Exploring the histogenesis of STK11 adnexal tumour using electron microscopy.

STK11 adnexal tumour is a recently described female genital tract tumour, usually identified in a paratubal location, often associated with Peutz-Jeghers syndrome (PJS) and with STK11 gene alterations identified in most of the cases. Morphologically, this tumour is composed of cells arranged in a variety of patterns, including cords, trabeculae, tubules and cystic and acinar structures. The cells are only moderately pleomorphic and mitotic activity is variable. As tumour cells express epithelial, sex cord stromal and mesothelial markers, STK11 adnexal tumour may be of sex cord stromal, epithelial or mesothelial origin; a Wolffian origin has also been suggested. We report the ultrastructural features of two STK11 adnexal tumours and compare their ultrastructural features with those of other sex cord stromal tumours, a granulosa cell tumour cell line, as well as the known ultrastructural features of epithelial, mesothelial and Wolffian cells. On ultrastructural examination, two STK11 adnexal tumours showed an admixture of elongated cells with regular elongated nuclei and polygonal cells with nuclei showing markedly irregular outlines and prominent nucleoli. Extracellular collagen fibres were identified. These are common ultrastructural features of sex cord stromal tumours, principally sex cord tumour with annular tubules; no ultrastructural features of epithelial, mesothelial or Wolffian cells were found. These findings in conjunction with the shared clinical and genetic association with PJS and shared molecular changes in STK11 gene suggest that STK11 adnexal tumour represents a poorly differentiated sex cord tumour.

Genetic screening for anticancer genes highlights FBLN5 as a synthetic lethal partner of MYC.

BACKGROUND: When ectopically overexpressed, anticancer genes, such as TRAIL, PAR4 and ORCTL3, specifically destroy tumour cells without harming untransformed cells. Anticancer genes can not only serve as powerful tumour specific therapy tools but studying their mode of action can reveal mechanisms underlying the neoplastic transformation, sustenance and spread. METHODS: Anticancer gene discovery is normally accidental. Here we describe a systematic, gain of function, forward genetic screen in mammalian cells to isolate novel anticancer genes of human origin. Continuing with over 30,000 transcripts from our previous study, 377 cell death inducing genes were subjected to screening. FBLN5 was chosen, as a proof of principle, for mechanistic gene expression profiling, comparison pathways analyses and functional studies. RESULTS: Sixteen novel anticancer genes were isolated; these included non-coding RNAs, protein-coding genes and novel transcripts, such as ZNF436-AS1, SMLR1, TMEFF2, LINC01529, HYAL2, NEIL2, FBLN5, YPEL4 and PHKA2-processed transcript. FBLN5 selectively caused inhibition of MYC in COS-7 (transformed) cells but not in CV-1 (normal) cells. MYC was identified as synthetic lethality partner of FBLN5 where MYC transformed CV-1 cells experienced cell death upon FBLN5 transfection, whereas FBLN5 lost cell death induction in MCF-7 cells upon MYC knockdown. CONCLUSIONS: Sixteen novel anticancer genes are present in human genome including FBLN5. MYC is a synthetic lethality partner of FBLN5. Video Abstract.

TMEFF2: A Transmembrane Proteoglycan with Multifaceted Actions in Cancer and Disease.

Transmembrane protein with an EGF-like and two Follistatin-like domains 2 (TMEFF2) is a 374-residue long type-I transmembrane proteoglycan which is proteolytically shed from the cell surface. The protein is involved in a range of functions including metabolism, neuroprotection, apoptosis, embryonic development, onco-suppression and endocrine function. TMEFF2 is methylated in numerous cancers, and an inverse correlation with the stage, response to therapy and survival outcome has been observed. Moreover, TMEFF2 methylation increases with breast, colon and gastric cancer progression. TMEFF2 is methylated early during oncogenesis in breast and colorectal cancer, and the detection of methylated free-circulating TMEFF2 DNA has been suggested as a potential diagnostic tool. The TMEFF2 downregulation signature equals and sometimes outperforms the Gleason and pathological scores in prostate cancer. TMEFF2 is downregulated in glioma and cotricotropinomas, and it impairs the production of adrenocorticotropic hormone in glioma cells. Interestingly, through binding the amyloid ß protein, its precursor and derivatives, TMEFF2 provides neuroprotection in Alzheimer's disease. Despite undergoing extensive investigation over the last two decades, the primary literature regarding TMEFF2 is incoherent and offers conflicting information, in particular, the oncogenic vs. onco-suppressive role of TMEFF2 in prostate cancer. For the first time, we have compiled, contextualised and critically analysed the vast body of TMEFF2-related literature and answered the apparent discrepancies regarding its function, tissue expression, intracellular localization and oncogenic vs. onco-suppressive role.

Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer.

Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel-treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was investigated and revealed significant resensitization of docetaxel-resistant PCa cells for docetaxel treatment in a dose- and time-dependent manner, in which a complete restoration of docetaxel sensitivity was achieved in both androgen receptor (AR)-negative and AR-positive cell lines. Mechanistically, we demonstrated down-regulation of Bcl-xL and Bcl-2 upon GR antagonism, thereby defining potential treatment targets. In conclusion, we describe the involvement of the GR in the acquisition of docetaxel resistance in human PCa. Therapeutic targeting of the GR effectively resensitizes docetaxel-resistant PCa cells. These findings warrant further investigation of the clinical utility of the GR antagonists in the management of patients with advanced and docetaxel-resistant PCa.