature, which allows specific pharmacological targeting, miRs are attractive targets for anti-tumor therapy. In this review, we cover a recent update on our understanding of dysregulated miRs in the TME and provide an overview of how these miRs are involved in current cancer-therapeutic approaches from bench to bedside. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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18 pages, 1131 KiB

Open AccessReview

Therapeutic Targeting of the Tumour Microenvironment in Metastatic Colorectal Cancer

by Rhynelle S. Dmello, Sarah Q. To and Ashwini L. Chand

Int. J. Mol. Sci. 2021, 22(4), 2067; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042067 - 19 Feb 2021

Cited by 14 | Viewed by 4983

Abstract

Liver metastasis is the primary contributor to the death of patients with colorectal cancer. Despite the overall success of current treatments including targeted therapy, chemotherapy, and immunotherapy combinations in colorectal cancer patients, the prognosis of patients with liver metastasis remains poor. Recent studies have highlighted the importance of the tumour microenvironment and the crosstalk within that determines the fate of circulating tumour cells in distant organs. Understanding the interactions between liver resident cells and tumour cells colonising the liver opens new therapeutic windows for the successful treatment of metastatic colorectal cancer. Here we discuss critical cellular interactions within the tumour microenvironment in primary tumours and in liver metastases that highlight potential therapeutic targets. We also discuss recent therapeutic advances for the treatment of metastatic colorectal cancer. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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14 pages, 1279 KiB

Open AccessReview

Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment

by Mariam Mroweh, Gaël Roth, Thomas Decaens, Patrice N. Marche, Hervé Lerat and Zuzana Macek Jílková

Int. J. Mol. Sci. 2021, 22(4), 1794; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041794 - 11 Feb 2021

Cited by 27 | Viewed by 3448

Abstract

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide, and its incidence is rising. HCC develops almost exclusively on the background of chronic liver inflammation, which can be caused by chronic alcohol consumption, viral hepatitis, or an unhealthy diet. The key role of chronic inflammation in the process of hepatocarcinogenesis, including in the deregulation of innate and adaptive immune responses, has been demonstrated. The inhibition of Akt (also known as Protein Kinase B) directly affects cancer cells, but this therapeutic strategy also exhibits indirect anti-tumor activity mediated by the modulation of the tumor microenvironment, as demonstrated by using Akt inhibitors AZD5363, MK-2206, or ARQ 092. Moreover, the isoforms of Akt converge and diverge in their designated roles, but the currently available Akt inhibitors fail to display an isoform specificity. Thus, selective Akt inhibition needs to be better explored in the context of HCC and its possible combination with immunotherapy. This review presents a compact overview of the current knowledge concerning the role of Akt in HCC and the effect of Akt inhibition on the HCC and liver tumor microenvironment. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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18 pages, 1368 KiB

Open AccessReview

Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer

by Faye K. Tsogas, Daniel Majerczyk and Peter C. Hart

Int. J. Mol. Sci. 2021, 22(2), 867; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020867 - 16 Jan 2021

Cited by 11 | Viewed by 3896

Abstract

Growing evidence suggests that the immune component of the tumor microenvironment (TME) may be highly involved in the progression of high-grade serous ovarian cancer (HGSOC), as an immunosuppressive TME is associated with worse patient outcomes. Due to the poor prognosis of HGSOC, new therapeutic strategies targeting the TME may provide a potential path forward for preventing disease progression to improve patient survival. One such postulated approach is the repurposing of the type 2 diabetes medication, metformin, which has shown promise in reducing HGSOC tumor progression in retrospective epidemiological analyses and through numerous preclinical studies. Despite its potential utility in treating HGSOC, and that the immune TME is considered as a key factor in the disease’s progression, little data has definitively shown the ability of metformin to target this component of the TME. In this brief review, we provide a summary of the current understanding of the effects of metformin on leukocyte function in ovarian cancer and, coupled with data from other related disease states, posit the potential mechanisms by which the drug may enhance the anti-tumorigenic effects of immune cells to improve HGSOC patient survival. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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19 pages, 1196 KiB

Open AccessReview

Natural and Synthetic PPARγ Ligands in Tumor Microenvironment: A New Potential Strategy against Breast Cancer

by Giuseppina Augimeri, Luca Gelsomino, Pierluigi Plastina, Cinzia Giordano, Ines Barone, Stefania Catalano, Sebastiano Andò and Daniela Bonofiglio

Int. J. Mol. Sci. 2020, 21(24), 9721; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249721 - 19 Dec 2020

Cited by 16 | Viewed by 2809

Abstract

Multiple lines of evidence indicate that activation of the peroxisome proliferator-activated receptor γ (PPARγ) by natural or synthetic ligands exerts tumor suppressive effects in different types of cancer, including breast carcinoma. Over the past decades a new picture of breast cancer as a complex disease consisting of neoplastic epithelial cells and surrounding stroma named the tumor microenvironment (TME) has emerged. Indeed, TME is now recognized as a pivotal element for breast cancer development and progression. Novel strategies targeting both epithelial and stromal components are under development or undergoing clinical trials. In this context, the aim of the present review is to summarize PPARγ activity in breast TME focusing on the role of this receptor on both epithelial/stromal cells and extracellular matrix components of the breast cancer microenvironment. The information provided from the in vitro and in vivo research indicates PPARγ ligands as potential agents with regards to the battle against breast cancer. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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25 pages, 4310 KiB

Open AccessReview

Interleukin-6: Molecule in the Intersection of Cancer, Ageing and COVID-19

by Jan Brábek, Milan Jakubek, Fréderic Vellieux, Jiří Novotný, Michal Kolář, Lukáš Lacina, Pavol Szabo, Karolína Strnadová, Daniel Rösel, Barbora Dvořánková and Karel Smetana, Jr.

Int. J. Mol. Sci. 2020, 21(21), 7937; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217937 - 26 Oct 2020

Cited by 44 | Viewed by 6349

Abstract

Interleukin-6 (IL-6) is a cytokine with multifaceted effects playing a remarkable role in the initiation of the immune response. The increased level of this cytokine in the elderly seems to be associated with the chronic inflammatory setting of the microenvironment in aged individuals. IL-6 also represents one of the main signals in communication between cancer cells and their non-malignant neighbours within the tumour niche. IL-6 also participates in the development of a premetastatic niche and in the adjustment of the metabolism in terminal-stage patients suffering from a malignant disease. IL-6 is a fundamental factor of the cytokine storm in patients with severe COVID-19, where it is responsible for the fatal outcome of the disease. A better understanding of the role of IL-6 under physiological as well as pathological conditions and the preparation of new strategies for the therapeutic control of the IL-6 axis may help to manage the problems associated with the elderly, cancer, and serious viral infections. Full article

(This article belongs to the Special Issue Pharmacologic Targeting of the Tumor Microenvironment)

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