The role of tumor microenvironment on cancer stem cell fate in solid tumors.

In the last few decades, the role of cancer stem cells in initiating tumors, metastasis, invasion, and resistance to therapies has been recognized as a potential target for tumor therapy. Understanding the mechanisms by which CSCs contribute to cancer progression can help to provide novel therapeutic approaches against solid tumors. In this line, the effects of mechanical forces on CSCs such as epithelial-mesenchymal transition, cellular plasticity, etc., the metabolism pathways of CSCs, players of the tumor microenvironment, and their influence on the regulating of CSCs can lead to cancer progression. This review focused on some of these mechanisms of CSCs, paving the way for a better understanding of their regulatory mechanisms and developing platforms for targeted therapies. While progress has been made in research, more studies will be required in the future to explore more aspects of how CSCs contribute to cancer progression. Video Abstract.

Decellularized Extracellular Matrix as a Potent Natural Biomaterial for Regenerative Medicine.

Decellularization technique is a favorable method used to fabricate natural and tissue-like scaffolds. This technique is important because of its remarkable ability to perfectly mimic the natural extracellular matrix (ECM). ECM-based scaffolds/hydrogels provide structural support for cell differentiation and maturation. Therefore, novel natural-based bioinks, ECM-based hydrogels, and particulate forms of the ECM provide promising strategies for whole organ regeneration. Despite its efficacious characteristics, removal of residual detergent and the presence of various protocols make this technique challenging for scientists and regenerative medicine-related programs. This chapter reviews the most effective physical, chemical, and enzymatic protocols used to remove the cellular components and their challenges. We discuss the applications of decellularized ECM (dECM) in tissue engineering and regenerative medicine with an emphasis on hard tissues.

An in situ forming gelatin-based hydrogel loaded with soluble amniotic membrane promotes full-thickness wound regeneration in rats.

Objectives: Early effective treatment and appropriate coverage are vital for full-thickness wounds. Amnion membrane-derived products have recently emerged in tissue engineering. However, the optimal concentration, carrier for controlled release, and handling have remained challenges. This study aims to develop and optimize an in situ forming, amniotic-based hydrogel for wound healing. Materials and Methods: Here, a composite matrix was fabricated with gelatin hydrogel modified with methacrylate functional group conjugated (GelMA) and keratose (wt.1%), loaded with mesenchymal stem cells (MSCs, 1×105 cell/ml) and optimized soluble amniotic membrane (SAM, 0.5 mg/ml). The physicochemical properties of the final subject were evaluated in vitro and in vivo environments. Results: The results of the in vitro assay demonstrated that conjugation of the methacryloyl group with gelatin resulted in the formation of GelMA hydrogel (26.7±1.2 kPa) with higher mechanical stability. Modification of GelMA with a glycosaminoglycan sulfate (Keratose) increased controlled delivery of SAM (47.3% vs. 84.3%). Metabolic activity (93%) and proliferation (21.2 ± 1.5 µg/ml) of MSCs encapsulated in hydrogel improved by incorporation of SAM (0.5 mg/ml). Furthermore, the migration of fibroblasts was facilitated in the scratched assay by SAM (0.5 mg/ml)/MSCs (1×105 cell/ml) conditioned medium. The GelMA hydrogel groupes revealed regeneration of full-thickness skin defects in rats after 3 weeks due to the high angiogenesis (6.3 ± 0.3), cell migration, and epithelialization. Conclusion: The results indicated in situ forming and tunable GelMA hydrogels containing SAM and MSCs could be used as efficient substrates for full-thickness wound regeneration.

Functional Enrichment Analysis of Tumor Microenvironment-Driven Molecular Alterations That Facilitate Epithelial-to-Mesenchymal Transition and Distant Metastasis.

Nowadays, hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths, and identifying the effective factors in causing this disease can play an important role in its prevention and treatment. Tumors provide effective agents for invasion and metastasis to other organs by establishing appropriate communication between cancer cells and the microenvironment. Epithelial-to-mesenchymal transition (EMT) can be mentioned as one of the effective phenomena in tumor invasion and metastasis. Several factors are involved in inducing this phenomenon in the tumor microenvironment, which helps the tumor survive and migrate to other places. It can be effective to identify these factors in the use of appropriate treatment strategies and greater patient survival. This study investigated the molecular differences between tumor border cells and tumor core cells or internal tumor cells in HCC for specific EMT genes. Expression of NOTCH1, ID1, and LST1 genes showed a significant increase at the HCC tumor border. Targeting these genes can be considered as a useful therapeutic strategy to prevent distant metastasis in HCC patients.

Functionality of immune cells in COVID-19 infection: development of cell-based therapeutics.

Introduction: In late December 2019, a sudden severe respiratory illness of unknown origin was reported in China. In early January 2020, the cause of COVID-19 infection was announced a new coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Examination of the SARS-CoV-2 genome sequence revealed a close resemblance to the previously reported SARS-CoV and coronavirus Middle East respiratory syndrome (MERS-CoV). However, initial testing of drugs used against SARS-CoV and MERS-CoV has been ineffective in controlling SARS-CoV-2. One of the key strategies to fight the virus is to look at how the immune system works against the virus, which has led to a better understanding of the disease and the development of new therapies and vaccine designs. Methods: This review discussed the innate and acquired immune system responses and how immune cells function against the virus to shed light on the human body's defense strategies. Results: Although immune responses have been revealed critical to eradicating infections caused by coronaviruses, dysregulated immune responses can lead to immune pathologies thoroughly investigated. Also, the benefit of mesenchymal stem cells, NK cells, Treg cells, specific T cells, and platelet lysates have been submitted as promising solutions to prevent the effects of infection in patients with COVID-19. Conclusion: It has been concluded that none of the above has undoubtedly been approved for the treatment or prevention of COVID-19, but clinical trials are underway better to understand the efficacy and safety of these cellular therapies.

New Insights into Cartilage Tissue Engineering: Improvement of Tissue-Scaffold Integration to Enhance Cartilage Regeneration.

Distinctive characteristics of articular cartilage such as avascularity and low chondrocyte conversion rate present numerous challenges for orthopedists. Tissue engineering is a novel approach that ameliorates the regeneration process by exploiting the potential of cells, biodegradable materials, and growth factors. However, problems exist with the use of tissue-engineered construct, the most important of which is scaffold-cartilage integration. Recently, many attempts have been made to address this challenge via manipulation of cellular, material, and biomolecular composition of engineered tissue. Hence, in this review, we highlight strategies that facilitate cartilage-scaffold integration. Recent advances in where efficient integration between a scaffold and native cartilage could be achieved are emphasized, in addition to the positive aspects and remaining problems that will drive future research.

GPX2 and BMP4 as Significant Molecular Alterations in The Lung Adenocarcinoma Progression: Integrated Bioinformatics Analysis.

Objective: Non-small cell lung adenocarcinoma (NSCLC) is the most common type of lung cancer, which is considered as the most lethal and prevalent cancer worldwide. Recently, molecular changes have been implicated to play a significant role in the cancer progression. Despite of numerous studies, the molecular mechanism of NSCLC pathogenesis in each sub-stage remains unclear. Studying these molecular alterations gives us a chance to design successful therapeutic plans which is aimed in this research. Materials and Methods: In this bioinformatics study, we compared the expression profile of 7 minor stages of NSCLC adenocarcinoma, including GSE41271, GSE42127, and GSE75037, to clarify the relation of molecular alterations and tumorigenesis. At first, 99 common differentially expressed genes (DEG) were obtained. Then, functional enrichment analysis and protein-protein interaction (PPI) network construction were performed to uncover the association of significant cellular and molecular changes. Finally, gene expression profile interactive analysis (GEPIA) was employed to validate the results by RNA-seq expression data. Results: Primary analysis showed that BMP4 was downregulated through the tumor progression to the stage IB and GPX2 was upregulated in the course of final tumor development to the stage IV and distant metastasis. Functional enrichment analysis indicated that BMP4 in the TGF-ß signaling pathway and GPX2 in the glutathione metabolism pathway may be the key genes for NSCLC adenocarcinoma progression. GEPIA analysis revealed a correlation between BMP4 downregulation and GPX2 upregulation and lung adenocarcinoma (LUAD) progression and lower survival chances in LUAD patients which confirm microarray data. Conclusion: Taken together, we suggested GPX2 as an oncogene by inhibiting apoptosis, promoting EMT and increasing glucose uptake in the final stages and BMP4 as a tumor suppressor via inducing apoptosis and arresting cell cycle in the early stages through lung adenocarcinoma (ADC) development to make them candidate genes to further cancer therapy investigations.

The risk of pancreatic adenocarcinoma following SARS-CoV family infection.

COVID 19 disease has become a global catastrophe over the past year that has claimed the lives of over two million people around the world. Despite the introduction of vaccines against the disease, there is still a long way to completely eradicate it. There are concerns about the complications following infection with SARS-CoV-2. This research aimed to evaluate the possible correlation between infection with SARS-CoV viruses and cancer in an in-silico study model. To do this, the relevent dataset was selected from GEO database. Identification of differentially expressed genes among defined groups including SARS-CoV, SARS-dORF6, SARS-BatSRBD, and H1N1 were screened where the |Log FC| ≥ 1and p < 0.05 were considered statistically significant. Later, the pathway enrichment analysis and gene ontology (GO) were used by Enrichr and Shiny GO databases. Evaluation with STRING online was applied to predict the functional interactions of proteins, followed by Cytoscape analysis to identify the master genes. Finally, analysis with GEPIA2 server was carried out to reveal the possible correlation between candidate genes and cancer development. The results showed that the main molecular function of up- and down-regulated genes was "double-stranded RNA binding" and actin-binding, respectively. STRING and Cytoscape analysis presented four genes, PTEN, CREB1, CASP3, and SMAD3 as the key genes involved in cancer development. According to TCGA database results, these four genes were up-regulated notably in pancreatic adenocarcinoma. Our findings suggest that pancreatic adenocarcinoma is the most probably malignancy happening after infection with SARS-CoV family.