Chemokines driven ovarian cancer progression, metastasis and chemoresistance: Potential pharmacological targets for cancer therapy.

Ovarian cancer is a leading cause of death among women globally often characterized by poor prognosis and aggressive tumor growth. The therapeutic outcomes of ovarian cancer patients are majorly limited by the development of acquired chemo/radioresistance and the lack of targeted therapies. The tumor microenvironment (TME) comprises a diverse population of cells including adipocytes, fibroblasts, tumor cells, and immune cells which play an imperative role in promoting tumor growth, invasion, and malignant phenotypes of cancer cells. The cells present in TME secrete various inflammatory mediators including chemokines and cytokines, which regulate the tumor progression and metastasis. This review article highlights new insights about the general mechanisms associated with chemokines-mediated cell proliferation, inflammation, tumor initiation, progression, metastasis, chemoresistance, and immune evasion in ovarian cancer. We also discuss the microRNAs (miRNAs) regulating the oncogenic potential of chemokines. Overall, this is a comparatively less explored area that could provide important insights into ovarian cancer development and a promising avenue for targeted therapy of ovarian cancer.

Expression Profile, Molecular Association, and Clinical Significance of POLD4 in Glioblastoma.

The POLD4 gene encodes a subunit (δ4) of DNA polymerase delta, which is a key enzyme involved in DNA replication and repair. Recent studies have suggested that POLD4 plays a crucial role in developing certain cancers. However, there is a lack of knowledge regarding the role of POLD4 in the context of glioblastoma (GBM). Therefore, in this study we have used various cancer bioinformatics tools to explore the role of POLD4 in glioblastoma. Data from various sources were accessed to analyze POLD4 gene expression and estimate tumor-infiltrating immune cells in glioblastoma. Methylation data were retrieved using the MEXPRESS web browser and analyzed. UALCAN webserver was used to analyze the protein expression of POLD4. Gene correlation and pathway enrichment analysis were performed using cBioPortal and GSEA software, respectively. Afterward, survival analysis was performed. POLD4 was significantly upregulated in glioblastoma at both gene and protein levels in GBM, and ROC curve analysis revealed it as a potential biomarker in glioblastoma. GSEA analysis of TCGA-GBM pan-cancer study exhibited that POLD4 expression was associated with critical pathways, such as interferon-gamma response, G2M checkpoint, inflammatory response, E2F targets, EMT transition, and KRAS signaling pathways. Furthermore, POLD4 expression was positively correlated with DNA methylation at 3 CpG sites, including Cg16509978, with a Pearson correlation coefficient value of 0.398 (p-value ≤ 0.01), while the promoter region had a positive correlation but was not significant. In addition, POLD4 is significantly linked with poor OS, PFS, and DFS. We also found association of POLD4 expression with altered immune cell infiltration. In conclusion, POLD4 is significantly upregulated in glioblastoma and may be used as a potential diagnostic or prognostic biomarker for GBM patients. However, to establish the same a large cohort study is needed. Using TCGA data and various cancer bioinformatics tools mentioned above we observed very high level of gene and protein expression of POLD4 in glioblastoma patients. The expression of POLD4 was significantly correlated with inflammatory and oncogenic pathways and it also has a significant correlation with adverse outcome in patients with glioblastoma.

Complexity of Tumor Microenvironment: Therapeutic Role of Curcumin and Its Metabolites.

The tumor microenvironment (TME) is a complex network of cellular and non-cellular components surrounding the tumor. The cellular component includes fibroblasts, adipocytes, endothelial cells, and immune cells, while non-cellular components are tumor vasculature, extracellular matrix and signaling molecules. The tumor cells have constant close interaction with their surrounding TME components that facilitate their growth, survival, and metastasis. Targeting a complex TME network and its interaction with the tumor can offer a novel strategy to disrupt cancer cell progression. Curcumin, from turmeric rhizome, is recognized as a safe and effective natural therapeutic agent against multiple diseases including cancer. Here the effects of curcumin and its metabolites on tumor-TME interaction modulating ability have been described. Curcumin and its metabolites regulate TME by inhibiting the growth of its cellular components such as cancer-associated adipocytes, cancer-associated fibroblast, tumor endothelial cells, tumor-stimulating immune cells, and inducing anticancer immune cells. They also inhibit the interplay of tumor cells to TME by suppressing non-cellular components such as extracellular matrix, and associated tumor promoting signaling-pathways. In addition, curcumin inhibits the inflammatory environment, suppresses angiogenic factors, and increases antioxidant status in TME. Overall, curcumin has the capability to regulate TME components and their interaction with tumor cells.

MicroRNAs: As Critical Regulators of Tumor- Associated Macrophages.

Emerging shreds of evidence suggest that tumor-associated macrophages (TAMs) modulate various hallmarks of cancer during tumor progression. Tumor microenvironment (TME) prime TAMs to execute important roles in cancer development and progression, including angiogenesis, matrix metalloproteinases (MMPs) secretion, and extracellular matrix (ECM) disruption. MicroRNAs (miRNAs) are critical epigenetic regulators, which modulate various functions in diverse types of cells, including macrophages associated with TME. In this review article, we provide an update on miRNAs regulating differentiation, maturation, activation, polarization, and recruitment of macrophages in the TME. Furthermore, extracellular miRNAs are secreted from cancerous cells, which control macrophages phenotypic plasticity to support tumor growth. In return, TAMs also secrete various miRNAs that regulate tumor growth. Herein, we also describe the recent updates on the molecular connection between tumor cells and macrophages. A better understanding of the interaction between miRNAs and TAMs will provide new pharmacological targets to combat cancer.

MiRNA-3163 limits ovarian cancer stem-like cells via targeting SOX-2 transcription factor.

Cancer stem cells (CSCs) are pivotal in both cancer progression and the acquisition of drug resistance. MicroRNAs (miRNAs) play a crucial role in modulating CSC properties and are being explored as potential targets for therapeutic interventions. MiR-3163 is primarily known for its tumor suppressive properties in various human malignancies, with lower expression reported across different cancer types. However, its role in regulating the ovarian CSC phenotype and the underlying mechanism remain largely unknown. Here, we report a remarkable downregulation of miR-3163 in ovarian cancer stem-like cells (CSLCs). Enforced expression of miR-3163 in ovarian adherent and CSLCs, significantly disrupts the stemness phenotype. Moreover, downregulation of miR-3163 expression in ovarian cancer cells (OV2008 and OVCAR-3) inhibits the stem-like cells characterized by CD44+CD117+ expression. Sphere formation assay results reveal that overexpression of miR-3163 in ovarian cancer cells significantly inhibits spheroid formation ability, confirming the regulatory properties of miR-3163 on ovarian CSLCs. Mechanistic investigation reveals that miR-3163 depletes ovarian CSLCs via targeting SOX-2. Furthermore, we establish SOX-2 as a direct target of miR-3163 through dual-luciferase assay. Taken together, our study demonstrates that overexpression of miR-3163 could be a promising strategy for efficiently eradicating the CSC population to prevent chemoresistance and tumor relapse in ovarian cancer patients.