Growth Differentiation Factor 15 (GDF-15) Plasma Levels Increase during Bleomycin- and Cisplatin-Based Treatment of Testicular Cancer Patients and Relate to Endothelial Damage

Abstract

IntroductionChemotherapy-related endothelial damage contributes to the early development of cardiovascular morbidity in testicular cancer patients. We aimed to identify relevant mechanisms of and search for candidate biomarkers for this endothelial damage.MethodsHuman micro-vascular endothelial cells (HMEC-1) were exposed to bleomycin or cisplatin with untreated samples as control. 18k cDNA microarrays were used. Gene expression differences were analysed at single gene level and in gene sets clustered in biological pathways and validated by qRT-PCR. Protein levels of a candidate biomarker were measured in testicular cancer patient plasma before, during and after bleomycin-etoposide-cisplatin chemotherapy, and related to endothelial damage biomarkers (von Willebrand Factor (vWF), high-sensitivity C-Reactive Protein (hsCRP)).ResultsMicroarray data identified several genes with highly differential expression; e.g. Growth Differentiation Factor 15 (GDF-15), Activating Transcription Factor 3 (ATF3) and Amphiregulin (AREG). Pathway analysis revealed strong associations with ‘p53’ and ‘Diabetes Mellitus’ gene sets. Based on known function, we measured GDF-15 protein levels in 41 testicular patients during clinical follow-up. Pre-chemotherapy GDF-15 levels equalled controls. Throughout chemotherapy GDF-15, vWF and hsCRP levels increased, and were correlated at different time-points.ConclusionAn unbiased approach in a preclinical model revealed genes related to chemotherapy-induced endothelial damage, like GDF-15. The increases in plasma GDF-15 levels in testicular cancer patients during chemotherapy and its association with vWF and hsCRP suggest that GDF-15 is a potentially useful biomarker related to endothelial damage.

Cell-to-Cell Variation in p53 Dynamics Leads to Fractional Killing

“…Etoposide, camptothecin and doxorubicin also caused a similar increase in IAP gene expression (Figure S5A). In addition, analysis of other microarray data sets (Altena et al, 2015; Hussner et al, 2012) revealed that induction of IAP genes after doxorubicin or cisplatin treatment occurs in other cancerous (HeLa, Figure S5B) and primary (HMEC-1, Figure S5C) cell lines. Together these results suggest that induction of IAP proteins by DNA damaging agents is not limited to cisplatin or HCT116 cells (Figure S5A–C).…”

Vascular fingerprint and vascular damage markers associated with vascular events in testicular cancer patients during and after chemotherapy

“…GDF-15 is also known to participate in vascular pathological processes [21]. In a preclinical model for chemotherapyinduced endothelial damage its genes were highly upregulated [22]. GDF-15 thus seems to reflect endothelial activation during chemotherapy.…”

Predictive Properties of Biomarkers GDF-15, NTproBNP, and hs-TnT for Morbidity and Mortality in Patients With Type 2 Diabetes With Nephropathy

“…Previously, we identified growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1, as a clinically valuable marker for predicting progression to microalbuminuria and macroalbuminuria in both T2D and hypertension patients (2), suggesting that GDF-15 may be a valuable marker for individual risk stratification in patients with normoalbuminuria and microalbuminuria. Although GDF-15 can be upregulated in diverse tissues in response to damage, circulating levels of GDF-15 appear to reflect primarily damage to the vascular endothelium (3)(4)(5). In addition to GDF-15, we later demonstrated in the same cohort of patients that the cardiac biomarker high-sensitivity troponin T (hs-TnT) also predicted the worsening of albuminuria in both T2D and hypertension (6).…”