GDF15 x NGF

Prostate cancer is one of the most common malignancies in men, and its early detection remains a considerable clinical challenge. Advances in biomarker research have pointed to the promising role of inflammatory and tumor-specific markers in improving diagnostic precision.

This study investigated the potential of novel ELISA-based biomarkers for the early detection of prostate cancer. It specifically examined the diagnostic significance of inflammatory markers-IL-8, TGF-β, MIC-1/GDF15, YKL-40, and NGF-alongside the tumor-specific biomarker PSMA, to aid in the identification of early-stage disease.

A case-control study was conducted at Al-Habboubi Teaching Hospital over a six-month period (January-June 2024), involving 150 prostate cancer patients and 50 healthy controls aged 45-75 years. Biomarker levels (PSMA, IL-8, TGF-β, MIC-1/GDF15, YKL-40, and NGF) were measured using BioTech USA ELISA kits. The study protocol, including inclusion and exclusion criteria, was approved by the institutional review board.  Result: Significant differences were observed between patients and controls in socio-demographic variables, such as family history and BMI. Prostate cancer patients demonstrated substantially higher serum concentrations of PSMA, IL-8, TGF-β, MIC-1/GDF15, YKL-40, and NGF compared to healthy individuals (p < 0.001). Disease severity showed strong correlations with these biomarkers, particularly PSMA, highlighting their diagnostic and disease-monitoring potential.

The observed elevations of PSMA, IL-8, TGF-β, MIC-1/GDF15, YKL-40, and NGF in prostate cancer patients emphasize their value as diagnostic and prognostic indicators. These biomarkers reflect activation of inflammatory and tumor-specific pathways, supporting their clinical application in early detection and disease progression monitoring.

Drug development for castration resistant prostate cancer (CRPC) is challenging, since this cancer is still associated with high mortality and limited therapeutic options. In 2004, docetaxel became the first-line chemotherapy for CRPC improving survival by a few months and remains the standard of care in CRPC patients. However, existing or developing resistance to docetaxel in patients is the main limitation of its efficacy. The present review presents the molecular mechanisms involved in docetaxel toxicity and in docetaxel resistance in prostate cancer cells. We outlined the endogenous mechanisms of resistance and the role of tumor microenvironment in the resistance of CRPC to docetaxel. This has led us to focus on molecules associated with resistance, such as the molecular chaperones heat shock proteins (HSPs) and clusterin (CLU), and the cytokines interleukin-6 (IL-6) and the divergent member of the tumor growth factor family MIC-1 (macrophage inhibitory cytokine-1 also named GDF-15). We discuss their interest as blood-based markers to monitor docetaxel resistance. Finally, new therapies intended to overcome docetaxel resistance of CRPC targeted on these molecular resistance pathways are present.

The major goal of the study was to compare the genetic programs utilized by the neuropoietic cytokine Interleukin-6 (IL-6) and the neurotrophin (NT) Nerve Growth Factor (NGF) for neuronal differentiation.

The designer cytokine Hyper-IL-6 in which IL-6 is covalently linked to its soluble receptor s-IL-6R as well as NGF were used to stimulate PC12 cells for 24 hours. Changes in gene expression levels were monitored using Affymetrix GeneChip technology. We found different expression for 130 genes in IL-6- and 102 genes in NGF-treated PC12 cells as compared to unstimulated controls. The gene set shared by both stimuli comprises only 16 genes.A key step is upregulation of growth factors and functionally related external molecules known to play important roles in neuronal differentiation. In particular, IL-6 enhances gene expression of regenerating islet-derived 3 alpha (REG3A; 1084-fold), regenerating islet-derived 3 beta (REG3B/PAPI; 672-fold), growth differentiation factor 15 (GDF15; 80-fold), platelet-derived growth factor alpha (PDGFA; 69-fold), growth hormone releasing hormone (GHRH; 30-fold), adenylate cyclase activating polypeptide (PACAP; 20-fold) and hepatocyte growth factor (HGF; 5-fold). NGF recruits GDF15 (131-fold), transforming growth factor beta 1 (TGFB1; 101-fold) and brain-derived neurotrophic factor (BDNF; 89-fold). Both stimuli activate growth-associated protein 43 (GAP-43) indicating that PC12 cells undergo substantial neuronal differentiation.Moreover, IL-6 activates the transcription factors retinoic acid receptor alpha (RARA; 20-fold) and early growth response 1 (Egr1/Zif268; 3-fold) known to play key roles in neuronal differentiation.Ingenuity biological function analysis revealed that completely different repertoires of molecules are recruited to exert the same biological functions in neuronal differentiation. Major sub-categories include cellular growth and differentiation, cell migration, chemotaxis, cell adhesion, small molecule biochemistry aiming at changing intracellular concentrations of second messengers such as Ca2+ and cAMP as well as expression of enzymes involved in posttranslational modification of proteins.

The current data provide novel candidate genes involved in neuronal differentiation, notably for the neuropoietic cytokine IL-6. Our findings may also have impact on the clinical treatment of peripheral nerve injury. Local application of a designer cytokine such as H-IL-6 with drastically enhanced bioactivity in combination with NTs may generate a potent reparative microenvironment.