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Targeting Tumor Microenvironment for Cancer Therapy
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Targeting Tumor Microenvironment for Cancer Therapy

A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 30060

Special Issue Editors

Dr. Ming-Wei Lin

E-Mail Website
Guest Editor
1. Department of Medical Research, E-Da Hospital/E-Da Cancer Hospital, Kaohsiung, Taiwan
2. Department of Nursing, College of Medicine, I-Shou University, Kaohsiung, Taiwan
Interests: tumor microenvironment; GRP78; exosome; mitochondria; gastric cancer; breast cancer; cancer stemness
Special Issues, Collections and Topics in MDPI journals
Dr. Cheng-Che Lee

E-Mail Website
Guest Editor
School of Medicine for International Student, I-Shou University, Kaohsiung, Taiwan
Interests: MEC-17; EGFR; tumor invasion; autophagy; apoptosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Chemotherapy is the treatment of choice for cancer, but the currently available therapeutic drugs for it have limited efficacy. Recent studies have suggested that cancer stem cells in the tumor microenvironment may play an important role in the drug resistance of chemotherapy. The tumor microenvironment comprising cellular components, such as cancer-associated fibroblasts, tumor-associated macrophages, tumor-associated neutrophils and endothelial cells, has been recognized as a critical contributor to the development and progression of cancer. As the seed and soil hypothesis states that the tumor microenvironment, as a main driver, promotes cancer stemness and therapeutic resistance in most cancers, new agents or treatment strategies that modulate the tumor microenvironment are urgently needed. Regarding this concept, the focus of this issue is investigations on new treatment strategies and molecular mechanisms of tumor microenvironment targeting for cancer therapy. Topics related to cancer stemness or chemoresistance targeting and so on are welcome.

Dr. Ming-Wei Lin
Dr. Cheng-Che Lee
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 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

  • chemotherapy
  • cancer
  • tumor
  • tumor microenvironment
  • cancer stem cells
  • cancer therapy
  • cancer stemness
  • chemoresistance

Published Papers (16 papers)

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Research

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14 pages, 3698 KiB  
Article
The Involvement of Hypoxia in the Response of Neuroblastoma Cells to the Exposure of Atorvastatin
by Ana Salomé Correia, Lara Marques and Nuno Vale
Curr. Issues Mol. Biol. 2023, 45(4), 3333-3346; https://doi.org/10.3390/cimb45040218 - 11 Apr 2023
Cited by 1 | Viewed by 1402
Abstract
Cancer is a set of complex diseases, being one of the leading causes of death worldwide. Despite a lot of research on the molecular pathways and effective treatments, there are still huge gaps. Indeed, the development of new anti-cancer drugs is a complex [...] Read more.
Cancer is a set of complex diseases, being one of the leading causes of death worldwide. Despite a lot of research on the molecular pathways and effective treatments, there are still huge gaps. Indeed, the development of new anti-cancer drugs is a complex process. To face this problem, drug repurposing is being increasingly applied. This approach aims to identify new indications for already approved drugs. In this regard, statins (clinically used for reducing cholesterol levels) are reported to induce anti-cancer effects, particularly by inducing apoptosis and altering the tumor microenvironment. Atorvastatin is a type of statin with several potentialities as an anti-cancer agent, supported by several studies. Our study aimed to explore the effect of this drug in SH-SY5Y human neuroblastoma cells. Additionally, we also aimed to understand how this drug acts under hypoxia and the inhibition of hypoxia-inducible factor-1 (HIF-1). For that purpose, we assessed cellular viability/morphology after exposure to different concentrations of atorvastatin, with or without chemically induced hypoxia with chloride cobalt (CoCl2) and with or without echinomycin (HIF-1α inhibitor). Our results supported the cytotoxic effects of atorvastatin. Additionally, we also revealed that besides these effects, under hypoxia, this drug induced proliferation of the neuroblastoma cells, supporting the importance of different stimuli and environment on the effect of drugs on cancer cells. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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17 pages, 3238 KiB  
Article
Do Elevated YKL-40 Levels Drive the Immunosuppressive Tumor Microenvironment in Colorectal Cancer? Assessment of the Association of the Expression of YKL-40, MMP-8, IL17A, and PD-L1 with Coexisting Type 2 Diabetes, Obesity, and Active Smoking
by Błażej Ochman, Sylwia Mielcarska, Agnieszka Kula, Miriam Dawidowicz, Julia Robotycka, Jerzy Piecuch, Monika Szrot, Sylwia Dzięgielewska-Gęsiak, Małgorzata Muc-Wierzgoń, Dariusz Waniczek and Elżbieta Świętochowska
Curr. Issues Mol. Biol. 2023, 45(4), 2781-2797; https://doi.org/10.3390/cimb45040182 - 27 Mar 2023
Cited by 3 | Viewed by 1702
Abstract
The influence of chitinase-3-like protein 1 (YKL-40 or CHI3L1) expression on the immunological properties of the tumor microenvironment, which may affect the effectiveness of immunotherapy, is currently not sufficiently understood in colorectal cancer (CRC). The aim of this study was to investigate the [...] Read more.
The influence of chitinase-3-like protein 1 (YKL-40 or CHI3L1) expression on the immunological properties of the tumor microenvironment, which may affect the effectiveness of immunotherapy, is currently not sufficiently understood in colorectal cancer (CRC). The aim of this study was to investigate the relationship between YKL-40 expression and the immunological properties of the tumor microenvironment in CRC. We performed in silico analysis, including analysis of immune cell infiltration scores and the immune landscape depending on YKL-40 expression, gene set enrichment analysis (GSEA), and analysis of three Gene Expression Omnibus (GEO) datasets. In 48 CRC tissue homogenates and the surgical margin, we analyzed the expression of YKL-40, MMP8, IL17A, and PD-L1. Moreover, we analyzed the expression of YKL-40 in tissue homogenates retrieved from patients with coexisting diabetes, obesity, and smoking. The expression of YKL-40 was significantly higher in CRC tumor tissue compared to healthy tissue and correlated with MMP-8, IL17A, and PD-L1 expression. In silico analysis revealed an association of YKL-40 with disease recurrence, and GSEA revealed a potential link between elevated YKL-40 expression and immunosuppressive properties of the tumor microenvironment in CRC. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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14 pages, 5832 KiB  
Article
Correlations of PTEN and ERG Immunoexpression in Prostate Carcinoma and Lesions Related to Its Natural History: Clinical Perspectives
by Olga Voulgari, Dimitrios Goutas, Alexandros Pergaris, Konstantinos Belogiannis, Eirini Thymara, Nikolaos Kavantzas and Andreas C. Lazaris
Curr. Issues Mol. Biol. 2023, 45(4), 2767-2780; https://doi.org/10.3390/cimb45040181 - 25 Mar 2023
Cited by 1 | Viewed by 1344
Abstract
Purpose: The aim of our study was to observe the associations between the ETS-related gene (ERG) and the phosphatase and tensin homolog gene (PTEN) immunoexpression in prostate cancer and related lesions and highlight the clinical significance of these findings. [...] Read more.
Purpose: The aim of our study was to observe the associations between the ETS-related gene (ERG) and the phosphatase and tensin homolog gene (PTEN) immunoexpression in prostate cancer and related lesions and highlight the clinical significance of these findings. Methods: We evaluated the immunohistochemical expression of ERG and PTEN in a series of 151 invasive prostate adenocarcinomas, including low-grade (Gleason grade pattern 3) and high-grade (Gleason grade patterns 4, 5) morphological patterns which corresponded to 45.5% and 54.4% of the cases, respectively. Additionally, we evaluated the immunoexpression of the two markers both in foci of high-grade prostatic intraepithelial neoplasia (HGPIN), as a precursor lesion of cancer, and in foci of intraductal carcinoma of the prostate (IDCP). Finally, to ensure the malignant nature of the prostate glands examined, we employed p63 and alpha-methylacyl-CoA racemase (AMACR) expression. Results: We found that PTEN loss was observed in 50.7%, and ERG positivity was detected in 41.8% of our cancerous samples. In HGPIN, PTEN loss appeared to be linked with a high-grade adjacent invasive carcinoma component which also displayed PTEN loss. As far as IDCP is concerned, ERG immunonegativity was correlated with adjacent high-grade invasive cancer, which was also ERG immunonegative. Conclusions: Our findings suggest that the clonal expansion of invasive cancer appears to be associated with distinct immunophenotypic cellular alterations of both early and late cancer-related histological lesions. Patients with PTEN loss in HGPIN in prostate biopsies should be closely monitored due to the increased likelihood of having an associated invasive high-grade carcinoma that may have not been sampled. Given the clinical significance that derives from PTEN expression in HGPIN lesions, we suggest the routine use of PTEN immunohistochemistry in prostate cancer biopsies in which HGPIN is the only finding. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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18 pages, 2261 KiB  
Article
In Vitro Evidence of Differential Immunoregulatory Response between MDA-MB-231 and BT-474 Breast Cancer Cells Induced by Bone Marrow-Derived Mesenchymal Stromal Cells Conditioned Medium
by Víctor M. Arenas-Luna, Juan J. Montesinos, Víctor A. Cortés-Morales, José R. Navarro-Betancourt, Janneth Peralta-Ildefonso, Bulmaro Cisneros and Salomón Hernández-Gutiérrez
Curr. Issues Mol. Biol. 2023, 45(1), 268-285; https://doi.org/10.3390/cimb45010020 - 30 Dec 2022
Cited by 1 | Viewed by 1906
Abstract
Inside tumors, cancer cells display several mechanisms to create an immunosuppressive environment. On the other hand, by migration processes, mesenchymal stromal cells (MSCs) can be recruited by different cancer tumor types from tissues as distant as bone marrow and contribute to tumor pathogenesis. [...] Read more.
Inside tumors, cancer cells display several mechanisms to create an immunosuppressive environment. On the other hand, by migration processes, mesenchymal stromal cells (MSCs) can be recruited by different cancer tumor types from tissues as distant as bone marrow and contribute to tumor pathogenesis. However, the impact of the immunoregulatory role of MSCs associated with the aggressiveness of breast cancer cells by soluble molecules has not been fully elucidated. Therefore, this in vitro work aimed to study the effect of the conditioned medium of human bone marrow-derived-MSCs (hBM-MSC-cm) on the immunoregulatory capability of MDA-MB-231 and BT-474 breast cancer cells. The hBM-MSC-cm on MDA-MB-231 cells induced the overexpression of TGF-β, IDO, and IL-10 genes. Additionally, immunoregulation assays of mononuclear cells (MNCs) in co-culture with MDA-MB-231 and hBM-MSC-cm decreased lymphocyte proliferation, and increased proteins IL-10, TGF-β, and IDO while also reducing TNF levels, shooting the proportion of regulatory T cells. Conversely, the hBM-MSC-cm did not affect the immunomodulatory capacity of BT-474 cells. Thus, a differential immunoregulatory effect was observed between both representative breast cancer cell lines from different origins. Thus, understanding the immune response in a broader tumor context could help to design therapeutic strategies based on the aggressive behavior of tumor cells. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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20 pages, 5592 KiB  
Article
Novel Strategies for Cancer Combat: Drug Combination Using Repurposed Drugs Induces Synergistic Growth Inhibition of MCF-7 Breast and HT-29 Colon Cancer Cells
by Diana Duarte, Inês Guerreiro and Nuno Vale
Curr. Issues Mol. Biol. 2022, 44(10), 4930-4949; https://doi.org/10.3390/cimb44100335 - 16 Oct 2022
Cited by 4 | Viewed by 2201
Abstract
Our group developed a new model of drug combination consisting of the use of antineoplastic drugs and different repurposed drugs, having demonstrated that antimalarial and central nervous system (CNS) drugs have a promising anticancer profile as standalone agents, as well as in combined [...] Read more.
Our group developed a new model of drug combination consisting of the use of antineoplastic drugs and different repurposed drugs, having demonstrated that antimalarial and central nervous system (CNS) drugs have a promising anticancer profile as standalone agents, as well as in combined regimens. Here, we evaluated the anticancer profiles of two different CNS drugs (edaravone and quetiapine), both alone and in combination with antineoplastic agents for breast and colon cancer, to explore whether these repurposed drugs could synergistically enhance the anticancer potential of chemotherapeutic drugs. We also developed a new model of combination using two repurposed drugs, to explore whether this model of combination could also be suitable for application in breast and colon cancer therapy. MCF-7 and HT-29 cancer cells were incubated for 48 h with each individual drug (0.01–100 µM) to determine their IC50. Cells were then treated with the IC50 value for doxorubicin or paclitaxel (MCF-7) or 5-fluorouracil (HT-29) and combined with increasing concentrations of edaravone or quetiapine for 48 h. Both cell lines were also treated with a combination of two antimalarial drugs (mefloquine and pyronaridine) or two CNS drugs (fluphenazine and sertraline) for 48 h. We found that the use of quetiapine in combined therapies seems to synergistically enhance the anticancer activity of doxorubicin for the management of breast cancer. Both CNS drugs significantly improved the cytotoxic potential of 5-fluorouracil in HT-29 cells, with quetiapine synergistically interacting with the antineoplastic drug in this drug combination. Regarding the combination of repurposed drugs, only found one synergic combination regimen (sertraline IC50 plus variable concentrations of fluphenazine) with anticancer potential against HT-29 colon cancer cells was found. Taken together, these results suggest that quetiapine and edaravone can be used as adjuvant agents in chemotherapy for colon cancer. It was also found that the combination of repurposed drugs, specifically the CNS drugs sertraline and fluphenazine, may have an interesting profile for application in colon cancer novel therapies. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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18 pages, 4319 KiB  
Article
Dynamic Expression of Palmitoylation Regulators across Human Organ Development and Cancers Based on Bioinformatics
by Zixian Jia, Deyu Long and Yingcui Yu
Curr. Issues Mol. Biol. 2022, 44(10), 4472-4489; https://doi.org/10.3390/cimb44100306 - 27 Sep 2022
Cited by 1 | Viewed by 1532
Abstract
Protein palmitoylation is a reversible modification process that links palmitate to cysteine residues via a reversible thioester bond. Palmitoylation exerts an important role in human organ development and tumor progression. However, a comprehensive landscape regarding the dynamic expression of palmitoylation regulators in human [...] Read more.
Protein palmitoylation is a reversible modification process that links palmitate to cysteine residues via a reversible thioester bond. Palmitoylation exerts an important role in human organ development and tumor progression. However, a comprehensive landscape regarding the dynamic expression of palmitoylation regulators in human organ development remains unclear. In this study, we analyzed the dynamic expression of palmitoylation regulators in seven organ development and eight cancer types based on bioinformatics. We found that the expression levels of most palmitoylation regulators were altered after birth. In particular, ZDHHC7/20/21 exhibited converse expression patterns in multiple cancer types. Survival analysis showed that the poor prognosis in patients with kidney renal clear carcinoma (KIRC) is related to low expression of ZDHHC7/20/21, and a high expression of ZDHHC7/20/21 is related to worse survival in patients with liver hepatocellular carcinoma (LIHC). Furthermore, we found that the expression of ZDHHC7 is associated with infiltration levels of some types of immune cells in the tumor microenvironment (TME), and we explored the relationship between ZDHHC7 expression and immune checkpoint (ICP) genes across 33 cancer types. In addition, gene set enrichment analysis (GSEA) results indicated that ZDHHC7 might regulate different genes to mediate the same pathway in different organs. In summary, the comprehensive analysis of palmitoylation regulators reveals their functions in human organ development and cancer, which may provide new insights for developing new tumor markers. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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11 pages, 2032 KiB  
Article
COPS5 Conferred the Platinum Resistance in Epithelial Ovarian Cancer
by Hongqin Zhang, Tianqing Yan, Ailing Zhong, Lin Guo and Renquan Lu
Curr. Issues Mol. Biol. 2022, 44(9), 3948-3958; https://doi.org/10.3390/cimb44090271 - 01 Sep 2022
Cited by 2 | Viewed by 1356
Abstract
Development of platinum resistance is one of the major causes of epithelial ovarian cancer (EOC) treatment failure. COP9 signalosome subunit 5 (COPS5) was found to take part in the progression of EOC in our previous study. Herein, we aim to uncover the potential [...] Read more.
Development of platinum resistance is one of the major causes of epithelial ovarian cancer (EOC) treatment failure. COP9 signalosome subunit 5 (COPS5) was found to take part in the progression of EOC in our previous study. Herein, we aim to uncover the potential utility of COPS5 in EOC chemoresistance. COPS5 levels were analyzed to define clinic pathologic correlates using a matched tissue microarray and online datasets. The effect of COPS5 inhibition by the lentivirus-mediated short hairpin RNA on cell viability, proliferation and migration was accessed in vitro and in vivo. Results showed that COPS5 was upregulated in patients after platinum resistance. Kaplan–Meier survival curves revealed that COPS5 overexpression was correlated with shorter PFS and OS. COPS5 downregulation inhibited the cell proliferation, migration, and reduced the sensitivity of EOC to platinum. Overall, our data indicated that COPS5 inhibition might represent a new therapeutic strategy for overcoming platinum resistance in patients with EOC. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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13 pages, 1635 KiB  
Article
Assessment of T Cell Receptor Complex Expression Kinetics in Natural Killer Cells
by Khder H. Rasul, Alamdar Hussain, Hazel Reilly, Maria Karvouni, Carin I. M. Dahlberg, Mustafa S. Al-Attar, Arnika K. Wagner, Evren Alici and Dara K. Mohammad
Curr. Issues Mol. Biol. 2022, 44(9), 3859-3871; https://doi.org/10.3390/cimb44090265 - 25 Aug 2022
Cited by 2 | Viewed by 2112
Abstract
Among the polypeptides that comprise the T cell receptor (TCR), only CD3ζ is found in Natural Killer (NK) cells, where it transmits signals from activating receptors such as CD16 and NKp46. NK cells are potent immune cells that recognize target cells through germline-encoded [...] Read more.
Among the polypeptides that comprise the T cell receptor (TCR), only CD3ζ is found in Natural Killer (NK) cells, where it transmits signals from activating receptors such as CD16 and NKp46. NK cells are potent immune cells that recognize target cells through germline-encoded activating and inhibitory receptors. Genetic engineering of NK cells enables tumor-specific antigen recognition and, thus, has a significant promise in adoptive cell therapy. Ectopic expression of engineered TCR components in T cells leads to mispairing with the endogenous components, making a knockout of the endogenous TCR necessary. To circumvent the mispairing of TCRs or the need for knockout technologies, TCR complex expression has been studied in NK cells. In the current study, we explored the cellular processing of the TCR complex in NK cells. We observed that in the absence of CD3 subunits, the TCR was not expressed on the surface of NK cells and vice versa. Moreover, a progressive increase in surface expression of TCR between day three and day seven was observed after transduction. Interestingly, the TCR complex expression in NK92 cells was enhanced with a proteasome inhibitor (bortezomib) but not a lysosomal inhibitor (chloroquine). Additionally, we observed that the TCR complex was functional in NK92 cells as measured by estimating CD107a as a degranulation marker, IFNγ cytokine production, and killing assays. NK92 cells strongly degranulated when CD3ε was engaged in the presence of TCR, but not when only CD3 was overexpressed. Therefore, our findings encourage further investigation to unravel the mechanisms that prevent the surface expression of the TCR complex. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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11 pages, 2080 KiB  
Article
Genetically Engineered Hepatitis C Virus-like Particles (HCV-LPs) Tagged with SP94 Peptide to Acquire Selectivity to Liver Cancer Cells via Grp78
by Dina Mofed, Mohamed A. Wahba and Tamer Z. Salem
Curr. Issues Mol. Biol. 2022, 44(8), 3746-3756; https://doi.org/10.3390/cimb44080256 - 20 Aug 2022
Cited by 2 | Viewed by 2468
Abstract
Targeted cancer therapy is a challenging area that includes multiple chemical and biological vehicles. Virus-like particles (VLPs) combine safety and efficacy in their roles as potential vaccines and drug delivery vehicles. In this study, we propose a novel drug delivery system based on [...] Read more.
Targeted cancer therapy is a challenging area that includes multiple chemical and biological vehicles. Virus-like particles (VLPs) combine safety and efficacy in their roles as potential vaccines and drug delivery vehicles. In this study, we propose a novel drug delivery system based on HCV-LPs engineered with SP94 and RGD peptides mediated by a specific molecular chaperone (Grp78) associated with cancer drug resistance. The PCR primers were designed for engineering two constructs, SP94-EGFP-CORE-HIS and RGD-EGFP-CORE-HIS, by sequential PCR reactions. The two fragments were cloned into pFastBac Dual under the polyhedrin promoter and then used to produce two recombinant baculoviruses (AcSP94 and AcRGD). The VLP’s expression was optimized by recombinant virus infection with different MOIs, ranging from 1 to 20 MOI. Recombinant VLP2 were purified by Ni-NTA and their sizes and shapes were confirmed with TEM. They were incubated with different types of cells prior to examination using the fluorescence microscope to test the binding specificity. The effect of the overexpression of the Grp78 on the binding affinity of the engineered VLPs was tested in HepG2 and HeLa cells. The protocol optimization revealed that MOI 10 produced the highest fluorescence intensities after 72 h for the two recombinant proteins (SP94-core and RGD-core). Moreover, the binding assay tested on different types of mammalian cells (HeLa, HEK-293T, and HepG2 cells) showed green fluorescence on the periphery of all tested cell lines when using the RGD-core protein; while, the SP94-core protein showed green fluorescence only with the liver cancer cells, HepG2 and HuH7. Overexpression of Grp78 in HepG2 and HeLa cells enhanced the binding efficiency of the engineered VLPs. We confirmed that the SP94 peptide can be specifically used to target liver cancer cells, while the RGD peptide is sufficiently functional for most types of cancer cells. The overexpression of the Grp78 improved the binding capacity of both SP94 and RGD peptides. It is worth noting that the SP94 peptide can function properly as a recombinant peptide, and not only as a chemically conjugated peptide, as heretofore commonly used. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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11 pages, 2364 KiB  
Article
Sonicated Bordetella bronchiseptica Bacterin Can Protect Dendritic Cells from Differential Cytotoxicity Caused by Doxorubicin and Vincristine and Enhance Their Antigen-Presenting Capability
by Ji Yun Sung and Hong-Gu Joo
Curr. Issues Mol. Biol. 2022, 44(7), 3089-3099; https://doi.org/10.3390/cimb44070213 - 06 Jul 2022
Viewed by 1290
Abstract
Doxorubicin (DOX) and vincristine (VC) are anti-cancer drugs commonly used for lymphoma in veterinary and human medicine. However, there are several side effects caused by these drugs. In this study, the protective effects of sonicated Bordetella bronchiseptica bacterin (sBb) on dendritic cells (DCs) [...] Read more.
Doxorubicin (DOX) and vincristine (VC) are anti-cancer drugs commonly used for lymphoma in veterinary and human medicine. However, there are several side effects caused by these drugs. In this study, the protective effects of sonicated Bordetella bronchiseptica bacterin (sBb) on dendritic cells (DCs) damaged by two anti-cancer drugs were investigated. DCs play important roles in the innate and adaptive immunity of hosts, especially activating T cells that can suppress tumor growth. The metabolic activity of DCs significantly increased after the treatment with sBb compared to that of control DCs. In addition, there was a marked change in mitochondrial integrity between DOX-treated DC and DOX + sBb-treated DCs. Flow cytometric analysis also demonstrated that sBb upregulated the expression of the surface markers of DCs, particularly CD54. In mixed lymphocyte responses, sBb significantly increased the antigen-presenting capability of DCs. In particular, sBb increased the capability of control DCs by approximately 150% and that of VC-treated DCs by 221%. These results suggest that sBb can be used as a potential immunostimulatory agent to protect DCs from anti-cancer drug-induced damage and provide fundamental information about using a combination of DCs and vincristine in immunotherapy. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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14 pages, 3628 KiB  
Article
Using Next-Generation Sequencing and Bioinformatic Methods to Predict New Genes That May Be Regulated by CD47 in Oral Squamous Cell Carcinoma
by Chung-Chih Tseng, Chen-Han Tsou, Shi-Ying Huang, Chia-Wei Wu and Tsung-Hua Hsieh
Curr. Issues Mol. Biol. 2022, 44(5), 2243-2256; https://doi.org/10.3390/cimb44050152 - 17 May 2022
Cited by 1 | Viewed by 2034
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the world, and the incidence and death rate of OSCC in men is twice that of women. CD47 is a ubiquitous cell surface transmembrane protein, also known as integrin-related protein [...] Read more.
Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the world, and the incidence and death rate of OSCC in men is twice that of women. CD47 is a ubiquitous cell surface transmembrane protein, also known as integrin-related protein (IAP). Previous studies have pointed out that CD47 can inhibit the growth of OSCC, but the detailed mechanism is not clear. This study aimed to explore the effect of CD47 gene expression profiles in OSCC. The OSCC cell lines, OECM-1 and OC-2, overexpressed CD47, and the expression profiles of mRNAs were analyzed through next-generation sequencing (NGS) with a bioinformatic approach. A total of 14 differentially expressed genes (DEGs) were listed. In addition, ingenuity pathway analysis (IPA) was used to analyze the molecular function (MF), biological process (BP), and cellular component (CC) network signaling. The human protein atlas (HPA) database was used to analyze gene expression and the survivability of human cancer. The results found that HSPA5, HYOU1, and PDIA4 were involved in the IPA network and when highly expressed, mediated the survivability of cancer. In addition, HSPA5 was positively and significantly correlated with CD47 expression (p < 0.0001) and induced by CD47-overexpression in the OECM-1 and OC-2 OSCC cancer cell lines. These findings provide important insights into possible new diagnostic strategies, including unfolded protein for OSCC-targeting CD47. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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15 pages, 21035 KiB  
Article
Effects of Luteolin on Human Breast Cancer Using Gene Expression Array: Inferring Novel Genes
by Shih-Ho Wang, Chin-Hu Wu, Chin-Chuan Tsai, Tai-Yu Chen, Kuen-Jang Tsai, Chao-Ming Hung, Chia-Yi Hsu, Chia-Wei Wu and Tsung-Hua Hsieh
Curr. Issues Mol. Biol. 2022, 44(5), 2107-2121; https://doi.org/10.3390/cimb44050142 - 09 May 2022
Cited by 7 | Viewed by 2562
Abstract
Taraxacum officinale (dandelion) is often used in traditional Chinese medicine for the treatment of cancer; however, the downstream regulatory genes and signaling pathways mediating its effects on breast cancer remain unclear. The present study aimed to explore the effects of luteolin, the main [...] Read more.
Taraxacum officinale (dandelion) is often used in traditional Chinese medicine for the treatment of cancer; however, the downstream regulatory genes and signaling pathways mediating its effects on breast cancer remain unclear. The present study aimed to explore the effects of luteolin, the main biologically active compound of T. officinale, on gene expression profiles in MDA-MB-231 and MCF-7 breast cancer cells. The results revealed that luteolin effectively inhibited the proliferation and motility of the MDA-MB-231 and MCF-7 cells. The mRNA expression profiles were determined using gene expression array analysis and analyzed using a bioinformatics approach. A total of 41 differentially expressed genes (DEGs) were found in the luteolin-treated MDA-MB-231 and MCF-7 cells. A Gene Ontology analysis revealed that the DEGs, including AP2B1, APP, GPNMB and DLST, mainly functioned as oncogenes. The human protein atlas database also found that AP2B1, APP, GPNMB and DLST were highly expressed in breast cancer and that AP2B1 (cut-off value, 75%) was significantly associated with survival rate (p = 0.044). In addition, a Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the DEGs were involved in T-cell leukemia virus 1 infection and differentiation. On the whole, the findings of the present study provide a scientific basis that may be used to evaluate the potential benefits of luteolin in human breast cancer. Further studies are required, however, to fully elucidate the role of the related molecular pathways. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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Review

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16 pages, 795 KiB  
Review
The Current Status and Future Perspectives of Chimeric Antigen Receptor-Engineered T Cell Therapy for the Management of Patients with Endometrial Cancer
by Ji-Young Choi and Tae-Jin Kim
Curr. Issues Mol. Biol. 2023, 45(4), 3359-3374; https://doi.org/10.3390/cimb45040220 - 12 Apr 2023
Viewed by 1921
Abstract
Endometrial cancer (EC) is a gynecological neoplasm that is increasing in occurrence and mortality rates. Although endometrial cancer in the early stages shows a relatively favorable prognosis, there is an increase in cancer-related mortality rates in the advanced or recurrent endometrial carcinoma population [...] Read more.
Endometrial cancer (EC) is a gynecological neoplasm that is increasing in occurrence and mortality rates. Although endometrial cancer in the early stages shows a relatively favorable prognosis, there is an increase in cancer-related mortality rates in the advanced or recurrent endometrial carcinoma population and patients in the metastatic setting. This discrepancy has presented an opportunity for research and development of target therapies in this population. After obtaining promising results with hematologic cancers, chimeric antigen receptor (CAR)-T cell immunotherapy is gaining acceptance as a treatment for solid neoplasms. This treatment platform allows T cells to express tumor-specific CARs on the cell surface, which are administered to the patient to treat neoplastic cells. Given that CAR-T cell therapy has shown potential and clinical benefit compared to other T cell treatment platforms, additional research is required to overcome physiological limitations such as CAR-T cell depletion, immunosuppressive tumor microenvironment, and the lack of specific target molecules. Different approaches and development are ongoing to overcome these complications. This review examines CAR-T cell therapy’s current use for endometrial carcinomas. We also discuss the significant adverse effects and limitations of this immunotherapeutic approach. Finally, we consolidate signal-seeking early-phase clinical trials and advancements that have shown promising results, leading to the approval of new immunotherapeutic agents for the disease. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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18 pages, 1142 KiB  
Review
NOTCH Signaling in Osteosarcoma
by Zhenhao Zhang, Wei Wu and Zengwu Shao
Curr. Issues Mol. Biol. 2023, 45(3), 2266-2283; https://doi.org/10.3390/cimb45030146 - 08 Mar 2023
Cited by 5 | Viewed by 1846
Abstract
The combination of neoadjuvant chemotherapy and surgery has been promoted for the treatment of osteosarcoma; however, the local recurrence and lung metastasis rates remain high. Therefore, it is crucial to explore new therapeutic targets and strategies that are more effective. The NOTCH pathway [...] Read more.
The combination of neoadjuvant chemotherapy and surgery has been promoted for the treatment of osteosarcoma; however, the local recurrence and lung metastasis rates remain high. Therefore, it is crucial to explore new therapeutic targets and strategies that are more effective. The NOTCH pathway is not only involved in normal embryonic development but also plays an important role in the development of cancers. The expression level and signaling functional status of the NOTCH pathway vary in different histological types of cancer as well as in the same type of cancer from different patients, reflecting the distinct roles of the Notch pathway in tumorigenesis. Studies have reported abnormal activation of the NOTCH signaling pathway in most clinical specimens of osteosarcoma, which is closely related to a poor prognosis. Similarly, studies have reported that NOTCH signaling affected the biological behavior of osteosarcoma through various molecular mechanisms. NOTCH-targeted therapy has shown potential for the treatment of osteosarcoma in clinical research. After the introduction of the composition and biological functions of the NOTCH signaling pathway, the review paper discussed the clinical significance of dysfunction in osteosarcoma. Then the paper reviewed the recent relevant research progress made both in the cell lines and in the animal models of osteosarcoma. Finally, the paper explored the potential of the clinical application of NOTCH-targeted therapy for the treatment of osteosarcoma. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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12 pages, 764 KiB  
Review
Tumor Molecular and Microenvironment Characteristics in EBV-Associated Malignancies as Potential Therapeutic Targets: Focus on Gastric Cancer
by Aviva Atri-Schuller, Hassan Abushukair, Ludimila Cavalcante, Stijn Hentzen, Azhar Saeed and Anwaar Saeed
Curr. Issues Mol. Biol. 2022, 44(11), 5756-5767; https://doi.org/10.3390/cimb44110390 - 18 Nov 2022
Cited by 3 | Viewed by 1677
Abstract
Although most people are infected with Epstein-Barr Virus (EBV) during their lifetime, only a minority of them develop an EBV-associated malignancy. EBV acts in both direct and indirect ways to transform infected cells into tumor cells. There are multiple ways in which the [...] Read more.
Although most people are infected with Epstein-Barr Virus (EBV) during their lifetime, only a minority of them develop an EBV-associated malignancy. EBV acts in both direct and indirect ways to transform infected cells into tumor cells. There are multiple ways in which the EBV, host, and tumor environment interact to promote malignant transformation. This paper focuses on some of the mechanisms that EBV uses to transform the tumor microenvironment (TME) of EBV-associated gastric cancer (EBVaGC) for its benefit, including overexpression of Indoleamine 2,3-Dioxygenase 1 (IDO1), synergism between H. pylori and EBV co-infection, and M1 to M2 switch. In this review, we expand on different modalities and combinatorial approaches to therapeutically target this mechanism. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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11 pages, 2601 KiB  
Case Report
Pathological Evidence for Residual SARS-CoV-2 in the Micrometastatic Niche of a Patient with Ovarian Cancer
by Takuma Hayashi, Kenji Sano, Nobuo Yaegashi and Ikuo Konishi
Curr. Issues Mol. Biol. 2022, 44(12), 5879-5889; https://doi.org/10.3390/cimb44120400 - 26 Nov 2022
Viewed by 1228
Abstract
In previous clinical studies, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer patients has a high risk of aggravation and mortality than in healthy infected individuals. Inoculation with coronavirus disease 2019 (COVID-19) vaccine reduces the risk of SARS-CoV-2 infection and COVID-19 [...] Read more.
In previous clinical studies, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer patients has a high risk of aggravation and mortality than in healthy infected individuals. Inoculation with coronavirus disease 2019 (COVID-19) vaccine reduces the risk of SARS-CoV-2 infection and COVID-19 severity. However, vaccination-induced anti-SARS-CoV-2 antibody production is said to be lower in cancer patients than in healthy individuals. In addition, the rationale for why the condition of patients with cancer worsens with COVID-19 is not well understood. Therefore, we examined the infection status of SARS-CoV-2 in the primary tumor and micrometastasis tissues of the patient with cancer and COVID-19. In this study, the expression of angiotensin-converting enzyme 2 (ACE2) was observed, and SARS-CoV-2 particles was detected in ovarian tissue cells in contact with the micrometastatic niche of the patient with high-grade serous ovarian cancer. We believe that the severity of COVID-19 in patients with cancer can be attributed to these pathological features. Therefore, the pathological findings of patients with advanced and recurrent ovarian cancer infected with SARS-CoV-2 may help decrease COVID-19 severity in patients with other cancer types. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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