The therapeutic effect of MSCs and their extracellular vesicles on neuroblastoma.

Neuroblastoma is a common inflammatory-related cancer during infancy. Standard treatment modalities including surgical interventions, high-dose chemotherapy, radiotherapy, and immunotherapy are not able to increase survival rate and reduce tumor relapse in high-risk patients. Mesenchymal stem cells (MSCs) are known for their tumor-targeting and immunomodulating properties. MSCs could be engineered to express anticancer agents (i.e., growth factors, cytokines, pro-apoptotic agents) or deliver oncolytic viruses in the tumor microenvironment. As many functions of MSCs are mediated through their secretome, researchers have tried to use extracellular vesicles (EVs) from MSCs for targeted therapy of neuroblastoma. Here, we reviewed the studies to figure out whether the use of MSCs could be worthwhile in neuroblastoma therapy or not. Native MSCs have shown a promoting or inhibiting role in cancers including neuroblastoma. Therefore, MSCs are proposed as a vehicle to deliver anticancer agents such as oncolytic viruses to the neuroblastoma tumor microenvironment. Although modified MSCs or their EVs have been shown to suppress the tumorigenesis of neuroblastoma, further pre-clinical and clinical studies are required to come to a conclusion.

The functional role of circular RNAs in the pathogenesis of retinoblastoma: a new potential biomarker and therapeutic target?

Retinoblastoma (RB) is a common cancer in infants and children. It is a curable disease; however, a delayed diagnosis or treatment makes the treatment difficult. Genetic mutations have a central role in the pathogenesis of RB. Genetic materials such as RNAs (coding and non-coding RNAs) are also involved in the progression of the tumor. Circular RNA (circRNA) is the most recently identified RNA and is involved in regulating gene expression mainly through "microRNA sponges". The dysregulation of circRNAs has been observed in several diseases and tumors. Also, various studies have shown that circRNAs expression is changed in RB tissues. Due to their role in the pathogenesis of the disease, circRNAs might be helpful as a diagnostic or prognostic biomarker in patients with RB. In addition, circRNAs could be a suitable therapeutic target to treat RB in a targeted therapy approach.

Hypoxia-circular RNA crosstalk to promote breast cancer.

The expression of hypoxia-inducible factors (HIFs), particularly HIF-1, plays a major role in the adaptation of solid tumors to hypoxic conditions. The activation of the HIF pathway results in an expression of genes involved in the promotion of cell growth, proliferation, vascularization, metastasis, and therapeutic resistance. Circular RNA (CircRNA) is considered as a major regulator of gene expression. CircRNAs could regulate the HIF-1 pathway in cancer cells. In addition, they might be regulated by the HIF-1 pathway to promote cancer progression. Therefore, the crosstalk between hypoxia and circRNA might be involved in the pathogenesis of cancers, including breast cancer. In this review, we discussed the function of HIF-related circRNAs in the progression, angiogenesis, metabolic reprogramming, and stemness maintenance of breast cancer. In addition, the correlation between HIF-related circRNAs and clinical features of breast cancer is reviewed.

The role of hypoxia-inducible factors in breast cancer stem cell specification.

Breast tumor is heterogeneous cancer with high morbidity and mortality rates, particularly in developing countries. Despite new efforts to reduce the breast cancer implications, the number of newly diagnosed cases is increasing worldwide. It is believed that cancer stem cells (CSCs) are responsible for the implication of cancers including breast cancer. Although CSCs compose a small population in tumor bulks, they play a crucial role in tumor initiation, progression, metastasis, and chemotherapeutic resistance. These events are mediated by the hypoxia-inducible factor (HIF) pathway which regulates the transcription of genes involved in CSC maintenance and tumorigenesis. In this review, we discussed the mechanisms by which hypoxia- or chemotherapy-induced HIFs promote breast CSC specification.

Recent advancements to engineer mesenchymal stem cells and their extracellular vesicles for targeting and destroying tumors.

Mesenchymal stem cells (MSCs) have the ability to migrate into tumor sites and release growth factors to modulate the tumor microenvironment. MSC therapy have shown a dual role in cancers, promoting or inhibiting. However, MSCs could be used as a carrier of anticancer agents for targeted tumor therapy. Recent technical improvements also allow engineering MSCs to improve tumor-targeting properties, protect anticancer agents, and decrease the cytotoxicity of drugs. While some of MSC functions are mediated through their secretome, MSCs-derived extracellular vesicles (EVs) are also proposed as a possible viechle for cancer therapy. EVs allow efficient loading of anticancer agents and have an intrinsic ability to target tumor cells, making them suitable for targeted therapy of tumors. In addition, the specificity and selectivity of EVs to the tumor sites could be enhanced by surface modification. In this review, we addressed the current approaches used for engineering MSCs and EVs to effectively target tumor sites and deliver anticancer agents.

PI3K/AKT/mTOR signaling pathway modulation by circular RNAs in breast cancer progression.

The PI3K/Akt/mTOR signaling pathway is responsible for many cellular behaviors, including survival, growth, and proliferation. A newly identified RNA, circular RNA (circRNA), plays a crucial role in the regulation of gene expression. The upregulation of the PI3K/Akt pathway through dysregulated circRNAs promotes breast tumor initiation, growth, and progression. The dysregulation of PI3K/Akt-regulating circRNAs seems to be directly correlated with breast cancer clinical features, including overall survival, tumor size, cancer stage, and lymph node metastasis. In addition, targeting these circRNAs may be a promising option in cancer-targeted therapy. Understanding the molecular pathogenesis of the circRNA-PI3K/AKT axis may give the insight to develop new therapeutic and diagnostic approaches for breast cancer therapy. Here we reviewed the expression and functions of PI3K/AKT-regulating circRNAs, and their correlation with breast cancer clinical features. In addition, the potential of PI3K/AKT-regulating circRNAs as diagnostic/prognostic biomarkers or therapeutic targets was discussed.

Current understanding of epigenetics role in melanoma treatment and resistance.

Melanoma is the most aggressive form of skin cancer resulting from genetic mutations in melanocytes. Several factors have been considered to be involved in melanoma progression, including genetic alteration, processes of damaged DNA repair, and changes in mechanisms of cell growth and proliferation. Epigenetics is the other factor with a crucial role in melanoma development. Epigenetic changes have become novel targets for treating patients suffering from melanoma. These changes can alter the expression of microRNAs and their interaction with target genes, which involves cell growth, differentiation, or even death. Given these circumstances, we conducted the present review to discuss the melanoma risk factors and represent the current knowledge about the factors related to its etiopathogenesis. Moreover, various epigenetic pathways, which are involved in melanoma progression, treatment, and chemo-resistance, as well as employed epigenetic factors as a solution to the problems, will be discussed in detail.

Exosome application in treatment and diagnosis of B-cell disorders: leukemias, multiple sclerosis, and arthritis rheumatoid.

Exosomes, known as a type of extracellular vesicles (EVs), are lipid particles comprising heterogeneous contents such as nucleic acids, proteins, and DNA. These bi-layered particles are naturally released into the extracellular periphery by a variety of cells such as neoplastic cells. Given that exosomes have unique properties, they can be used as vectors and carriers of biological and medicinal particles like drugs for delivering to the desired areas. The proteins and RNAs being encompassed by the circulating exosomes in B-cell malignancies are deemed as the promising sources for diagnostic and prognostic biomarkers, as well as therapeutic agents. Exosomes can also provide a "snapshot" view of the tumor and metastatic landscape at any particular time. Further, clinical research has shown that exosomes are produced by immune cells such as dendritic cells can stimulate the immune system, so these exosomes can be used in antitumor vaccines. Despite the great potential of exosomes in the fields of diagnostic and treatment, further studies are in need for these purposes to reach a convergence notion. This review highlights the applications of exosomes in multiple immune-related diseases, including chronic lymphocytic leukemia, multiple sclerosis, and arthritis rheumatoid, as well as explaining sundry aspects of exosome therapy and the function of exosomes in diagnosing diseases.

Circular RNAs in neuroblastoma: Pathogenesis, potential biomarker, and therapeutic target.

Neuroblastoma (NB) is a common cancer in childhood responsible for 15 % of fatalities by pediatric cancers. Epigenetic factors play an important role in the pathogenesis of NB. Recently, it has been demonstrated that circular RNAs (circRNAs, ciRNAs), a newly identified class of non-coding RNAs, are also dysregulated in NB. CircRNAs mediate their functions by regulating gene expression mainly through microRNA (miRNA) sponging. The dysregulation (abnormal upregulation or downregulation) of circRNAs is involved in tumorigenesis of a variety of tumors including NB. It seems that the expression of some circRNAs is correlated with NB prognosis and clinical features. CircRNAs might be favorable as a diagnostic/prognostic biomarker and therapeutic target. However, due to the lack of studies, it is difficult to make a conclusion regarding the clinical benefits of circRNAs. In this review, we discussed the circRNAs that experimentally have been proved to be dysregulated in NB tissues and cancer cells.

Recent Advances in Glioma Cancer Treatment: Conventional and Epigenetic Realms.

Glioblastoma (GBM) is the most typical and aggressive form of primary brain tumor in adults, with a poor prognosis. Successful glioma treatment is hampered by ineffective medication distribution across the blood-brain barrier (BBB) and the emergence of drug resistance. Although a few FDA-approved multimodal treatments are available for glioblastoma, most patients still have poor prognoses. Targeting epigenetic variables, immunotherapy, gene therapy, and different vaccine- and peptide-based treatments are some innovative approaches to improve anti-glioma treatment efficacy. Following the identification of lymphatics in the central nervous system, immunotherapy offers a potential method with the potency to permeate the blood-brain barrier. This review will discuss the rationale, tactics, benefits, and drawbacks of current glioma therapy options in clinical and preclinical investigations.

Exosome-based strategies for diagnosis and therapy of glioma cancer.

Glioblastoma belongs to the most aggressive type of cancer with a low survival rate that is characterized by the ability in forming a highly immunosuppressive tumor microenvironment. Intercellular communication are created via exosomes in the tumor microenvironment through the transport of various biomolecules. They are primarily involved in tumor growth, differentiation, metastasis, and chemotherapy or radiation resistance. Recently several studies have highlighted the critical role of tumor-derived exosomes against immune cells. According to the structural and functional properties, exosomes could be essential instruments to gain a better molecular mechanism for tumor understanding. Additionally, they are qualified as diagnostic/prognostic markers and therapeutic tools for specific targeting of invasive tumor cells such as glioblastomas. Due to the strong dependency of exosome features on the original cells and their developmental status, it is essential to review their critical modulating molecules, clinical relevance to glioma, and associated signaling pathways. This review is a non-clinical study, as the possible role of exosomes and exosomal microRNAs in glioma cancer are reported. In addition, their content to overcome cancer resistance and their potential as diagnostic biomarkers are analyzed.

The therapeutic effect of exosomes from mesenchymal stem cells on colorectal cancer: Toward cell-free therapy.

Colorectal cancer (CRC) is known for its high mortality rate and affects more men than women. The treatment requires invasive surgical interventions, however, the progression of CRC metastasis is difficult to control in most cases. Mesenchymal stem cells (MSCs) with their outstanding characteristics have been widely used in the treatment of degenerative diseases as well as cancers. They affect the tumor microenvironment through either cell-cell interactions or communications with their secretome. While stem cells may represent a dual role in tumor proliferation and progression, exosomes have attracted much attention as a cell-free therapy in CRC treatment. Exosomes derived from native or genetically modified MSCs, as well as exosomal microRNAs (miRNAs), have been evaluated on CRC progression. Moreover, MSC-derived exosomes have been used as a carrier to deliver anticancer agents in colorectal cancer. In this review, we overview and discuss the current knowledge in both stem cell-based and cell-free exosome therapy of CRC.

PI3K/Akt/mTOR signaling pathway in cancer stem cells.

Cancer stem cells (CSCs) as a small subpopulation in tumor bulk are believed to initiate tumor formation and are responsible for the resistance to cancer therapy. The proliferation and differentiation of CSCs result in heterogeneity in a tumor which increases the chance of tumor survival and invasion. Many signaling pathways are abnormally activated or repressed in CSCs. Understanding these pathways and the metabolisms in CSCs may help targeted therapy in drug-resistant tumors. The PI3K/Akt/mTOR pathway is one of the major signaling pathways in CSCs involved in the maintenance of stemness, proliferation, differentiation, epithelial to mesenchymal transition (EMT), migration, and autophagy. Thus, suppressing the PI3K/Akt/mTOR pathway with inhibitors might be a promising strategy for targeted cancer therapy. Although the pathway is well-recognized and reviewed in tumor bulks, the functions in CSCs have not been well focused. Here, we reviewed the PI3K/Akt/mTOR signaling pathway and its functions in CSCs and addressed the potential therapeutic applications in drug-resistant tumors.

The role of epigenetic modifications in drug resistance and treatment of breast cancer.

BACKGROUND: Breast cancer is defined as a biological and molecular heterogeneous disorder that originates from breast cells. Genetic predisposition is the most important factor giving rise to this malignancy. The most notable mutations in breast cancer occur in the BRCA1 and BRCA2 genes. Owing to disease heterogeneity, lack of therapeutic target, anti-cancer drug resistance, residual disease, and recurrence, researchers are faced with challenges in developing strategies to treat patients with breast cancer. RESULTS: It has recently been reported that epigenetic processes such as DNA methylation and histone modification, as well as microRNAs (miRNAs), have potently contributed to the pathophysiology, diagnosis, and treatment of breast cancer. These observations have persuaded researchers to move their therapeutic approaches beyond the genetic framework toward the epigenetic concept. CONCLUSION: Herein we discuss the molecular and epigenetic mechanisms underlying breast cancer progression and resistance as well as various aspects of epigenetic-based therapies as monotherapy and combined with immunotherapy.

Revisiting characteristics of oncogenic extrachromosomal DNA as mobile enhancers on neuroblastoma and glioma cancers.

Cancer can be induced by a variety of possible causes, including tumor suppressor gene failure and proto-oncogene hyperactivation. Tumor-associated extrachromosomal circular DNA has been proposed to endanger human health and speed up the progression of cancer. The amplification of ecDNA has raised the oncogene copy number in numerous malignancies according to whole-genome sequencing on distinct cancer types. The unusual structure and function of ecDNA, and its potential role in understanding current cancer genome maps, make it a hotspot to study tumor pathogenesis and evolution. The discovery of the basic mechanisms of ecDNA in the emergence and growth of malignancies could lead researchers to develop new cancer therapies. Despite recent progress, different aspects of ecDNA require more investigation. We focused on the features, and analyzed the bio-genesis, and origin of ecDNA in this review, as well as its functions in neuroblastoma and glioma cancers.

Anti-cancer peptide-based therapeutic strategies in solid tumors.

BACKGROUND: Nowadays, conventional medical treatments such as surgery, radiotherapy, and chemotherapy cannot cure all types of cancer. A promising approach to treat solid tumors is the use of tumor-targeting peptides to deliver drugs or active agents selectively. RESULT: Introducing beneficial therapeutic approaches, such as therapeutic peptides and their varied methods of action against tumor cells, can aid researchers in the discovery of novel peptides for cancer treatment. The biomedical applications of therapeutic peptides are highly interesting. These peptides, owing to their high selectivity, specificity, small dimensions, high biocompatibility, and easy modification, provide good opportunities for targeted drug delivery. In recent years, peptides have shown considerable promise as therapeutics or targeting ligands in cancer research and nanotechnology. CONCLUSION:  This study reviews a variety of therapeutic peptides and targeting ligands in cancer therapy. Initially, three types of tumor-homing and cell-penetrating peptides (CPPs) are described, and then their applications in breast, glioma, colorectal, and melanoma cancer research are discussed.

Exosome application in tumorigenesis: diagnosis and treatment of melanoma.

Melanoma is the most aggressive of skin cancer derived from genetic mutations in the melanocytes. Current therapeutic approaches include surgical resection, chemotherapy, photodynamic therapy, immunotherapy, biochemotherapy, and targeted therapy. However, the efficiency of these strategies may be decreased due to the development of diverse resistance mechanisms. Here, it has been proven that therapeutic monoclonal antibodies (mAbs) can improve the efficiency of melanoma therapies and also, cancer vaccines are another approach for the treatment of melanoma that has already improved clinical outcomes in these patients. The use of antibodies and gene vaccines provides a new perspective in melanoma treatment. Since the tumor microenvironment is another important factor for cancer progression and metastasis, in recent times, a mechanism has been identified to provide an opportunity for melanoma cells to communicate with remote cells. This mechanism is involved by a novel molecular structure, named extracellular vesicles (EVs). Depending on the functional status of origin cells, exosomes contain various cargos and different compositions. In this review, we presented recent progress of exosome applications in the treatment of melanoma. Different aspects of exosome therapy and ongoing efforts in this field will be discussed too.

Extra chromosomal DNA in different cancers: Individual genome with important biological functions.

Cancer can be caused by various factors, including the malfunction of tumor suppressor genes and the hyper-activation of proto-oncogenes. Tumor-associated extrachromosomal circular DNA (eccDNA) has been shown to adversely affect human health and accelerate malignant actions. Whole-genome sequencing (WGS) on different cancer types suggested that the amplification of ecDNA has increased the oncogene copy number in various cancers. The unique structure and function of ecDNA, its profound significance in cancer, and its help in the comprehension of current cancer genome maps, renders it as a hotspot to explore the tumor pathogenesis and evolution. Illumination of the basic mechanisms of ecDNA may provide more insights into cancer therapeutics. Despite the recent advances, different features of ecDNA require further elucidation. In the present review, we primarily discussed the characteristics, biogenesis, genesis, and origin of ecDNA and later highlighted its functions in both tumorigenesis and therapeutic resistance of different cancers.

SARS-CoV-2 Proteome Harbors Peptides Which Are Able to Trigger Autoimmunity Responses: Implications for Infection, Vaccination, and Population Coverage.

Autoimmune diseases (ADs) could occur due to infectious diseases and vaccination programs. Since millions of people are expected to be infected with SARS-CoV-2 and vaccinated against it, autoimmune consequences seem inevitable. Therefore, we have investigated the whole proteome of the SARS-CoV-2 for its ability to trigger ADs. In this regard, the entire proteome of the SARS-CoV-2 was chopped into more than 48000 peptides. The produced peptides were searched against the entire human proteome to find shared peptides with similar experimentally confirmed T-cell and B-cell epitopes. The obtained peptides were checked for their ability to bind to HLA molecules. The possible population coverage was calculated for the most potent peptides. The obtained results indicated that the SARS-CoV-2 and human proteomes share 23 peptides originated from ORF1ab polyprotein, nonstructural protein NS7a, Surface glycoprotein, and Envelope protein of SARS-CoV-2. Among these peptides, 21 peptides had experimentally confirmed equivalent epitopes. Amongst, only nine peptides were predicted to bind to HLAs with known global allele frequency data, and three peptides were able to bind to experimentally confirmed HLAs of equivalent epitopes. Given the HLAs which have already been reported to be associated with ADs, the ESGLKTIL, RYPANSIV, NVAITRAK, and RRARSVAS were determined to be the most harmful peptides of the SARS-CoV-2 proteome. It would be expected that the COVID-19 pandemic and the vaccination against this pathogen could significantly increase the ADs incidences, especially in populations harboring HLA-B*08:01, HLA-A*024:02, HLA-A*11:01 and HLA-B*27:05. The Southeast Asia, East Asia, and Oceania are at higher risk of AD development.