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Therapeutic Molecular Targets in Tumor Microenvironment
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Therapeutic Molecular Targets in Tumor Microenvironment

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 48256

Special Issue Editor

Prof. Dr. Piotr Dzięgiel

E-Mail Website
Guest Editor
Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-367 Wroclaw, Poland
Interests: cancer biology; cell proliferation; cancer biomarkers; tumor microenvironment; immunohistochemistry; histology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The complexity and dynamic nature of the tumor microenvironment (TME) still remains a challenge for the pre- and clinical studies of tumors. TME components such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs) or tumor-infiltrating lymphocytes (TILs) are promising therapeutic targets associated with tumor regression and patient prognosis. They are mostly involved in cancer promotion and progression controlling various processes, i.e., cancer cell proliferation, angiogenesis, metastasis formation or epithelial to mesenchymal transition (EMT) phenomenon. TME promotes tumorigenesis by secreting cytokines and initiating extracellular matrix (ECM) remodeling. ECM proteins such as fibronectin, tenascin-C, and periostin can also play an important role in the regulation of cancer cell biology, metastatic potential, and patient outcome. Recent cancer immunotherapies are focused equally on tumor cells and on key components of the TME. In this Special Issue, we will discuss the biology and composition of TME, its prognostic and predictive value, as well as potential therapeutic strategies for cellular and molecular TME targets.

Prof. Piotr Dzięgiel
Guest Editor

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Keywords

  • Cancer
  • Microenvironment
  • Extracellular matrix
  • Immune response
  • Fibronectin
  • Cancer-associated fibroblasts
  • Lymphocytes

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Published Papers (7 papers)

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Research

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20 pages, 2104 KiB  
Article
Possibility for Transcriptional Targeting of Cancer-Associated Fibroblasts—Limitations and Opportunities
by Dina V. Antonova, Marina V. Zinovyeva, Liya G. Kondratyeva, Alexander V. Sass, Irina V. Alekseenko and Victor V. Pleshkan
Int. J. Mol. Sci. 2021, 22(7), 3298; https://doi.org/10.3390/ijms22073298 - 24 Mar 2021
Cited by 5 | Viewed by 2796
Abstract
Cancer-associated fibroblasts (CAF) are attractive therapeutic targets in the tumor microenvironment. The possibility of using CAFs as a source of therapeutic molecules is a challenging approach in gene therapy. This requires transcriptional targeting of transgene expression by cis-regulatory elements (CRE). Little is known [...] Read more.
Cancer-associated fibroblasts (CAF) are attractive therapeutic targets in the tumor microenvironment. The possibility of using CAFs as a source of therapeutic molecules is a challenging approach in gene therapy. This requires transcriptional targeting of transgene expression by cis-regulatory elements (CRE). Little is known about which CREs can provide selective transgene expression in CAFs. We hypothesized that the promoters of FAP, CXCL12, IGFBP2, CTGF, JAG1, SNAI1, and SPARC genes, the expression of whose is increased in CAFs, could be used for transcriptional targeting. Analysis of the transcription of the corresponding genes revealed that unique transcription in model CAFs was characteristic for the CXCL12 and FAP genes. However, none of the promoters in luciferase reporter constructs show selective activity in these fibroblasts. The CTGF, IGFBP2, JAG1, and SPARC promoters can provide higher transgene expression in fibroblasts than in cancer cells, but the nonspecific viral promoters CMV, SV40, and the recently studied universal PCNA promoter have the same features. The patterns of changes in activity of various promoters relative to each other observed for human cell lines were similar to the patterns of activity for the same promoters both in vivo and in vitro in mouse models. Our results reveal restrictions and features for CAF transcriptional targeting. Full article
(This article belongs to the Special Issue Therapeutic Molecular Targets in Tumor Microenvironment)
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18 pages, 12031 KiB  
Article
Prognostic Significance of Stromal Periostin Expression in Non-Small Cell Lung Cancer
by Katarzyna Ratajczak-Wielgomas, Alicja Kmiecik, Jedrzej Grzegrzołka, Aleksandra Piotrowska, Agnieszka Gomulkiewicz, Aleksandra Partynska, Konrad Pawelczyk, Katarzyna Nowinska, Marzenna Podhorska-Okolow and Piotr Dziegiel
Int. J. Mol. Sci. 2020, 21(19), 7025; https://doi.org/10.3390/ijms21197025 - 24 Sep 2020
Cited by 26 | Viewed by 3324
Abstract
Background: The microenvironment of solid tumours is significant in cancer development and progression. The aim of this study was to determine periostin (POSTN) expression by cancer-associated fibroblasts (CAFs) in non-small-cell lung cancer (NSCLC), as well as to assess associations with clinicopathological factors and [...] Read more.
Background: The microenvironment of solid tumours is significant in cancer development and progression. The aim of this study was to determine periostin (POSTN) expression by cancer-associated fibroblasts (CAFs) in non-small-cell lung cancer (NSCLC), as well as to assess associations with clinicopathological factors and prognosis. Materials and Methods: Immunohistochemical analysis of POSTN expression was performed on NSCLC (N = 700) and non-malignant lung tissue (NMLT) (N = 110) using tissue microarrays. Laser capture microdissection (LCM) for isolation of stromal and cancer cells of NSCLC was employed, and subsequently, POSTN mRNA expression was detected by real-time PCR. Immunofluorescence reaction and colocalisation analysis were performed by confocal microscopy. Results: Expression of POSTN in CAFs was significantly higher in NSCLC and in the adenocarcinoma (AC) and squamous cell carcinoma (SCC) subtypes compared to NMLT. POSTN expression in CAFs increased with clinical cancer stage, grades (G) of malignancy, and lymph node involvement in NSCLC. Higher POSTN expression in CAFs was an independent prognostic factor for overall survival (OS). LCM confirmed significantly higher POSTN mRNA expression in the stromal cells (CAFs) compared to the lung cancer cells. Conclusions: POSTN produced by CAFs might be crucial for NSCLC progression and can be an independent negative prognostic factor in NSCLC. Full article
(This article belongs to the Special Issue Therapeutic Molecular Targets in Tumor Microenvironment)
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17 pages, 2007 KiB  
Article
Modeling Immune Checkpoint Inhibitor Efficacy in Syngeneic Mouse Tumors in an Ex Vivo Immuno-Oncology Dynamic Environment
by Daniel T. Doty, Julia Schueler, Vienna L. Mott, Cassie M. Bryan, Nathan F. Moore, John C. Ho and Jeffrey T. Borenstein
Int. J. Mol. Sci. 2020, 21(18), 6478; https://doi.org/10.3390/ijms21186478 - 4 Sep 2020
Cited by 6 | Viewed by 4041
Abstract
The immune checkpoint blockade represents a revolution in cancer therapy, with the potential to increase survival for many patients for whom current treatments are not effective. However, response rates to current immune checkpoint inhibitors vary widely between patients and different types of cancer, [...] Read more.
The immune checkpoint blockade represents a revolution in cancer therapy, with the potential to increase survival for many patients for whom current treatments are not effective. However, response rates to current immune checkpoint inhibitors vary widely between patients and different types of cancer, and the mechanisms underlying these varied responses are poorly understood. Insights into the antitumor activities of checkpoint inhibitors are often obtained using syngeneic mouse models, which provide an in vivo preclinical basis for predicting efficacy in human clinical trials. Efforts to establish in vitro syngeneic mouse equivalents, which could increase throughput and permit real-time evaluation of lymphocyte infiltration and tumor killing, have been hampered by difficulties in recapitulating the tumor microenvironment in laboratory systems. Here, we describe a multiplex in vitro system that overcomes many of the deficiencies seen in current static histocultures, which we applied to the evaluation of checkpoint blockade in tumors derived from syngeneic mouse models. Our system enables both precision-controlled perfusion across biopsied tumor fragments and the introduction of checkpoint-inhibited tumor-infiltrating lymphocytes in a single experiment. Through real-time high-resolution confocal imaging and analytics, we demonstrated excellent correlations between in vivo syngeneic mouse and in vitro tumor biopsy responses to checkpoint inhibitors, suggesting the use of this platform for higher throughput evaluation of checkpoint efficacy as a tool for drug development. Full article
(This article belongs to the Special Issue Therapeutic Molecular Targets in Tumor Microenvironment)
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18 pages, 2104 KiB  
Article
Searching for Promoters to Drive Stable and Long-Term Transgene Expression in Fibroblasts for Syngeneic Mouse Tumor Models
by Dina V. Antonova, Irina V. Alekseenko, Anastasiia K. Siniushina, Alexey I. Kuzmich and Victor V. Pleshkan
Int. J. Mol. Sci. 2020, 21(17), 6098; https://doi.org/10.3390/ijms21176098 - 24 Aug 2020
Cited by 9 | Viewed by 4788
Abstract
Tumor is a complex system of interactions between cancer cells and other cells of the tumor microenvironment. The cancer-associated fibroblasts (CAFs) of the tumor microenvironment remain in close contact with the cancer cells and play an important role in cancer progression. Genetically, CAFs [...] Read more.
Tumor is a complex system of interactions between cancer cells and other cells of the tumor microenvironment. The cancer-associated fibroblasts (CAFs) of the tumor microenvironment remain in close contact with the cancer cells and play an important role in cancer progression. Genetically, CAFs are more stable than cancer cells, making them an attractive target for genetic modification in gene therapy. However, the efficiency of various promoters for transgene expression in fibroblasts is scarcely studied. We performed a comparative analysis of transgene long-term expression under the control of strong cytomegalovirus promoter (pCMV), constitutive cell promoter of the PCNA gene (pPCNA), and the potentially fibroblast-specific promoter of the IGFBP2 gene (pIGFBP2). In vitro expression of the transgene under the control of pCMV in fibroblasts was decreased soon after transduction, whereas the expression was more stable under the control of pIGFBP2 and pPCNA. The efficiency of transgene expression was higher under pPCNA than that under pIGFBP2. Additionally, in a mouse model, pPCNA provided more stable and increased transgene expression in fibroblasts as compared to that under pCMV. We conclude that PCNA promoter is the most efficient for long-term expression of transgenes in fibroblasts both in vitro and in vivo. Full article
(This article belongs to the Special Issue Therapeutic Molecular Targets in Tumor Microenvironment)
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Review

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29 pages, 3787 KiB  
Review
Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment
by Valeria De Pasquale and Luigi Michele Pavone
Int. J. Mol. Sci. 2020, 21(18), 6588; https://doi.org/10.3390/ijms21186588 - 9 Sep 2020
Cited by 49 | Viewed by 6233
Abstract
In the last few decades, heparan sulfate (HS) proteoglycans (HSPGs) have been an intriguing subject of study for their complex structural characteristics, their finely regulated biosynthetic machinery, and the wide range of functions they perform in living organisms from development to adulthood. From [...] Read more.
In the last few decades, heparan sulfate (HS) proteoglycans (HSPGs) have been an intriguing subject of study for their complex structural characteristics, their finely regulated biosynthetic machinery, and the wide range of functions they perform in living organisms from development to adulthood. From these studies, key roles of HSPGs in tumor initiation and progression have emerged, so that they are currently being explored as potential biomarkers and therapeutic targets for cancers. The multifaceted nature of HSPG structure/activity translates in their capacity to act either as inhibitors or promoters of tumor growth and invasion depending on the tumor type. Deregulation of HSPGs resulting in malignancy may be due to either their abnormal expression levels or changes in their structure and functions as a result of the altered activity of their biosynthetic or remodeling enzymes. Indeed, in the tumor microenvironment, HSPGs undergo structural alterations, through the shedding of proteoglycan ectodomain from the cell surface or the fragmentation and/or desulfation of HS chains, affecting HSPG function with significant impact on the molecular interactions between cancer cells and their microenvironment, and tumor cell behavior. Here, we overview the structural and functional features of HSPGs and their signaling in the tumor environment which contributes to tumorigenesis and cancer progression. Full article
(This article belongs to the Special Issue Therapeutic Molecular Targets in Tumor Microenvironment)
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25 pages, 421 KiB  
Review
Vitamins and Uterine Fibroids: Current Data on Pathophysiology and Possible Clinical Relevance
by Michał Ciebiera, Mohamed Ali, Magdalena Zgliczyńska, Maciej Skrzypczak and Ayman Al-Hendy
Int. J. Mol. Sci. 2020, 21(15), 5528; https://doi.org/10.3390/ijms21155528 - 1 Aug 2020
Cited by 18 | Viewed by 13951
Abstract
Uterine fibroid (UF) is the most common benign tumor pathology of the female reproductive organs. UFs constitute the main reason for a hysterectomy and hospitalization due to gynecological conditions. UFs consist of uterine smooth muscle immersed in a large amount of extracellular matrix [...] Read more.
Uterine fibroid (UF) is the most common benign tumor pathology of the female reproductive organs. UFs constitute the main reason for a hysterectomy and hospitalization due to gynecological conditions. UFs consist of uterine smooth muscle immersed in a large amount of extracellular matrix (ECM). Genetic studies have demonstrated that UFs are monoclonal tumors originating from the myometrial stem cells that have underwent specific molecular changes to tumor initiating stem cells which proliferate and differentiate later under the influence of steroid hormones. There is growing interest in the role of micronutrients, for example, vitamins, in UFs. This article is a comprehensive review of publications regarding the available data concerning the role of vitamins in the biology and management of UFs. In summary, the results showed that some vitamins are important in the biology and pathophysiology of UFs. For example, vitamins A and D deserve particular attention following studies of their influence on the treatment of UF tumors. Vitamins B3, C, and E have not been as widely studied as the abovementioned vitamins. However, more research could reveal their potential role in UF biology. Full article
(This article belongs to the Special Issue Therapeutic Molecular Targets in Tumor Microenvironment)
26 pages, 1551 KiB  
Review
The Role of miRNA and Related Pathways in Pathophysiology of Uterine Fibroids—From Bench to Bedside
by Michał Ciebiera, Marta Włodarczyk, Stanisław Zgliczyński, Tomasz Łoziński, Klaudia Walczak and Artur Czekierdowski
Int. J. Mol. Sci. 2020, 21(8), 3016; https://doi.org/10.3390/ijms21083016 - 24 Apr 2020
Cited by 29 | Viewed by 12231
Abstract
Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. Their prevalence usually is estimated at 30–40%, but may reach up to 70–80% in predisposed groups of women. UFs may cause various clinical issues which might constitute the major [...] Read more.
Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. Their prevalence usually is estimated at 30–40%, but may reach up to 70–80% in predisposed groups of women. UFs may cause various clinical issues which might constitute the major reason of the overall deterioration of the quality of life. The mechanisms leading to UFs formation and growth still remain poorly understood. The transformation of smooth muscle cells of the uterus into abnormal, immortal cells, capable of clonal division, is thought to be a starting point of all pathways leading to UF formation. Micro-ribonucleic acids (miRNAs) are non-coding single-stranded RNAs about 22 nucleotides in length, that regulate gene expression. One of recent advances in this field is the comprehension of the role of miRNAs in tumorigenesis. Alterations in the levels of miRNAs are related to the formation and growth of several tumors which show a distinct miRNA signature. The aim of this review is to summarize the current data about the role of miRNAs in the pathophysiology of UFs. We also discuss future directions in the miRNA research area with an emphasis on novel diagnostic opportunities or patient-tailored therapies. In our opinion data concerning the regulation of miRNA and its gene targets in the UFs are still insufficient in comparison with gynecological malignancies. The potential translational use of miRNA and derived technologies in the clinical care is at the early phase and needs far more evidence. However, it is one of the main areas of interest for the future as the use of miRNAs in the diagnostics and treatment of UFs is a new and exciting opportunity. Full article
(This article belongs to the Special Issue Therapeutic Molecular Targets in Tumor Microenvironment)
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