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19 pages, 10074 KiB

Open AccessFeature PaperArticle

GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment

by Han-Gyu Chang, Yong-Hyeon Choi, JinWoo Hong, Joung-Woo Choi, A-Rum Yoon and Chae-Ok Yun

Cells 2021, 10(11), 2811; https://doi.org/10.3390/cells10112811 - 20 Oct 2021

Cited by 2 | Viewed by 2082

Abstract

Oncolytic adenoviruses (oAds) have been evaluated in numerous clinical trials due to their promising attributes as cancer therapeutics. However, the therapeutic efficacy of oAds was limited due to variable coxsackie and adenovirus receptor (CAR) expression levels and the dense extracellular matrix (ECM) of [...] Read more.

Oncolytic adenoviruses (oAds) have been evaluated in numerous clinical trials due to their promising attributes as cancer therapeutics. However, the therapeutic efficacy of oAds was limited due to variable coxsackie and adenovirus receptor (CAR) expression levels and the dense extracellular matrix (ECM) of heterogenic clinical tumors. To overcome these limitations, our present report investigated the therapeutic efficacy of combining GM101, an oAd with excellent tumor ECM degrading properties, and histone deacetylase inhibitor (HDACi). Four different HDACi (suberohydroxamic acid (SBHA), MS-275, trichostatin A (TSA), and valproic acid) candidates in combination with replication-incompetent and GFP-expressing Ad (dAd/GFP) revealed that SBHA and MS-275 exerted more potent enhancement in Ad transduction efficacy than TSA or valproic acid. Further characterization revealed that SBHA and MS-275 effectively upregulated CAR expression in cancer cells, improved the binding of Ad with cancer cell membranes, and led to dynamin 2- and clathrin-mediated endocytosis of Ad. The combination of GM101 with HDACi induced superior cancer cell killing effects compared to any of the monotherapies, without any additional cytotoxicity in normal cell lines. Further, GM101+SBHA and GM101+MS-275 induced more potent antitumor efficacy than any monotherapy in U343 xenograft tumor model. Potent antitumor efficacy was achieved via the combination of GM101 with HDACi, inducing necrotic and apoptotic cancer cell death, inhibiting cancer cell proliferation, degrading ECM in tumor tissue, and thus exerting the highest level of virus dispersion and accumulation. Collectively, these data demonstrate that the combination of GM101 and HDACi can enhance intratumoral dispersion and accumulation of oAd through multifaced mechanisms, making it a promising strategy to address the challenges toward successful clinical development of oAd. Full article

(This article belongs to the Special Issue Cell and Gene Therapy of Cancer)

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19 pages, 34059 KiB

Open AccessArticle

Optimizing Active Tumor Targeting Biocompatible Polymers for Efficient Systemic Delivery of Adenovirus

by Jun Young Lee, Jin Woo Hong, Thavasyappan Thambi, A-Rum Yoon, Joung-Woo Choi, Yi Li, Quang Nam Bui, Doo Sung Lee and Chae-Ok Yun

Cells 2021, 10(8), 1896; https://doi.org/10.3390/cells10081896 - 26 Jul 2021

Cited by 5 | Viewed by 2120

Abstract

Adenovirus (Ad) has risen to be a promising alternative to conventional cancer therapy. However, systemic delivery of Ad, which is necessary for the treatment of metastatic cancer, remains a major challenge within the field, owing to poor tumor tropism and nonspecific hepatic tropism [...] Read more.

Adenovirus (Ad) has risen to be a promising alternative to conventional cancer therapy. However, systemic delivery of Ad, which is necessary for the treatment of metastatic cancer, remains a major challenge within the field, owing to poor tumor tropism and nonspecific hepatic tropism of the virus. To address this limitation of Ad, we have synthesized two variants of folic acid (FA)-conjugated methoxy poly(ethylene glycol)-b-poly{N-[N-(2-aminoethyl)-2-aminoethyl]-L-glutamate (P₅N₂LG-FA and P₅N₅LG-FA) using 5 kDa poly(ethylene glycol) (PEG) with a different level of protonation (N₂ < N₅ in terms of charge), along with a P₅N₅LG control polymer without FA. Our findings demonstrate that P₅N₅LG, P₅N₂LG-FA, and P₅N₅LG-FA exert a lower level of cytotoxicity compared to 25 kDa polyethyleneimine. Furthermore, green fluorescent protein (GFP)-expressing Ad complexed with P₅N₂LG-FA and P₅N₅LG-FA (Ad/P₅N₂LG-FA and Ad/P₅N₅LG-FA, respectively) exerted superior transduction efficiency compared to naked Ad or Ad complexed with P₅N₅LG (Ad/P₅N₅LG) in folate receptor (FR)-overexpressing cancer cells (KB and MCF7). All three nanocomplexes (Ad/P₅N₅LG, Ad/P₅N₂LG-FA, and Ad/P₅N₅LG-FA) internalized into cancer cells through coxsackie adenovirus receptor-independent endocytic mechanism and the cell uptake was more efficient than naked Ad. Importantly, the cell uptake of the two FA functionalized nanocomplexes (Ad/P₅N₂LG-FA and Ad/P₅N₅LG-FA) was dependent on the complementary interaction of FA–FR. Systemically administered Ad/P₅N₅LG, Ad/P₅N₂LG-FA, and Ad/P₅N₅LG-FA showed exponentially higher retainment of the virus in blood circulation up to 24 h post-administration compared with naked Ad. Both tumor-targeted nanocomplexes (Ad/P₅N₂LG-FA and Ad/P₅N₅LG-FA) showed significantly higher intratumoral accumulation than naked Ad or Ad/P₅N₅LG via systemic administration. Both tumor-targeted nanocomplexes accumulated at a lower level in liver tissues compared to naked Ad. Notably, the nonspecific accumulation of Ad/P₅N₂LG-FA was significantly lower than Ad/P₅N₅LG-FA in several normal organs, while exhibiting a significantly higher intratumoral accumulation level, showing that careful optimization of polyplex surface charge is critical to successful tumor-targeted systemic delivery of Ad nanocomplexes. Full article

(This article belongs to the Special Issue Cell and Gene Therapy of Cancer)

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20 pages, 3815 KiB

Open AccessArticle

Development and Validation of a Good Manufacturing Process for IL-4-Driven Expansion of Chimeric Cytokine Receptor-Expressing CAR T-Cells

by May C. I. van Schalkwyk, Sjoukje J. C. van der Stegen, Leticia Bosshard-Carter, Helen Graves, Sophie Papa, Ana C. Parente-Pereira, Farzin Farzaneh, Christopher D. Fisher, Andrew Hope, Antonella Adami and John Maher

Cells 2021, 10(7), 1797; https://doi.org/10.3390/cells10071797 - 15 Jul 2021

Cited by 4 | Viewed by 5503

Abstract

Adoptive cancer immunotherapy using chimeric antigen receptor (CAR) engineered T-cells holds great promise, although several obstacles hinder the efficient generation of cell products under good manufacturing practice (GMP). Patients are often immune compromised, rendering it challenging to produce sufficient numbers of gene-modified cells. [...] Read more.

Adoptive cancer immunotherapy using chimeric antigen receptor (CAR) engineered T-cells holds great promise, although several obstacles hinder the efficient generation of cell products under good manufacturing practice (GMP). Patients are often immune compromised, rendering it challenging to produce sufficient numbers of gene-modified cells. Manufacturing protocols are labour intensive and frequently involve one or more open processing steps, leading to increased risk of contamination. We set out to develop a simplified process to generate autologous gamma retrovirus-transduced T-cells for clinical evaluation in patients with head and neck cancer. T-cells were engineered to co-express a panErbB-specific CAR (T1E28z) and a chimeric cytokine receptor (4αβ) that permits their selective expansion in response to interleukin (IL)-4. Using peripheral blood as starting material, sterile culture procedures were conducted in gas-permeable bags under static conditions. Pre-aliquoted medium and cytokines, bespoke connector devices and sterile welding/sealing were used to maximise the use of closed manufacturing steps. Reproducible IL-4-dependent expansion and enrichment of CAR-engineered T-cells under GMP was achieved, both from patients and healthy donors. We also describe the development and approach taken to validate a panel of monitoring and critical release assays, which provide objective data on cell product quality. Full article

(This article belongs to the Special Issue Cell and Gene Therapy of Cancer)

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23 pages, 7570 KiB

Open AccessArticle

A Personalized Genomics Approach of the Prostate Cancer

by Sanda Iacobas and Dumitru A. Iacobas

Cells 2021, 10(7), 1644; https://doi.org/10.3390/cells10071644 - 30 Jun 2021

Cited by 10 | Viewed by 2618

Abstract

Decades of research identified genomic similarities among prostate cancer patients and proposed general solutions for diagnostic and treatments. However, each human is a dynamic unique with never repeatable transcriptomic topology and no gene therapy is good for everybody. Therefore, we propose the Genomic [...] Read more.

Decades of research identified genomic similarities among prostate cancer patients and proposed general solutions for diagnostic and treatments. However, each human is a dynamic unique with never repeatable transcriptomic topology and no gene therapy is good for everybody. Therefore, we propose the Genomic Fabric Paradigm (GFP) as a personalized alternative to the biomarkers approach. Here, GFP is applied to three (one primary—“A”, and two secondary—“B” & “C”) cancer nodules and the surrounding normal tissue (“N”) from a surgically removed prostate tumor. GFP proved for the first time that, in addition to the expression levels, cancer alters also the cellular control of the gene expression fluctuations and remodels their networking. Substantial differences among the profiled regions were found in the pathways of P53-signaling, apoptosis, prostate cancer, block of differentiation, evading apoptosis, immortality, insensitivity to anti-growth signals, proliferation, resistance to chemotherapy, and sustained angiogenesis. ENTPD2, AP5M1 BAIAP2L1, and TOR1A were identified as the master regulators of the “A”, “B”, “C”, and “N” regions, and potential consequences of ENTPD2 manipulation were analyzed. The study shows that GFP can fully characterize the transcriptomic complexity of a heterogeneous prostate tumor and identify the most influential genes in each cancer nodule. Full article

(This article belongs to the Special Issue Cell and Gene Therapy of Cancer)

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16 pages, 3627 KiB

Open AccessFeature PaperArticle

C-REV Retains High Infectivity Regardless of the Expression Levels of cGAS and STING in Cultured Pancreatic Cancer Cells

by Daishi Morimoto, Shigeru Matsumura, Itzel Bustos-Villalobos, Patricia Angela Sibal, Toru Ichinose, Yoshinori Naoe, Ibrahim Ragab Eissa, Mohamed Abdelmoneim, Nobuaki Mukoyama, Noriyuki Miyajima, Maki Tanaka, Yasuhiro Kodera and Hideki Kasuya

Cells 2021, 10(6), 1502; https://doi.org/10.3390/cells10061502 - 15 Jun 2021

Cited by 7 | Viewed by 2862

Abstract

Oncolytic virus (OV) therapy is widely considered as a major breakthrough in anti-cancer treatments. In our previous study, the efficacy and safety of using C-REV for anti-cancer therapy in patients during stage I clinical trial was reported. The stimulator of interferon genes (STING)–TBK1–IRF3–IFN [...] Read more.

Oncolytic virus (OV) therapy is widely considered as a major breakthrough in anti-cancer treatments. In our previous study, the efficacy and safety of using C-REV for anti-cancer therapy in patients during stage I clinical trial was reported. The stimulator of interferon genes (STING)–TBK1–IRF3–IFN pathway is known to act as the central cellular host defense against viral infection. Recent reports have linked low expression levels of cGAS and STING in cancer cells to poor prognosis among patients. Moreover, downregulation of cGAS and STING has been linked to higher susceptibility to OV infection among several cancer cell lines. In this paper, we show that there is little correlation between levels of cGAS/STING expression and susceptibility to C-REV among human pancreatic cancer cell lines. Despite having a responsive STING pathway, BxPC-3 cells are highly susceptible to C-REV infection. Upon pre-activation of the STING pathway, BxPc-3 cells exhibited resistance to C-REV infection. However, without pre-activation, C-REV completely suppressed the STING pathway in BxPC-3 cells. Additionally, despite harboring defects in the STING pathway, other high-grade cancer cell lines, such as Capan-2, PANC-1 and MiaPaCa-2, still exhibited low susceptibility to C-REV infection. Furthermore, overexpression of STING in MiaPaCa-2 cells altered susceptibility to a limited extent. Taken together, our data suggest that the cGAS–STING pathway plays a minor role in the susceptibility of pancreatic cancer cell lines to C-REV infection. Full article

(This article belongs to the Special Issue Cell and Gene Therapy of Cancer)

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17 pages, 2799 KiB

Open AccessArticle

Anti-Tumor Effects of MAPK-Dependent Tumor-Selective Oncolytic Vaccinia Virus Armed with CD/UPRT against Pancreatic Ductal Adenocarcinoma in Mice

by Hajime Kurosaki, Motomu Nakatake, Teruhisa Sakamoto, Nozomi Kuwano, Masato Yamane, Kenta Ishii, Yoshiyuki Fujiwara and Takafumi Nakamura

Cells 2021, 10(5), 985; https://doi.org/10.3390/cells10050985 - 23 Apr 2021

Cited by 9 | Viewed by 2899

Abstract

Engineered vaccinia virus serves as an oncolytic virus for cancer virotherapy. We evaluated the oncolytic characteristics of VGF- and O1-deleted recombinant mitogen-activated protein kinase (MAPK)-dependent vaccinia virus (MDRVV). We found that compared with viruses with the deletion of either gene alone, [...] Read more.

Engineered vaccinia virus serves as an oncolytic virus for cancer virotherapy. We evaluated the oncolytic characteristics of VGF- and O1-deleted recombinant mitogen-activated protein kinase (MAPK)-dependent vaccinia virus (MDRVV). We found that compared with viruses with the deletion of either gene alone, MDRVV is more attenuated in normal cells and can replicate in cancer cells that exhibit constitutive ERK1/2 activation in the MAPK pathway. We armed MDRVV with a bifunctional fusion gene encoding cytosine deaminase and uracil phosphoribosyltransferase (CD/UPRT), which converts 5-fluorocytosine (5-FC) into chemotherapeutic agents, and evaluated its oncolytic activity alone or in combination with 5-FC in human pancreatic cancer cell lines, tumor mouse models of peritoneal dissemination and liver metastasis, and ex vivo-infected live pancreatic cancer patient-derived tissues. CD/UPRT-armed MDRVV alone could efficiently eliminate pancreatic cancers, and its antitumor effects were partially enhanced in combination with 5-FC in vitro and in vivo. Moreover, the replication of MDRVV was detected in tumor cells of patient-derived, surgically resected tissues, which showed enlarged nuclei and high expression of pERK1/2 and Ki-67, and not in stromal cells. Our findings suggest that systemic injections of CD/UPRT-armed MDRVV alone or in combination with 5-FC are promising therapeutic strategies for pancreatic ductal adenocarcinoma. Full article

(This article belongs to the Special Issue Cell and Gene Therapy of Cancer)

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14 pages, 6944 KiB

Open AccessArticle

Systemic Delivery of Oncolytic Adenovirus to Tumors Using Tumor-Infiltrating Lymphocytes as Carriers

by Joao Santos, Camilla Heiniö, Dafne Quixabeira, Sadia Zafar, James Clubb, Santeri Pakola, Victor Cervera-Carrascon, Riikka Havunen, Anna Kanerva and Akseli Hemminki

Cells 2021, 10(5), 978; https://doi.org/10.3390/cells10050978 - 22 Apr 2021

Cited by 20 | Viewed by 3024

Abstract

Immunotherapy with tumor-infiltrating lymphocytes (TIL) or oncolytic adenoviruses, have shown promising results in cancer treatment, when used as separate therapies. When used in combination, the antitumor effect is synergistically potentiated due oncolytic adenovirus infection and its immune stimulating effects on T cells. Indeed, [...] Read more.

Immunotherapy with tumor-infiltrating lymphocytes (TIL) or oncolytic adenoviruses, have shown promising results in cancer treatment, when used as separate therapies. When used in combination, the antitumor effect is synergistically potentiated due oncolytic adenovirus infection and its immune stimulating effects on T cells. Indeed, studies in hamsters have shown a 100% complete response rate when animals were treated with oncolytic adenovirus coding for TNFa and IL-2 (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) and TIL therapy. In humans, one caveat with oncolytic virus therapy is that intratumoral injection has been traditionally preferred over systemic administration, for achieving sufficient virus concentrations in tumors, especially when neutralizing antibodies emerge. We have previously shown that 5/3 chimeric oncolytic adenovirus can bind to human lymphocytes for avoidance of neutralization. In this study, we hypothesized that incubation of oncolytic adenovirus (TILT-123) with TILs prior to systemic injection would allow delivery of virus to tumors. This approach would deliver both components in one self-amplifying product. TILs would help deliver TILT-123, whose replication will recruit more TILs and increase their cytotoxicity. In vitro, TILT-123 was seen binding efficiently to lymphocytes, supporting the idea of dual administration. We show in vivo in different models that virus could be delivered to tumors with TILs as carriers. Full article

(This article belongs to the Special Issue Cell and Gene Therapy of Cancer)

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21 pages, 4173 KiB

Open AccessArticle

Periostin Short Fragment with Exon 17 via Aberrant Alternative Splicing Is Required for Breast Cancer Growth and Metastasis

by Yuka Ikeda-Iwabu, Yoshiaki Taniyama, Naruto Katsuragi, Fumihiro Sanada, Nobutaka Koibuchi, Kana Shibata, Kenzo Shimazu, Hiromi Rakugi and Ryuichi Morishita

Cells 2021, 10(4), 892; https://doi.org/10.3390/cells10040892 - 14 Apr 2021

Cited by 5 | Viewed by 2964

Abstract

Background: Periostin (POSTN) is a 93 kDa matrix protein that helps to regulate collagen gene expression in the extracellular matrix. POSTN overexpression is a prognostic factor in malignant cancers; however, some researchers have observed it in the stroma, whereas others have reported it [...] Read more.

Background: Periostin (POSTN) is a 93 kDa matrix protein that helps to regulate collagen gene expression in the extracellular matrix. POSTN overexpression is a prognostic factor in malignant cancers; however, some researchers have observed it in the stroma, whereas others have reported it on tumors. Objective: This study aimed to investigate the function of POSTN on tumors. Methods and Results: We found that POSTN in cancer cells can be detected by using an antibody against the POSTN C-terminal region exon 17 (Ex17 antibody), but not with an antibody against the POSTN N-terminal region exon 12 (Ex12 antibody) in patients with breast cancer. In a fraction secreted from fibroblasts, LC–MS/MS analysis revealed a short fragment of POSTN of approximately 40 kDa with exon 17. In addition, molecular interaction analysis showed that POSTN with exon 17, but not POSTN without exon 17, bound specifically to wnt3a, and the Ex17 antibody inhibited the binding. Conclusion: A short fragment of POSTN with exon 17, which originates in the fibroblasts, is transported to cancer cells, whereas POSTN fragments without exon 17 are retained in the stroma. The Ex17 antibody inhibits the binding between POSTN exon 17 and wnt3a. Full article

(This article belongs to the Special Issue Cell and Gene Therapy of Cancer)

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16 pages, 5780 KiB

Open AccessArticle

Cytokine-Coding Oncolytic Adenovirus TILT-123 Is Safe, Selective, and Effective as a Single Agent and in Combination with Immune Checkpoint Inhibitor Anti-PD-1

by Riikka Havunen, Riikka Kalliokoski, Mikko Siurala, Suvi Sorsa, João M. Santos, Victor Cervera-Carrascon, Marjukka Anttila and Akseli Hemminki

Cells 2021, 10(2), 246; https://doi.org/10.3390/cells10020246 - 27 Jan 2021

Cited by 25 | Viewed by 3545

Abstract

Oncolytic viruses provide a biologically multi-faceted treatment option for patients who cannot be cured with currently available treatment options. We constructed an oncolytic adenovirus, TILT-123, to support T-cell therapies and immune checkpoint inhibitors in solid tumors. Adenoviruses are immunogenic by nature, are easy [...] Read more.

Oncolytic viruses provide a biologically multi-faceted treatment option for patients who cannot be cured with currently available treatment options. We constructed an oncolytic adenovirus, TILT-123, to support T-cell therapies and immune checkpoint inhibitors in solid tumors. Adenoviruses are immunogenic by nature, are easy to produce in large quantities, and can carry relatively large transgenes. They are the most commonly used gene therapy vectors and are well tolerated in patients. TILT-123 expresses two potent cytokines, tumor necrosis factor alpha and interleukin-2, to stimulate especially the T-cell compartment in the tumor microenvironment. Before entering clinical studies, the safety and biodistribution of TILT-123 was studied in Syrian hamsters and in mice. The results show that TILT-123 is safe in animals as monotherapy and in combination with an immune checkpoint inhibitor anti-PD-1. The virus treatment induces acute changes in circulating immune cell compartments, but the levels return to normal by the middle of the treatment period. The virus is rapidly cleared from healthy tissues, and it does not cause damage to vital organs. The results support the initiation of a phase 1 dose-escalation trial, where melanoma patients receiving a tumor-infiltrating lymphocyte therapy are treated with TILT-123 (NCT04217473). Full article

(This article belongs to the Special Issue Cell and Gene Therapy of Cancer)

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16 pages, 3702 KiB

Open AccessArticle

A Tumor-Targeted Replicating Oncolytic Adenovirus Ad-TD-nsIL12 as a Promising Therapeutic Agent for Human Esophageal Squamous Cell Carcinoma

by Zifang Zhang, Chunyang Zhang, Jinxin Miao, Zhizhong Wang, Zhimin Wang, Zhenguo Cheng, Pengju Wang, Louisa S. Chard Dunmall, Nicholas R. Lemoine and Yaohe Wang

Cells 2020, 9(11), 2438; https://doi.org/10.3390/cells9112438 - 10 Nov 2020

Cited by 16 | Viewed by 2552

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in China and existing therapies have been unable to significantly improve prognosis. Oncolytic adenoviruses (OAds) are novel promising anti-tumor drugs and have been evaluated in several cancers including ESCC. However, the [...] Read more.

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in China and existing therapies have been unable to significantly improve prognosis. Oncolytic adenoviruses (OAds) are novel promising anti-tumor drugs and have been evaluated in several cancers including ESCC. However, the antitumour efficacy of the first generation OAds (H101) as single agent is limited. Therefore, more effective OAds are needed. Our previous studies demonstrated that the novel oncolytic adenovirus Ad-TD-nsIL12 (human adenovirus type 5 with E1ACR2, E1B19K, E3gp19K-triple deletions)harboring human non-secretory IL-12 had significant anti-tumor effect, with no toxicity, in a Syrian hamster pancreatic cancer model. In this study, we evaluated the anti-tumor effect of Ad-TD-nsIL12 in human ESCC. The cytotoxicity of Ad-TD-nsIL12, H101 and cisplatin were investigated in two newly established patient-derived tumor cells (PDCs) and a panel of ESCC cell lines in vitro. A novel adenovirus-permissive, immune-deficient Syrian hamster model of PDCs subcutaneous xenograft was established for in vivo analysis of efficacy. The results showed that Ad-TD-nsIL12 was more cytotixic to and replicated more effectively in human ESCC cell lines than H101. Compared with cisplatin and H101, Ad-TD-nsIL12 could significantly inhibit tumor growth and tumor angiogenesis as well as enhance survival rate of animals with no side effects. These findings suggest that Ad-TD-nsIL12 has superior anti-tumor potency against human ESCC with a good safety profile. Full article

(This article belongs to the Special Issue Cell and Gene Therapy of Cancer)

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Review

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20 pages, 1351 KiB

Open AccessReview

Regulation of RNA Splicing: Aberrant Splicing Regulation and Therapeutic Targets in Cancer

by Koji Kitamura and Keisuke Nimura

Cells 2021, 10(4), 923; https://doi.org/10.3390/cells10040923 - 16 Apr 2021

Cited by 17 | Viewed by 5299

Abstract

RNA splicing is a critical step in the maturation of precursor mRNA (pre-mRNA) by removing introns and exons. The combination of inclusion and exclusion of introns and exons in pre-mRNA can generate vast diversity in mature mRNA from a limited number of genes. [...] Read more.

RNA splicing is a critical step in the maturation of precursor mRNA (pre-mRNA) by removing introns and exons. The combination of inclusion and exclusion of introns and exons in pre-mRNA can generate vast diversity in mature mRNA from a limited number of genes. Cancer cells acquire cancer-specific mechanisms through aberrant splicing regulation to acquire resistance to treatment and to promote malignancy. Splicing regulation involves many factors, such as proteins, non-coding RNAs, and DNA sequences at many steps. Thus, the dysregulation of splicing is caused by many factors, including mutations in RNA splicing factors, aberrant expression levels of RNA splicing factors, small nuclear ribonucleoproteins biogenesis, mutations in snRNA, or genomic sequences that are involved in the regulation of splicing, such as 5’ and 3’ splice sites, branch point site, splicing enhancer/silencer, and changes in the chromatin status that affect the splicing profile. This review focuses on the dysregulation of RNA splicing related to cancer and the associated therapeutic methods. Full article

(This article belongs to the Special Issue Cell and Gene Therapy of Cancer)

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16 pages, 1596 KiB

Open AccessReview

Inflammatory Cytokines in Cancer: Comprehensive Understanding and Clinical Progress in Gene Therapy

by Tianxia Lan, Li Chen and Xiawei Wei

Cells 2021, 10(1), 100; https://doi.org/10.3390/cells10010100 - 8 Jan 2021

Cited by 105 | Viewed by 6374

Abstract

The relationship between chronic inflammation and neoplastic diseases is not fully understood. The inflammatory microenvironment of a tumor is an intricate network that consists of numerous types of cells, cytokines, enzymes and signaling pathways. Recent evidence shows that the crucial components of cancer-related [...] Read more.

The relationship between chronic inflammation and neoplastic diseases is not fully understood. The inflammatory microenvironment of a tumor is an intricate network that consists of numerous types of cells, cytokines, enzymes and signaling pathways. Recent evidence shows that the crucial components of cancer-related inflammation are involved in a coordinated system to influence the development of cancer, which may shed light on the development of potential anticancer therapies. Since the last century, considerable effort has been devoted to developing gene therapies for life-threatening diseases. When it comes to modulating the inflammatory microenvironment for cancer therapy, inflammatory cytokines are the most efficient targets. In this manuscript, we provide a comprehensive review of the relationship between inflammation and cancer development, especially focusing on inflammatory cytokines. We also summarize the clinical trials for gene therapy targeting inflammatory cytokines for cancer treatment. Future perspectives concerned with new gene-editing technology and novel gene delivery systems are finally provided. Full article

(This article belongs to the Special Issue Cell and Gene Therapy of Cancer)

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