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Cancers
Special Issues
RNA Drugs in Tumor Microenvironment
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RNA Drugs in Tumor Microenvironment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 20420

Special Issue Editor

Dr. Vittorio de Franciscis

E-Mail Website
Guest Editor
Istituto per l'Endocrinologia e Oncologia Sperimentale "G. Salvatore", Via Tommaso De Amicis 95 Via S. Pansini 5, 80145 Naples, Italy
Interests: RNA therapeutics; delivery of nucleic acid therapeutics; aptamer; tumor microenvironment; signal transduction; microRNA; targeted therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The presence of a complex tumor microenvironment (TME) is recognized to play a crucial role in tumor progression, resistance to therapy, and spreading across the major cancer types, emphasizing the need of precise-targeting therapeutic molecules.

Indeed, RNA-drugs—including siRNAs, miRNAs/antimiRs, lncRNAs, RNA guides (gRNAs), saRNAs, aptamers and ASOs—are emerging as new classes of precise and safe therapeutic drugs for several undruggable disorders, including cancer. On the other hand, several extracellular ncRNAs have recently been implicated in cancer intracellular communication and in TME–tumor interplay.

As such, this Special Issue is intended to highlight the recent advances in understanding the TME–tumor interplay and to underscore the advantages and limitations of using RNA-based therapeutics to target the TME.

Dr. Vittorio de Franciscis
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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • cancer therapy
  • exosome
  • RNA therapeutic
  • tumor microenvironment
  • Tumor associated macrophage
  • Cancer Associated fibroblast
  • ncRNA
  • extracellular RNA

Published Papers (6 papers)

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Research

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17 pages, 3060 KiB  
Article
The lncRNA H19-Derived MicroRNA-675 Promotes Liver Necroptosis by Targeting FADD
by Rona Harari-Steinfeld, Maytal Gefen, Alina Simerzin, Elina Zorde-Khvalevsky, Mila Rivkin, Ezra Ella, Tomer Friehmann, Mordechay Gerlic, Jessica Zucman-Rossi, Stefano Caruso, Mélissa Leveille, Jennifer L. Estall, Daniel S. Goldenberg, Hilla Giladi, Eithan Galun and Zohar Bromberg
Cancers 2021, 13(3), 411; https://doi.org/10.3390/cancers13030411 - 22 Jan 2021
Cited by 27 | Viewed by 3889
Abstract
The H19-derived microRNA-675 (miR-675) has been implicated as both tumor promoter and tumor suppressor and also plays a role in liver inflammation. We found that miR-675 promotes cell death in human hepatocellular carcinoma (HCC) cell lines. We show that Fas-associated protein with [...] Read more.
The H19-derived microRNA-675 (miR-675) has been implicated as both tumor promoter and tumor suppressor and also plays a role in liver inflammation. We found that miR-675 promotes cell death in human hepatocellular carcinoma (HCC) cell lines. We show that Fas-associated protein with death domain (FADD), a mediator of apoptotic cell death signaling, is downregulated by miR-675 and a negative correlation exists between miR-675 and FADD expression in mouse models of HCC (p = 0.014) as well as in human samples (p = 0.017). We demonstrate in a mouse model of liver inflammation that overexpression of miR-675 promotes necroptosis, which can be inhibited by the necroptosis-specific inhibitor Nec-1/Nec-1s. miR-675 induces the level of both p-MLKL (Mixed Lineage Kinase Domain-Like Pseudokinase) and RIP3 (receptor-interacting protein 3), which are key signaling molecules in necroptosis, and enhances MLKL binding to RIP3. miR-675 also inhibits the levels of cleaved caspases 8 and 3, suggesting that miR-675 induces a shift from apoptosis to a necroptotic cellular pathway. In conclusion, downregulation of FADD by miR-675 promotes liver necroptosis in response to inflammatory signals. We propose that this regulation cascade can stimulate and enhance the inflammatory response in the liver, making miR-675 an important regulator in liver inflammation and potentially also in HCC. Full article
(This article belongs to the Special Issue RNA Drugs in Tumor Microenvironment)
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16 pages, 2485 KiB  
Article
MiR-181 Family Modulates Osteopontin in Glioblastoma Multiforme
by Anantha Marisetty, Jun Wei, Ling-Yuan Kong, Martina Ott, Dexing Fang, Aria Sabbagh and Amy B. Heimberger
Cancers 2020, 12(12), 3813; https://doi.org/10.3390/cancers12123813 - 17 Dec 2020
Cited by 11 | Viewed by 2024
Abstract
MiRNAs can silence a wide range of genes, which may be an advantage for targeting heterogenous tumors like glioblastoma. Osteopontin (OPN) plays both an oncogenic role in a variety of cancers and can immune modulate macrophages. We conducted a genome wide profiling and [...] Read more.
MiRNAs can silence a wide range of genes, which may be an advantage for targeting heterogenous tumors like glioblastoma. Osteopontin (OPN) plays both an oncogenic role in a variety of cancers and can immune modulate macrophages. We conducted a genome wide profiling and bioinformatic analysis to identify miR-181a/b/c/d as potential miRNAs that target OPN. Luciferase assays confirmed the binding potential of miRNAs to OPN. Expression levels of miR-181a/b/c/d and OPN were evaluated by using quantitative real-time PCR and enzyme-linked immunosorbent assay in mouse and human glioblastomas and macrophages that showed these miRNAs were downregulated in Glioblastoma associated CD11b+ cells compared to their matched blood CD14b+ cells. miRNA mimicking and overexpression using lentiviruses showed that MiR-181a overexpression in glioblastoma cells led to decreased OPN production and proliferation and increased apoptosis in vitro. MiR-181a treatment of immune competent mice bearing intracranial glioblastoma demonstrated a 22% increase in median survival duration relative to that of control mice. Full article
(This article belongs to the Special Issue RNA Drugs in Tumor Microenvironment)
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Review

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20 pages, 662 KiB  
Review
Modulating the Crosstalk between the Tumor and the Microenvironment Using SiRNA: A Flexible Strategy for Breast Cancer Treatment
by Giuseppina Roscigno, Iolanda Scognamiglio, Francesco Ingenito, Rosario Vincenzo Chianese, Francesco Palma, Alan Chan and Gerolama Condorelli
Cancers 2020, 12(12), 3744; https://doi.org/10.3390/cancers12123744 - 13 Dec 2020
Cited by 14 | Viewed by 4806
Abstract
Tumorigenesis is a complex and multistep process in which sequential mutations in oncogenes and tumor-suppressor genes result in enhanced proliferation and apoptosis escape. Over the past decades, several studies have provided evidence that tumors are more than merely a mass of malignant cancer [...] Read more.
Tumorigenesis is a complex and multistep process in which sequential mutations in oncogenes and tumor-suppressor genes result in enhanced proliferation and apoptosis escape. Over the past decades, several studies have provided evidence that tumors are more than merely a mass of malignant cancer cells, with the tumor microenvironment (TME) also contributing to cancer progression. For this reason, the focus of cancer research in recent years has shifted from the malignant cancer cell itself to the TME and its interactions. Since the TME actively participates in tumor progression, therapeutic strategies targeting it have created great interest. In this context, much attention has been paid to the potential application of small interfering RNA (siRNA), a class of non-coding RNA that has the ability to downregulate the expression of target genes in a sequence-specific way. This is paving the way for a novel therapeutic approach for the treatment of several diseases, including cancer. In this review, we describe recent efforts in developing siRNA therapeutics for the treatment of breast cancer, with particular emphasis on TME regulation. We focus on studies that adapt siRNA design to reprogram/re-educate the TME and eradicate the interplay between cancer cells and TME. Full article
(This article belongs to the Special Issue RNA Drugs in Tumor Microenvironment)
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20 pages, 576 KiB  
Review
The Effects of Single Nucleotide Polymorphisms in Cancer RNAi Therapies
by Magdalena Gebert, Maciej Jaśkiewicz, Adrianna Moszyńska, James F. Collawn and Rafał Bartoszewski
Cancers 2020, 12(11), 3119; https://doi.org/10.3390/cancers12113119 - 25 Oct 2020
Cited by 6 | Viewed by 2880
Abstract
Tremendous progress in RNAi delivery methods and design has allowed for the effective development of siRNA-based therapeutics that are currently under clinical investigation for various cancer treatments. This approach has the potential to revolutionize cancer therapy by providing the ability to specifically downregulate [...] Read more.
Tremendous progress in RNAi delivery methods and design has allowed for the effective development of siRNA-based therapeutics that are currently under clinical investigation for various cancer treatments. This approach has the potential to revolutionize cancer therapy by providing the ability to specifically downregulate or upregulate the mRNA of any protein of interest. This exquisite specificity, unfortunately, also has a downside. Genetic variations in the human population are common because of the presence of single nucleotide polymorphisms (SNPs). SNPs lead to synonymous and non-synonymous changes and they occur once in every 300 base pairs in both coding and non-coding regions in the human genome. Much less common are the somatic mosaicism variations associated with genetically distinct populations of cells within an individual that is derived from postzygotic mutations. These heterogeneities in the population can affect the RNAi’s efficacy or more problematically, which can lead to unpredictable and sometimes adverse side effects. From a more positive viewpoint, both SNPs and somatic mosaicisms have also been implicated in human diseases, including cancer, and these specific changes could offer the ability to effectively and, more importantly, selectively target the cancer cells. In this review, we discuss how SNPs in the human population can influence the development and success of novel anticancer RNAi therapies and the importance of why SNPs should be carefully considered. Full article
(This article belongs to the Special Issue RNA Drugs in Tumor Microenvironment)
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35 pages, 2277 KiB  
Review
Back to the Future: Rethinking the Great Potential of lncRNAS for Optimizing Chemotherapeutic Response in Ovarian Cancer
by Abdelrahman M. Elsayed, Paola Amero, Salama A. Salama, Abdelaziz H. Abdelaziz, Gabriel Lopez-Berestein and Cristian Rodriguez-Aguayo
Cancers 2020, 12(9), 2406; https://doi.org/10.3390/cancers12092406 - 25 Aug 2020
Cited by 17 | Viewed by 2948
Abstract
Ovarian cancer (OC) is one of the most fatal cancers in women worldwide. Currently, platinum- and taxane-based chemotherapy is the mainstay for the treatment of OC. Yet, the emergence of chemoresistance results in therapeutic failure and significant relapse despite a consistent rate of [...] Read more.
Ovarian cancer (OC) is one of the most fatal cancers in women worldwide. Currently, platinum- and taxane-based chemotherapy is the mainstay for the treatment of OC. Yet, the emergence of chemoresistance results in therapeutic failure and significant relapse despite a consistent rate of primary response. Emerging evidence substantiates the potential role of lncRNAs in determining the response to standard chemotherapy in OC. The objective of this narrative review is to provide an integrated, synthesized overview of the current state of knowledge regarding the role of lncRNAs in the emergence of resistance to platinum- and taxane-based chemotherapy in OC. In addition, we sought to develop conceptual frameworks for harnessing the therapeutic potential of lncRNAs in strategies aimed at enhancing the chemotherapy response of OC. Furthermore, we offered significant new perspectives and insights on the interplay between lncRNAs and the molecular circuitries implicated in chemoresistance to determine their impacts on therapeutic response. Although this review summarizes robust data concerning the involvement of lncRNAs in the emergence of acquired resistance to platinum- and taxane-based chemotherapy in OC, effective approaches for translating these lncRNAs into clinical practice warrant further investigation. Full article
(This article belongs to the Special Issue RNA Drugs in Tumor Microenvironment)
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19 pages, 1520 KiB  
Review
Emerging Therapeutic RNAs for the Targeting of Cancer Associated Fibroblasts
by Laura Santana-Viera, Maria L. Ibba, Deborah Rotoli, Silvia Catuogno and Carla L. Esposito
Cancers 2020, 12(6), 1365; https://doi.org/10.3390/cancers12061365 - 26 May 2020
Cited by 9 | Viewed by 3327
Abstract
Tumor mass consists of a complex ensemble of malignant cancer cells and a wide variety of resident and infiltrating cells, secreted factors, and extracellular matrix proteins that are referred as tumor microenvironment (TME). Cancer associated fibroblasts (CAFs) are key TME components that support [...] Read more.
Tumor mass consists of a complex ensemble of malignant cancer cells and a wide variety of resident and infiltrating cells, secreted factors, and extracellular matrix proteins that are referred as tumor microenvironment (TME). Cancer associated fibroblasts (CAFs) are key TME components that support tumor growth, generating a physical barrier against drugs and immune infiltration, and contributing to regulate malignant progression. Thus, it is largely accepted that therapeutic approaches aimed at hampering the interactions between tumor cells and CAFs can enhance the effectiveness of anti-cancer treatments. In this view, nucleic acid therapeutics have emerged as promising molecules. Here, we summarize recent knowledge about their role in the regulation of CAF transformation and tumor-promoting functions, highlighting their therapeutic utility and challenges. Full article
(This article belongs to the Special Issue RNA Drugs in Tumor Microenvironment)
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