👤 Zoran Culig

Gonadotropin dysregulation seems to play a potential role in the carcinogenesis of testicular germ cell tumor (TGCT). The aim of this study was to explore the expression of specific genes related to sex hormone regulation, synthesis, and metabolism in TGCT and to define specific hormonal clusters. Two publicly available databases were used for this analysis (TCGA and GSE99420). By means of hard-threshold regularized KMEANS clustering, we assigned TGCT samples into four clusters defined in respect to different expression of the sex hormone-related genes. We analysed clinical data, protein and gene expression, signaling regarding hormonal clusters. Based on whole-transcriptome gene expression, prediction of anti-cancer drug response was made by RIDGE models. Cluster #1 (12-16%) consisted primarily of non-seminomatous germ cell tumor (NSGCT), characterized by high expression of PRL, GNRH1, HSD17B2 and SRD5A1. Cluster #2 (42-50%) included predominantly seminomas with high expression of SRD5A3, being highly infiltrated by T and B cells. Cluster #3 (8.3-18%) comprised of NSGCT with high expression of CGA, CYP19A1, HSD17B12, HSD17B1, SHBG. Cluster #4 (23-30%), which consisted primarily of NSGCT with a small fraction of seminomas, was outlined by increased expression of STAR, POMC, CYP11A1, CYP17A1, HSD3B2 and HSD17B3. Elevated fibroblast levels and increased extracellular matrix- and growth factor signaling-related gene signature scores were described in cluster #1 and #3. In the combined model of progression-free survival, S2/S3 tumor marker status, hormonal cluster #1 or #3 and teratoma histology, were independently associated with 25-30% increase of progression risk. Based on the increased receptor tyrosine kinase and growth factor signaling, cluster #1, #3 and #4 were predicted to be sensitive to tyrosine kinase inhibitors, FGFR inhibitors or EGFR/ERBB inhibitors. Cluster #2 and #4 were responsive to compounds interfering with DNA synthesis, cytoskeleton, cell cycle and epigenetics. Response to apoptosis modulators was predicted only for cluster #2. Hormonal cluster #1 or #3 is an independent prognostic factor regarding poor progression-free survival. Hormonal cluster assignment also affects the predicted drug response with cluster-dependent susceptibility to specific novel therapeutic compounds. Show less

Epithelial to mesencyhmal transition (EMT) has a central role in tumor metastasis and progression. EMT is regulated by several growth factors and pro-inflammatory cytokines. The most important role in this regulation could be attributed to transforming growth factor-β (TGF-β). In breast cancer, TGF-β effect on EMT could be potentiated by Fos-related antigen, oncogene HER2, epidermal growth factor, or mitogen-activated protein kinase kinase 5 - extracellular-regulated kinase signaling. Several microRNAs in breast cancer have a considerable role either in potentiation or in suppression of EMT thus acting as oncogenic or tumor suppressive modulators. At present, possibilities to target EMT are discussed but the results of clinical translation are still limited. In prostate cancer, many cellular events are regulated by androgenic hormones. Different experimental results on androgenic stimulation or inhibition of EMT have been reported in the literature. Thus, a possibility that androgen ablation therapy leads to EMT thus facilitating tumor progression has to be discussed. Novel therapy agents, such as the anti-diabetic drug metformin or selective estrogen receptor modulator ormeloxifene were used in pre-clinical studies to inhibit EMT in prostate cancer. Taken together, the results of pre-clinical and clinical studies in breast cancer may be helpful in the process of drug development and identify potential risk during the early stage of that process. Show less