Bicalutamide reveals immunomodulatory effects in prostate cancer by regulating immunogenic dendritic cell maturation.

Prostate cancer poses a significant global health challenge, ranking as the second most prevalent and fifth most lethal malignancy among males. The intricate interplay between androgen signaling and the immune microenvironment underscores the complexity of prostate cancer progression. Notably, androgen receptor (AR) signaling has been shown to affect immune response mediated by tumor antigen-presenting dendritic cells (DCs). Therefore, this study aimed to explore the potential of Bicalutamide, a nonsteroidal anti-androgen, in modulating DCs-mediated immune responses. Peripheral blood mononuclear cells (PBMCs) were isolated, and monocytes were extracted, followed by their differentiation into immature dendritic cells (iDCs) using GM-CSF and IL-4. Harvested tumor cell lysates from human prostate cancer cells were then utilized to induce the transformation of iDCs into mature dendritic cells (mDCs). Then, mDCs were treated with non-toxic concentration of Bicalutamide determined by annexin V/PI assay. The morphological characteristics of mDCs were investigated using an inverted light microscope. Flow cytometry was used to determine the cell surface expression of molecular markers of DC maturation, and qRT-PCR was employed to evaluate expression levels of proinflammatory genes involved in DC maturation. The obtained results indicated that Bicalutamide treatment of monocyte-derived mDCs induces an immunogenic and matured phenotype, marked by increased expression of CD86 and HLA-DR. Besides, qRT-PCR results evidenced that Bicalutamide decreased the expression of anti-inflammatory genes, including Interleukin-10 (IL-10) and TGF-beta, as an indication of immunogenic DCs. These findings suggest that beyond its established anti-androgen role, Bicalutamide may exert anti-tumor effects through the modulation of DCs-mediated immune responses. This novel immunomodulatory feature holds promise for the development of novel therapies, including combination therapies, in prostate cancer treatment.

Tumor necrosis factor­α in systemic lupus erythematosus: Structure, function and therapeutic implications (Review).

Tumor necrosis factor­α (TNF­α) is a pleiotropic pro­inflammatory cytokine that contributes to the pathophysiology of several autoimmune diseases, such as multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis and systemic lupus erythematosus (SLE). The specific role of TNF­α in autoimmunity is not yet fully understood however, partially, in a complex disease such as SLE. Through the engagement of the TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), both the two variants, soluble and transmembrane TNF­α, can exert multiple biological effects according to different settings. They can either function as immune regulators, impacting B­, T­ and dendritic cell activity, modulating the autoimmune response, or as pro­inflammatory mediators, regulating the induction and maintenance of inflammatory processes in SLE. The present study reviews the dual role of TNF­α, focusing on the different effects that TNF­α may have on the pathogenesis of SLE. In addition, the efficacy and safety of anti­TNF­α therapies in preclinical and clinical trials SLE are discussed.

Exploiting systems biology to investigate the gene modules and drugs in ovarian cancer: A hypothesis based on the weighted gene co-expression network analysis.

BACKGROUND: Ovarian cancer (OC) is one of the worrisome gynecological cancers worldwide. Given its considerable mortality rate, it is necessary to investigate its oncogenesis. METHODS: In this study, we used systems biology approaches to describe the key gene modules, hub genes, and regulatory drugs associated with serous OC as the novel biomarkers using weighted gene co-expression network analysis (WGCNA). FINDINGS: Our findings have demonstrated that the blue module genes (r = 0.8, p-value = 1e-16) are involved in OC progression. Based on gene enrichment analysis, the genes in this module are frequently involved in biological processes such as the Cyclic adenosine monophosphate (cAMP) signaling pathway and the cellular response to transforming growth factor-beta stimulation. The co-expression network has been built using the correlated module's top hub genes, which are ADORA1, ANO9, CD24P4, CLDN3, CLDN7, ELF3, KLHL14, PRSS8, RASAL1, RIPK4, SERINC2, and WNT7A. Finally, a drug-target network has been built to show the interaction of the FDA-approved drugs with hub genes. CONCLUSIONS: Our results have discovered that ADORA1, ANO9, SERINC2, and KLHL14 are hub genes associated with serous OC. These genes can be considered as novel candidate target genes for treating OC.

From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy.

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

Envisioning the immune system to determine its role in pancreatic ductal adenocarcinoma: Culprit or victim?

Pancreatic ductal adenocarcinoma has a poor 5-year survival rate that makes it one of the most fatal human malignancies. Unfortunately, despite the serious improvement in the survival of most cancers, there has been a minor advance in pancreatic cancer (PC). Major advances in PC treatment have been assessed over the bygone twenty-year time span, yet some complications make the survival of the patients shorter. Getting to know the PC tumor microenvironment (TME) and the immunosuppression that happens during the pathogenesis of this malignancy could be a great help to understand the nature of the immune system and find better treatment modalities based on it. Although many immune cells are present in PC, immunosuppression of the TME leads to severe immune dysfunction in the patients, therefore immune effectors fail to do their functions. Lately, immunotherapy has been presented as one of the promising treatment strategies for different malignancies including hepatocellular carcinoma, melanoma, non-small cell lung cancer, and kidney cancer. In PC, there has been shown promising results centered around the TME, immune checkpoint inhibitors, cancer vaccines, and other approaches especially when used as combinational therapy. Here we dig a little deeper into the role of the immune system and possible therapeutic options in the treatment of PC.

Targeting TGF-ß-Mediated SMAD Signaling Pathway via Novel Recombinant Cytotoxin II: A Potent Protein from Naja naja oxiana Venom in Melanoma.

Since the current treatments have not resulted in the desired outcomes for melanoma patients, there is a need to identify more effective medications. Together with other snake venom proteins, cytotoxin-II has shown promising results in tumoral cells. In this study, recombinant cytotoxin-II (rCTII) was expressed in SHuffle® T7 Express cells, while the epitope mapping of rCTII was performed to reveal the antibody-binding regions of rCTII. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to assess the viability of SK-MEL-3 and HFF-2 cells after treating these cells with rCTII. The qRT-PCR was performed to evaluate the expression levels of matrix metallopeptidase 3 (MMP-3), SMAD2, SMAD3, caspase-8, caspase-9, and miR-214 in order to reveal the rCTII-induced signaling pathways in melanoma. Our results have shown that two regions of amino acids, 6-16 and 19-44, as predicted epitopes of this toxin, are essential for understanding the toxicity of rCTII. Treating the melanoma cells with rCTII substantially inhibited the transforming growth factor-beta (TGF-ß)-SMAD signaling pathway and down-regulated the expression of MMP-3 and miR-214 as well. This cytotoxin also restored apoptosis mainly via the intrinsic pathway. The down-regulation of MMP-3 and miR-214 might be associated with the anti-metastatic property of rCTII in melanoma. The inhibitory effect of rCTII on the TGF-ß signaling pathway might be associated with increased apoptosis and decreased cancer cell proliferation. It is interesting to see that the IC50 value of rCTII has been lower in the melanoma cells than non-tumoral cells, which may indicate its potential effects as a drug. In conclusion, rCTII, as a novel medication, might serve as a potent and efficient anticancer drug in melanoma.