Micropeptides: potential treatment strategies for cancer.

Some noncoding RNAs (ncRNAs) carry open reading frames (ORFs) that can be translated into micropeptides, although noncoding RNAs (ncRNAs) have been previously assumed to constitute a class of RNA transcripts without coding capacity. Furthermore, recent studies have revealed that ncRNA-derived micropeptides exhibit regulatory functions in the development of many tumours. Although some of these micropeptides inhibit tumour growth, others promote it. Understanding the role of ncRNA-encoded micropeptides in cancer poses new challenges for cancer research, but also offers promising prospects for cancer therapy. In this review, we summarize the types of ncRNAs that can encode micropeptides, highlighting recent technical developments that have made it easier to research micropeptides, such as ribosome analysis, mass spectrometry, bioinformatics methods, and CRISPR/Cas9. Furthermore, based on the distribution of micropeptides in different subcellular locations, we explain the biological functions of micropeptides in different human cancers and discuss their underestimated potential as diagnostic biomarkers and anticancer therapeutic targets in clinical applications, information that may contribute to the discovery and development of new micropeptide-based tools for early diagnosis and anticancer drug development.

A double-edged sword: role of apoptosis repressor with caspase recruitment domain (ARC) in tumorigenesis and ischaemia/reperfusion (I/R) injury.

Apoptosis repressor with caspase recruitment domain (ARC) acts as a potent and multifunctional inhibitor of apoptosis, which is mainly expressed in postmitotic cells, including cardiomyocytes. ARC is special for its N-terminal caspase recruitment domain and caspase recruitment domain. Due to the powerful inhibition of apoptosis, ARC is mainly reported to act as a cardioprotective factor during ischaemia‒reperfusion (I/R) injury, preventing cardiomyocytes from being devastated by various catastrophes, including oxidative stress, calcium overload, and mitochondrial dysfunction in the circulatory system. However, recent studies have found that ARC also plays a potential regulatory role in tumorigenesis especially in colorectal cancer and renal cell carcinomas, through multiple apoptosis-associated pathways, which remains to be explored in further studies. Therefore, ARC regulates the body and maintains the balance of physiological activities with its interesting duplex. This review summarizes the current research progress of ARC in the field of tumorigenesis and ischaemia/reperfusion injury, to provide overall research status and new possibilities for researchers.

Reovirus enhances cytotoxicity of natural killer cells against colorectal cancer via TLR3 pathway.

BACKGROUND: Cetuximab has been approved for use for first-line treatment of patients with wild-type KRAS metastatic colorectal cancer (CRC). However, treatment with cetuximab has shown limited efficacy as a CRC monotherapy. In addition, natural killer (NK) cell function is known to be severely attenuated in cancer patients. The goal of this study was to develop a new strategy to enhance antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by NK cells, in combination with cetuximab against CRC cells. METHODS: Ex vivo expanded NK cells were stimulated with reovirus, and reovirus-activated NK cells mediated ADCC assay were performed on CRC cells in combination with cetuximab. The synergistic antitumor effects of reovirus-activated NK cells and cetuximab were tested on DLD-1 tumor-bearing mice. Finally, Toll-like receptor 3 (TLR3) knockdown in NK cells, along with chemical blockade of TLR3/dsRNA complex, and inhibition of the TLR3 downstream signaling pathway, were performed to explore the mechanisms by which reovirus enhances NK cell cytotoxicity. RESULTS: We first confirmed that exposure of NK cells to reovirus enhanced their cytotoxicity in a dose-dependent manner.We then investigated whether reovirus-activated NK cells exposed to cetuximab-bound CRC cells exhibited greater anti-tumor efficacy than either monotherapy. Co-culture of CRC cell lines with reovirus-activated NK cells indicated that NK cytotoxicity was significantly higher in combination with cetuximab, regardless of KRAS mutation status or EGFR expression level. We also found that reovirus activation of NK cells, in conjunction with cetuximab, resulted in significantly stronger anti-tumor efficacy.Finally, TLR3 knockdown, inhibition of TLR3/dsRNA complex or TBK1/IKKε demonstrated that activation of NK cells by reovirus was dependent on TLR3 and its downstream signaling pathway. CONCLUSIONS: This study demonstrated that combination treatment of reovirus-activated NK cells with cetuximab synergistically enhances their anti-tumor cytotoxicity, suggesting a strong candidate strategy for clinical treatment of CRC.

Identification of four genes and biological characteristics of esophageal squamous cell carcinoma by integrated bioinformatics analysis.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has become one of the most serious diseases affecting populations worldwide and is the primary subtype of esophageal cancer (EC). However, the molecular mechanisms governing the development of ESCC have not been fully elucidated. METHODS: The robust rank aggregation method was performed to identify the differentially expressed genes (DEGs) in six datasets (GSE17351, GSE20347, GSE23400, GSE26886, GSE38129 and GSE77861) from the Gene Expression Omnibus (GEO). The Search Tool for the Retrieval of Interacting Genes (STRING) database was utilized to extract four hub genes from the protein-protein interaction (PPI) network. Module analysis and disease free survival analysis of the four hub genes were performed by Cytoscape and GEPIA. The expression of hub genes was analyzed by GEPIA and the Oncomine database and verified by real-time quantitative PCR (qRT-PCR). RESULTS: In total, 720 DEGs were identified in the present study; these genes consisted of 302 upregulated genes and 418 downregulated genes that were significantly enriched in the cellular component of the extracellular matrix part followed by the biological process of the cell cycle phase and nuclear division. The primary enriched pathways were hsa04110:Cell cycle and hsa03030:DNA replication. Four hub genes were screened out, namely, SPP1, MMP12, COL10A1 and COL5A2. These hub genes all exhibited notably increased expression in ESCC samples compared with normal samples, and ESCC patients with upregulation of all four hub genes exhibited worse disease free survival. CONCLUSIONS: SPP1, MMP12, COL10A1 and COL5A2 may participate in the tumorigenesis of ESCC and demonstrate the potential to serve as molecular biomarkers in the early diagnosis of ESCC. This study may help to elucidate the molecular mechanisms governing ESCC and facilitate the selection of targets for early treatment and diagnosis.

Neferine sensitized Taxol-resistant nasopharygeal carcinoma to Taxol by inhibiting EMT via downregulating miR-130b-5p.

Taxol resistance led to the poor survival prognosis in advanced nasopharyngeal carcinoma (NPC). Epithelial-mesenchymal transition (EMT) plays an important role in tumor chemoresistance. Neferine (NEF) is found to sensitize the cancer cells to chemotherapeutic agents, but its effects and mechanisms on NPC Taxol resistance is unclear. In this study, we discovered that Taxol-resistant cell lines 5-8F/Taxol and CNE-1/Taxol had the greater ability to metastasis and the higher expression of EMT markers. Then we found that NEF could inhibit the viability and EMT process in the Taxol-resistant cell lines. Furthermore, we confirmed that NEF could augment therapeutic efficacy of Taxol on NPC Taxol-resistant cell lines. Further through Microarray based analysis, we found that miR-130b-5p was stably down-regulated after treating 5-8F/Taxol with NEF. Later we verified that up-regulation of miR-130b-5p could not only promote the EMT-related migration/invasion, but also impair the inhibition effects of NEF on the EMT-associated metastatic ability and the chemotherapy resistance to Taxol. In conclusion, our results firstly suggested that NEF may enhanced Taxol sensitivity in NPC Taxol-resistant cell lines through inhibition of EMT which mediated by miR-130b-5p downregulation in vitro and in vivo. NEF may be used as a Taxol sensitizer in chemotherapy of NPC.

The role of Caspase-1/GSDMD-mediated pyroptosis in Taxol-induced cell death and a Taxol-resistant phenotype in nasopharyngeal carcinoma regulated by autophagy.

Taxol has been widely used as a first-line chemotherapeutic agent for the treatment of advanced nasopharyngeal carcinoma (NPC). However, acquired drug resistance has caused great difficulties in clinical treatment. Pyroptosis is a newly discovered programmed cell death pathway, and Caspase-1 and gasdermin D (GSDMD) play key roles in driving canonical pyroptosis. Increasing evidence suggests that pyroptosis is associated with the development of cancer; however, the function and mechanism of pyroptosis in NPC remain obscure. In this study, we observed that Taxol treatment caused pyroptotic cell death, along with activation of Caspase-1 and maturation of IL-1ß, as well as cleavage of GSDMD, which is the canonical pyroptosis executor. Furthermore, Taxol-induced pyroptotic cell death could be suppressed by Caspase-1 inhibitor (Z-YVAD-FMK) and GSDMD knockout. Moreover, NPC parental cells demonstrated higher levels of pyroptosis than Taxol-resistant cells, and pyroptosis mediated by Caspase-1/GSDMD suppression induced by a Caspase-1 inhibitor and GSDMD knockout could induce a Taxol-resistant phenotype in vitro and in vivo. By transfecting an siRNA targeting Beclin-1 into NPC Taxol-resistant cells, we discovered that autophagy could negatively regulate pyroptosis by inhibiting Caspase-1/GSDMD activation. Taken together, our results indicated that Caspase-1/GSDMD mediated Taxol-induced pyroptosis and a Taxol-resistant phenotype in NPC cell lines, which may be regulated by autophagy. Thus, we provide novel insight into the mechanisms of Taxol-induced cell death and a promising approach to improve the therapeutic outcomes of patients with advanced NPC.

MiR-375 inhibits the hepatocyte growth factor-elicited migration of mesenchymal stem cells by downregulating Akt signaling.

The migration of mesenchymal stem cells (MSCs) is critical for their use in cell-based therapies. Accumulating evidence suggests that microRNAs are important regulators of MSC migration. Here, we report that the expression of miR-375 was downregulated in MSCs treated with hepatocyte growth factor (HGF), which strongly stimulates the migration of these cells. Overexpression of miR-375 decreased the transfilter migration and the migration velocity of MSCs triggered by HGF. In our efforts to determine the mechanism by which miR-375 affects MSC migration, we found that miR-375 significantly inhibited the activation of Akt by downregulating its phosphorylation at T308 and S473, but had no effect on the activity of mitogen-activated protein kinases. Further, we showed that 3'phosphoinositide-dependent protein kinase-1 (PDK1), an upstream kinase necessary for full activation of Akt, was negatively regulated by miR-375 at the protein level. Moreover, miR-375 suppressed the phosphorylation of focal adhesion kinase (FAK) and paxillin, two important regulators of focal adhesion (FA) assembly and turnover, and decreased the number of FAs at cell periphery. Taken together, our results demonstrate that miR-375 inhibits HGF-elicited migration of MSCs through downregulating the expression of PDK1 and suppressing the activation of Akt, as well as influencing the tyrosine phosphorylation of FAK and paxillin and FA periphery distribution.

A novel 6.3 kb deletion and the Rare 27.6 kb Deletion Causing α+-Thalassemia in two Chinese Patients.

We report a novel -α6.3 deletion and a rare -α27.6 deletion causing α+-thalassemia (α+-thal), in two Chinese patients. One patient was a 35-year-old Chinese man with a mild α+-thal phenotype [mean corpuscular volume (MCV) 83.6 fL] and the Hb A2 level (2.5%) was close to borderline of the normal range. Multiplex ligation-dependent probe amplification (MLPA) revealed a novel 6344 bp deletion involving the entire HBA1 gene. Mapping by gap-polymerase chain reaction (gap-PCR) defined the exact breakpoint of this deletion to be NG_000006.1: g.31022_37366del6344. It was unique relative to other forms of α-thalassemia (α-thal) reported in the literature, and was designated as -α6.3 deletion. The other patient, a 41-year-old woman had Hb H (ß4) disease [hemoglobin (Hb) level of 8.9 g/dL] with a compound heterozygosity for the - -SEA (NG_000006.1: g.26264_45564del19301) deletion. The MLPA and gap-PCR methodologies confirmed the breakpoint (NG_000006.1: g.9079_36718del27640) and identified it as the rare -α27.6 deletion.

Non­coding RNA: A promising diagnostic biomarker and therapeutic target for esophageal squamous cell carcinoma (Review).

Esophageal cancer (EC) is a common form of malignant tumor in the digestive system that is classified into two types: Esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinoma. ESCC is known for its early onset of symptoms, which can be difficult to identify, as well as its rapid progression and tendency to develop drug resistance to chemotherapy and radiotherapy. These factors contribute to the high incidence of disease and low cure rate. Therefore, a diagnostic biomarker and therapeutic target need to be identified for ESCC. Non-coding RNAs (ncRNAs) are a class of molecules that are transcribed from DNA but do not encode proteins. Initially, ncRNAs were considered to be non-functional segments generated during transcription. However, with advancements in high-throughput sequencing technologies in recent years, ncRNAs have been associated with poor prognosis, drug resistance and progression of ESCC. The present study provides a comprehensive overview of the biogenesis, characteristics and functions of ncRNAs, particularly focusing on microRNA, long ncRNAs and circular RNAs. Furthermore, the ncRNAs that could potentially be used as diagnostic biomarkers and therapeutic targets for ESCC are summarized to highlight their application value and prospects in ESCC.

Characterization of PKCα-rutin interactions and their application as a treatment strategy for pulmonary arterial hypertension by inhibiting ferroptosis.

As a common plant-derived dietary flavonoid, rutin receives widespread attention because of its good antioxidant bioactivities. Protein kinase Cα (PKCα) is a serine/threonine kinase that is involved in uncountable cellular processes, among which ferroptosis, a novel form of cell death, is triggered by lipid peroxidation and has been reported to be associated with pulmonary arterial hypertension (PAH). But it is still not well appreciated how rutin inhibits ferroptosis in PAH and what function PKCα has in this process. In this study, we first observed whether rutin could prevent PAH by attenuating ferroptosis with a PAH animal model and pulmonary artery smooth muscle cells (PASMCs) under hypoxia. Mitochondrial metabolomics and network pharmacology were employed to clarify the metabolic alterations and screen target proteins, and the results showed that PKCα was a vital node in rutin regulating mitochondrial metabolism related to ferroptosis in PAH. Based on molecular docking and multispectral analysis, we found that rutin could directly interact with PKCα through hydrogen bonds, which could induce static quenching, and then influence the secondary structure of PKCα. In conclusion, these findings mainly point to a novel mechanism that rutin protects PAH rats by modifying the structure and altering the activity of PKCα, and thus suppressing ferroptosis. This work reveals that the interaction behaviors between small molecules and bio-macromolecules are a critical factor to develop natural biological active ingredients and gives an insight into the potential applications of flavonoids in health and disease.

Insights into the interaction of cyclooxygenase and lipoxygenase with natural compound 3,4',5,7-Tetrahydroxyflavone based on multi-spectroscopic and metabolomics.

Hypoxia induce right ventricular dysfunction in human heart, but the molecular mechanism remains limited. As known, cyclooxygenases (COX) and lipoxygenases (LOX) play a key role in the cardiovascular system under hypoxia. 3,4',5,7-Tetrahydroxyflavone (THF), which widely exists in a variety of plants and vegetables, is famous for good ability to relieve cardiac injury, but the mechanism remains to be further understood. In this study, we firstly estimated the preventive role of THF against hypoxia-induced right ventricular dysfunction. Metabolomics analysis showed there were differential metabolites involved in above process, which helped us to screen the crucial regulated enzymes of these metabolites. Molecular docking and multi-spectroscopic revealed the molecular mechanism of interaction between THF and COX/LOX. Results suggested that THF bound to COX/LOX through static quenching and these bindings were driven by hydrogen bonds. After binding with THF, the secondary structure of COX/LOX was changed. In general, this study indicated that THF inhibited COX/LOX by spontaneously forming complexes with them.

Naringenin: A flavanone with anti-inflammatory and anti-infective properties.

Although a growing body of research has recently shown how crucial inflammation and infection are to all major diseases, several of the medications currently available on the market have various unfavourable side effects, necessitating the development of alternative therapeutic choices. Researchers are increasingly interested in alternative medications or active components derived from natural sources. Naringenin is a commonly consumed flavonoid found in many plants, and since it was discovered to have nutritional benefits, it has been utilized to treat inflammation and infections caused by particular bacteria or viruses. However, the absence of adequate clinical data and naringenin's poor solubility and stability severely restrict its usage as a medicinal agent. In this article, we discuss naringenin's effects and mechanisms of action on autoimmune-induced inflammation, bacterial infections, and viral infections based on recent research. We also present a few suggestions for enhancing naringenin's solubility, stability, and bioavailability. This paper emphasizes the potential use of naringenin as an anti-inflammatory and anti-infective agent and the next prophylactic substance for the treatment of various inflammatory and infectious diseases, even though some mechanisms of action are still unclear, and offers some theoretical support for its clinical application.

The emerging role of exosomes in the development of testicular.

The mechanisms of testicular development in mammals are complex. Testis is an organ that produces sperm and secretes androgens. It is rich in exosomes and cytokines that mediate signal transduction between tubule germ cells and distal cells, promoting testicular development and spermatogenesis. Exosomes are nanoscale extracellular vesicles that transmit information between cells. By transmitting information, exosomes play an important role in male infertility diseases such as azoospermia, varicocele, and testicular torsion. However, due to the wide range of sources of exosomes, extraction methods are numerous and complex. Therefore, there are many difficulties in studying the mechanisms of exosomal effects on normal development and male infertility. Therefore, in this review, first, we introduce the formation of exosomes and methods for culturing testis and sperm. Then, we introduce the effects of exosomes on different stages of testicular development. Finally, we summarize the prospects and shortcomings of exosomes when used in clinical applications. We lay the theoretical foundation for the mechanism of the influence of exosomes on normal development and male infertility.

Covid-19 omicron variant infection in neonates of Guangdong province-a report of 52 cases.

Objective: To analyze the clinical characteristics of neonatal infection during the outbreak of COVID-19 omicron variant in Guangdong province of China. Method: The clinical data of neonates infected with COVID-19 omicron variant were collected from three hospitals of Guangdong province, their epidemiological history, clinical manifestation and prognosis were summarized. Results: From December 12, 2022 to January 15, 2023, a total of 52 neonates with COVID-19 infection were identified across three hospitals in Guangdong Province, including 34 males and 18 females. The age of diagnosis was 18.42 ± 6.32 days. 24 cases had clear contact history with adults who were suspected to be infected with COVID-19. The most common clinical manifestation was fever (43/52, 82.7%), the duration of fever was 1-8 days. The other clinical manifestations were cough (27/52, 51.9%), rales (21/52, 40.4%), nasal congestion (10/52, 19.2%), shortness of breath (2/52, 3.8%), and vomiting (4/52, 7.7%). C-reactive protein was only increased in 3 cases. Chest radiological examination was performed in 42 neonates, twenty-three cases showed abnormal chest radiographic findings, including ground-glass opacity and consolidation. Fifty cases were admitted with COVID-19 presentation, two cases were admitted for jaundice. The hospital stay was 6.59 ± 2.77 days. The clinical classification included 3 cases of severe COVID-19 and one critical case. Fifty-one cases were cured and discharged after general treatment, and one critical case with respiratory failure was intubated and transferred to another hospital. Conclusion: The COVID-19 omicron variant infection in neonates is usually mild. The clinical manifestation and laboratory results are not specific, and the short-term prognosis is good.

Downregulation of S100A9 Reverses Cisplatin-Resistance and Inhibits Proliferation and Migration in Hypopharyngeal Carcinoma.

Purpose: Patients with hypopharyngeal carcinoma (HPC) often progress to an advanced clinical stage at diagnosis. Cisplatin has been widely used in first-line chemotherapy for advanced HPC. However, acquired chemotherapeutic resistance leads to recurrence, metastasis, and a poor survival rate. Therefore, identifying new drug targets to improve treatment effects is still in need. Methods: To screen the differential expression genes (DEGs) and proteins (DEPs), we conducted transcriptomic and proteomic analysis on cisplatin-sensitive cell lines (FaDu) and cisplatin-resistant cell lines (FaDu/DDP) of hypopharyngeal carcinoma. DEGs and DEPs, possibly the most associated with cisplatin-resistance, were verified by real-time polymerase chain reaction (RT-PCR) and western blot (WB), respectively, and the biological function of the screened S100A9 was further tested by CCK8, wound healing, and transwell assays. Results: We identified S100A9 as a target for resensitizing the response to cisplatin in an acquired resistance model. S100A9 overexpression was significantly related to cisplatin resistance. Functional studies in vitro models demonstrated that downregulation of S100A9 overcame cisplatin-resistance and inhibited proliferation and migration. Later, we verified that downregulation of S100A9 suppressed the interleukin-6 (IL6) expression and epithelial-mesenchymal transition (EMT) pathway. Conclusion: In all, S100A9 plays a crucial role in cisplatin-resistance, proliferation, and migration of HPC. Targeting S100A9 may become a novel strategy for the treatment of HPC.

hUC-MSCs: evaluation of acute and long-term routine toxicity testing in mice and rats.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are present in human umbilical connective tissue and can differentiate into various cell types. Our previous studies have proved that hUC-MSCs do not lead to allergies and tumorigenesis. In the present study, the acute and long-term toxicity of hUC-MSCs in mice and rats was evaluated. The acute toxicity of hUC-MSCs was assessed in 8-week-old mice receiving two caudal intravenous (i.v.) injections of hUC-MSCs at the maximum tolerated dose of 1.5 × 107 cells/kg with an interval of 8 h and the observation period sustained for 14 days. For the long-term toxicity evaluation, rats were randomly divided into control, low-dose (3.0 × 105 cells/kg), mid-dose (1.5 × 106 cells/kg), and high-dose (7.5 × 106 cells/kg) groups, which were treated with hUC-MSCs via a caudal i.v. injection every 3 days for 90 days. Weight and food intake evaluation was performed for all rats for 2 weeks after the hUC-MSC administration. The animals were then sacrificed for hematological, blood biochemical, and pathological analyses, as well as organ index determination. We observed no obvious acute toxicity of hUC-MSCs in mice at the maximum tolerated dose. Long-term toxicity tests in rats showed no significant differences between HUC-MSC-treated and control groups in the following parameters: body weight, hematological and blood biochemical parameters, and histopathologic changes in the heart, liver, kidneys, and lungs. This study provides evidence of the safety of i.v. hUC-MSCs infusion for future clinical therapies.

Early Warning Measurement of SARS-CoV-2 Variants of Concern in Wastewaters by Mass Spectrometry.

Wastewater surveillance has rapidly emerged as an early warning tool to track COVID-19. However, the early warning measurement of new SARS-CoV-2 variants of concern (VOCs) in wastewaters remains a major challenge. We herein report a rapid analytical strategy for quantitative measurement of VOCs, which couples nested polymerase chain reaction and liquid chromatography-mass spectrometry (nPCR-LC-MS). This method showed a greater selectivity than the current allele-specific quantitative PCR (AS-qPCR) for tracking new VOC and allowed the detection of multiple signature mutations in a single measurement. By measuring the Omicron variant in wastewaters across nine Ontario wastewater treatment plants serving over a three million population, the nPCR-LC-MS method demonstrated a better quantification accuracy than next-generation sequencing (NGS), particularly at the early stage of community spreading of Omicron. This work addresses a major challenge for current SARS-CoV-2 wastewater surveillance by rapidly and accurately measuring VOCs in wastewaters for early warning.

Immunoregulatory therapy strategies that target cytokine storms in patients with COVID-19 (Review).

A cytokine storm is an uncontrolled, excessive immune response that contributes to the pathogenesis of coronavirus disease 2019 (COVID-19). Viral infections lead to the loss of negative feedback in immune regulation and an abnormal elevation of the levels of multiple cytokines. In COVID-19, this causes diffuse damage to alveolar functions and may culminate in multiple organ dysfunction. Immunoregulatory therapies target the cytokine storms induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, and include monoclonal antibodies, recombinant granulocyte-macrophage colony stimulating factor, interferon, mesenchymal stem cell-based therapy, thymosin, immunoglobulins and blood purification therapies. These approaches may be effective in the alleviation of COVID-19 symptoms. In this review, cytokine storms caused by SARS-CoV-2 infections are evaluated and discussed, and advances in immunoregulatory therapy strategies for patients with COVID-19 are reviewed.

Mesenchymal stem cell carriers enhance anti-tumor efficacy of oncolytic virotherapy.

Oncolytic viruses (OVs) specifically infect, replicate and eventually destroy tumor cells, with no concomitant toxicity to adjacent normal cells. Furthermore, OVs can regulate tumor microenvironments and stimulate anti-tumor immune responses. Mesenchymal stem cells (MSCs) have inherent tumor tropisms and immunosuppressive functions. MSCs carrying OVs not only protect viruses from clearing by the immune system, but they also deliver the virus to tumor lesions. Equally, cytokines released by MSCs enhance anti-tumor immune responses, suggesting that MSCs carrying OVs may be considered as a promising strategy in enhancing the anti-tumor efficacies of virotherapy. In the present review, preclinical and clinical studies were evaluated and discussed, as well as the effectiveness of MSCs carrying OVs for tumor treatment.

Mesenchymal stem cell carriers enhance antitumor efficacy induced by oncolytic reovirus in acute myeloid leukemia.

Chemotherapy is the main treatment for acute myeloid leukemia (AML), but the therapeutic efficacy is modest, and most commonly manifests as relapse from remission. Thus, improving long-term AML survival is a crucial clinical challenge. In recent years, oncolytic virotherapy has provided an alternative approach for AML treatment. The use of oncolytic reoviruses has been explored in more than 30 clinical trials for safety and feasibility issues. However, like other oncolytic viruses, neutralizing antibodies (NAbs) reduce therapeutic efficacy. To tackle this problem, human umbilical cord mesenchymal stem cells (hUC-MSCs) were used to deliver reovirus using in vitro and in vivo models. Human UC-MSCs were successfully loaded with reovirus, without impairing biological function.We also observed in vitro protective effects of hUC-MSCs on reovirus in the presence of NAbs. In the immunocompromised AML mouse model, hUC-MSCs effectively carried reoviruses to tumor lesions and significantly prolonged the survival of AML xenografts in mice in the presence of a high titer anti-reovirus antibody (p = 0.001). However, reovirus-induced activation of AKT, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and NF-κB signaling led to the maintenance of intrinsic migratory properties and secretion of pro-inflammatory cytokines from hUC-MSCs, particularly CXCL10. In immuno-competent AML mice, MSCs carrying reovirus triggered immune responses, and eventually inhibited tumor growth. Therefore, these results suggest that MSCs as carriers of oncolytic reoviruses can enhance the antitumor efficacy of virotherapy.