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Novel Therapeutic Targets for Tumor Microenvironment in Cancer
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Novel Therapeutic Targets for Tumor Microenvironment in Cancer

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 (31 October 2022) | Viewed by 12614

Special Issue Editors

Dr. Laura Masuelli

E-Mail Website
Guest Editor
Department of Experimental Medicine, University of Rome “Sapienza”, 00164 Rome, Italy
Interests: cancer; cancer target therapy; nutraceutics; cancer vaccines; extracellular vesicles; biomarkers; ultrastructural pathology
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Roberto Bei

E-Mail Website
Guest Editor
Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
Interests: apoptosis; cancer biology; cell signaling; cell proliferation; cancer biomarkers

Special Issue Information

Dear Colleagues, 

Tumor microenvironment (TME) is a complex structure developing during tumor growth, mainly constituted by extracellular matrix, stromal cells and immune cells. TME is continuously remodelled during tumor growth and enabled tumor progression. TME remodelling is modulated by autocrine and paracrine signaling interaction between tumor and TME cells. The continuous remodeling of TME stimulates the maturation of the tumor niche and the development and dissemination of tumor cells. TME remodeling includes the increase in extracellular matrix that facilitates tumor invasion, formation of blood and lymphatic vessels that promotes metastasis and the recruitment of immunosuppressive immune cells that support immunological escape of tumor cells.

It is possible to control the tumor growth acting on the TME rather than directly on the neoplastic cells. Extracellular matrix, neoangiogenesis, tumor immune infiltrating cells, inflammation can be affected by different therapeutic approaches.

This special issue will focus on the discovery of novel targets and the development of novel therapeutic approaches targeting TME during tumor development and progression. The authors are invited to contribute with a review or full research paper for peer-review to this special issue.

Dr. Laura Masuelli
Prof. Dr. Roberto Bei
Guest Editors

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
  • TME remodelling
  • extracellular matrix
  • neoangiogenesis tumor
  • immune infiltrating cells
  • inflammation

Published Papers (6 papers)

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Editorial

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3 pages, 195 KiB  
Editorial
Novel Therapeutic Targets for Tumor Microenvironment in Cancer
by Roberto Bei and Laura Masuelli
Int. J. Mol. Sci. 2023, 24(8), 7240; https://doi.org/10.3390/ijms24087240 - 14 Apr 2023
Cited by 1 | Viewed by 1043
Abstract
The various immune effector cells that infiltrate the tumor microenvironment (TME) play a key role in directing the outcome of tumor growth [...] Full article
(This article belongs to the Special Issue Novel Therapeutic Targets for Tumor Microenvironment in Cancer)

Research

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18 pages, 3518 KiB  
Article
MK2 Promotes the Development and Progression of Pancreatic Neuroendocrine Tumors Mediated by Macrophages and Metabolomic Factors
by Damian Jacenik, Eric J. Lebish and Ellen J. Beswick
Int. J. Mol. Sci. 2022, 23(21), 13561; https://doi.org/10.3390/ijms232113561 - 05 Nov 2022
Cited by 6 | Viewed by 1861
Abstract
Cases of pancreatic neuroendocrine tumors (PNETs) are growing in number, and new treatment options are needed in order to improve patient outcomes. The mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a crucial regulator of cytokine/chemokine production. The significance of MK2 expression and [...] Read more.
Cases of pancreatic neuroendocrine tumors (PNETs) are growing in number, and new treatment options are needed in order to improve patient outcomes. The mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a crucial regulator of cytokine/chemokine production. The significance of MK2 expression and signaling pathway mediated by MK2 in PNETs has not been investigated. To characterize the impact of MK2 on PNET growth, we used the RipTag2 transgenic murine model of PNETs, and we developed a primary PNET cell line for both in vitro and in vivo studies. In the transgenic murine model of PNETs, we found that MK2 inhibition improves survival of mice and prevents PNET progression. MK2 blockade abolished cytokine/chemokine production, which was related to macrophage function. A role for MK2 in the regulation of metabolic factor secretion in PNETs was identified, making this the first study to identify a potential role for the MK2 pathway in regulation of tumor metabolism. Moreover, using an in vitro approach and allograft model of PNETs, we were able to show that macrophages with MK2 depletion exhibit increased cytotoxicity against PNET cells and substantially decreased production of pro-inflammatory cytokines and chemokines, as well as metabolic factors. Taken together, our work identifies MK2 as a potent driver of immune response and metabolic effectors in PNETs, suggesting it is a potential therapeutic target for patients with PNETs. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets for Tumor Microenvironment in Cancer)
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17 pages, 2752 KiB  
Article
MGL S3 Chimeric Enzyme Drives Apoptotic Death of EGFR-Dependent Cancer Cells through ERK Downregulation
by Nikolay Bondarev, Karina Ivanenko, Elmira Khabusheva, Timofey Lebedev, Ilya Manukhov and Vladimir Prassolov
Int. J. Mol. Sci. 2022, 23(21), 12807; https://doi.org/10.3390/ijms232112807 - 24 Oct 2022
Cited by 4 | Viewed by 1547
Abstract
Methionine dependence of malignant cells is one of the cancer hallmarks. It is well described that methionine deprivation drives cancer cells death, both in vitro and in vivo. Methionine gamma-lyase (MGL) isolated from different species or obtained by genetic engineering can be used [...] Read more.
Methionine dependence of malignant cells is one of the cancer hallmarks. It is well described that methionine deprivation drives cancer cells death, both in vitro and in vivo. Methionine gamma-lyase (MGL) isolated from different species or obtained by genetic engineering can be used for effective methionine depletion. In this work, we show that MGL S3, a genetically engineered protein comprised of MGL from Clostridium sporogenesis fused to epidermal growth factor (EGF)-like peptide, reduces, in vitro, the number of cancer cells of four different origins—neuroblastoma, lung, breast, and colon cancer. We reveal that MGL S3 is more toxic for neuroblastoma SH-SY5Y and lung cancer H1299 cells compared to MGL tetani, and causes cell death by the induction of apoptosis. In addition, the observed death of cells treated with MGL S3 is accompanied by the prominent downregulation of ERK activity. By the analysis of transcriptomic data of more than 1500 cancer cell lines and patient samples, we show that the high expression of four genes from the methionine metabolism pathway (AHCY, CBS, DNMT3A, and MTAP) is associated with poor prognosis for breast cancer and neuroblastoma patients. Additionally, cells of these origins are characterized by a high correlation between EGFR dependency and DNMT3A/CBS expression. Finally, we demonstrate the ability of MGL S3 to enhance the sensitivity of H1299 cells to EGFR inhibition with gefitinib. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets for Tumor Microenvironment in Cancer)
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21 pages, 3987 KiB  
Article
Generation and Characterization of a Tumor Stromal Microenvironment and Analysis of Its Interplay with Breast Cancer Cells: An In Vitro Model to Study Breast Cancer-Associated Fibroblast Inactivation
by Veronica Romano, Maria Rosaria Ruocco, Pietro Carotenuto, Anna Barbato, Alessandro Venuta, Vittoria Acampora, Sabrina De Lella, Elena Vigliar, Antonino Iaccarino, Giancarlo Troncone, Gaetano Calì, Luigi Insabato, Daniela Russo, Brunella Franco, Stefania Masone, Nunzio Velotti, Antonello Accurso, Tommaso Pellegrino, Giuseppe Fiume, Immacolata Belviso, Stefania Montagnani, Angelica Avagliano and Alessandro Arcucciadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(12), 6875; https://doi.org/10.3390/ijms23126875 - 20 Jun 2022
Cited by 4 | Viewed by 2633
Abstract
Breast cancer-associated fibroblasts (BCAFs), the most abundant non-cancer stromal cells of the breast tumor microenvironment (TME), dramatically sustain breast cancer (BC) progression by interacting with BC cells. BCAFs, as well as myofibroblasts, display an up regulation of activation and inflammation markers represented by [...] Read more.
Breast cancer-associated fibroblasts (BCAFs), the most abundant non-cancer stromal cells of the breast tumor microenvironment (TME), dramatically sustain breast cancer (BC) progression by interacting with BC cells. BCAFs, as well as myofibroblasts, display an up regulation of activation and inflammation markers represented by α-smooth muscle actin (α-SMA) and cyclooxygenase 2 (COX-2). BCAF aggregates have been identified in the peripheral blood of metastatic BC patients. We generated an in vitro stromal model consisting of human primary BCAFs grown as monolayers or 3D cell aggregates, namely spheroids and reverted BCAFs, obtained from BCAF spheroids reverted to 2D cell adhesion growth after 216 h of 3D culture. We firstly evaluated the state of activation and inflammation and the mesenchymal status of the BCAF monolayers, BCAF spheroids and reverted BCAFs. Then, we analyzed the MCF-7 cell viability and migration following treatment with conditioned media from the different BCAF cultures. After 216 h of 3D culture, the BCAFs acquired an inactivated phenotype, associated with a significant reduction in α-SMA and COX-2 protein expression. The deactivation of the BCAF spheroids at 216 h was further confirmed by the cytostatic effect exerted by their conditioned medium on MCF-7 cells. Interestingly, the reverted BCAFs also retained a less activated phenotype as indicated by α-SMA protein expression reduction. Furthermore, the reverted BCAFs exhibited a reduced pro-tumor phenotype as indicated by the anti-migratory effect exerted by their conditioned medium on MCF-7 cells. The deactivation of BCAFs without drug treatment is possible and leads to a reduced capability of BCAFs to sustain BC progression in vitro. Consequently, this study could be a starting point to develop new therapeutic strategies targeting BCAFs and their interactions with cancer cells. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets for Tumor Microenvironment in Cancer)
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24 pages, 7580 KiB  
Article
Role of Periostin Expression in Non-Small Cell Lung Cancer: Periostin Silencing Inhibits the Migration and Invasion of Lung Cancer Cells via Regulation of MMP-2 Expression
by Katarzyna Ratajczak-Wielgomas, Alicja Kmiecik and Piotr Dziegiel
Int. J. Mol. Sci. 2022, 23(3), 1240; https://doi.org/10.3390/ijms23031240 - 22 Jan 2022
Cited by 12 | Viewed by 2825
Abstract
The involvement of periostin (POSTN) in non-small-cell lung cancer (NSCLC) migration, invasion, and its underlying mechanisms has not been well established. The present study aims to determine epithelial POSTN expression in NSCLC and to assess associations with clinicopathological factors and prognosis as well [...] Read more.
The involvement of periostin (POSTN) in non-small-cell lung cancer (NSCLC) migration, invasion, and its underlying mechanisms has not been well established. The present study aims to determine epithelial POSTN expression in NSCLC and to assess associations with clinicopathological factors and prognosis as well as to explore the effects of POSTN knockdown on tumor microenvironment and the migration and invasion of lung cancer cells. Immunohistochemistry was used to evaluate epithelial POSTN expression in NSCLC. POSTN mRNA expression in the dissected lung cancer cells was confirmed by laser capture microdissection and real-time PCR. A549 cells were used for transfecting shRNA-POSTN lentiviral particles. Wound healing and Transwell invasion assays were used to assess the migratory and invasive abilities of A549 cells transfected with POSTN-specific short hairpin (sh)RNA. The results demonstrated significantly higher cytoplasmic POSTN expression in the whole NSCLC group compared to non-malignant lung tissue (NMLT). POSTN expression in cancer cells may be considered to be an independent prognostic factor for survival in NSCLC. POSTN knockdown significantly inhibited A549 cell migration and invasion capabilities in vitro. The activity and the expression level of matrix metalloproteinase-2 (MMP-2) were significantly decreased in A549.shRNA compared to control cells. In summary, POSTN may regulate lung cancer cell invasiveness by modulating the expression of MMP-2 and may represent a potential target for novel therapeutic intervention for NSCLC. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets for Tumor Microenvironment in Cancer)
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Review

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15 pages, 338 KiB  
Review
Monitoring of Current Cancer Therapy by Positron Emission Tomography and Possible Role of Radiomics Assessment
by Noboru Oriuchi, Hideki Endoh and Kyoichi Kaira
Int. J. Mol. Sci. 2022, 23(16), 9394; https://doi.org/10.3390/ijms23169394 - 20 Aug 2022
Cited by 4 | Viewed by 1969
Abstract
Evaluation of cancer therapy with imaging is crucial as a surrogate marker of effectiveness and survival. The unique response patterns to therapy with immune-checkpoint inhibitors have facilitated the revision of response evaluation criteria using FDG-PET, because the immune response recalls reactive cells such [...] Read more.
Evaluation of cancer therapy with imaging is crucial as a surrogate marker of effectiveness and survival. The unique response patterns to therapy with immune-checkpoint inhibitors have facilitated the revision of response evaluation criteria using FDG-PET, because the immune response recalls reactive cells such as activated T-cells and macrophages, which show increased glucose metabolism and apparent progression on morphological imaging. Cellular metabolism and function are critical determinants of the viability of active cells in the tumor microenvironment, which would be novel targets of therapies, such as tumor immunity, metabolism, and genetic mutation. Considering tumor heterogeneity and variation in therapy response specific to the mechanisms of therapy, appropriate response evaluation is required. Radiomics approaches, which combine objective image features with a machine learning algorithm as well as pathologic and genetic data, have remarkably progressed over the past decade, and PET radiomics has increased quality and reliability based on the prosperous publications and standardization initiatives. PET and multimodal imaging will play a definitive role in personalized therapeutic strategies by the precise monitoring in future cancer therapy. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets for Tumor Microenvironment in Cancer)
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