Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability

Sex-related differences have been reported in various cancers, in particular men with lactotroph tumors have a worse prognosis than women. While the underlying mechanism of this sexual dimorphism remains unclear, it has been suggested that a lower estrogen receptor alpha expression may drive the sex differences observed in aggressive and malignant lactotroph tumors that are resistant to dopamine agonists. Based on this observation, we aimed to explore the molecular importance of the estrogen pathway through a detailed analysis of the transcriptomic profile of lactotroph tumors from 20 men and 10 women. We undertook gene expression analysis of the selected lactotroph tumors following their pathological grading using the five-tiered classification. Chromosomic alterations were further determined in 13 tumors. Functional analysis showed that there were differences between tumors from men and women in gene signatures associated with cell morphology, cell growth, cell proliferation, development, and cell movement. Hundred-forty genes showed an increased or decreased expression with a minimum 2-fold change. A large subset of those genes belonged to the estrogen receptor signaling pathway, therefore confirming the potent role of this pathway in lactotroph tumor sex-associated aggressiveness. Genes belonging to the X chromosome, such as CTAG2, FGF13, and VEGF-D, were identified as appealing candidates with a sex-linked dysregulation in lactotroph tumors. Through our comparative genomic hybridization analyses (CGH), chromosomic gain, in particular chromosome 19p, was found only in tumors from men, while deletion of chromosome 11 was sex-independent, as it was found in most (5/6) of the aggressive and malignant tumors. Comparison of transcriptomic and CGH analysis revealed four genes (CRB3, FAM138F, MATK, and STAP2) located on gained regions of chromosome 19 and upregulated in lactotroph tumors from men. MATK and STAP2 are both implicated in cell growth and are reported to be associated with the estrogen signaling pathway. Our work confirms the proposed involvement of the estrogen signaling pathway in favoring the increased aggressiveness of lactotroph tumors in men. More importantly, we highlight a number of ER-related candidate genes and further identify a series of target molecules with sex-specific expression that could contribute to the aggressive behavior of lactotroph tumors in men

Réponses cellulaires et moléculaires de la signalisation FGF/FGFR dans la progression tumorale et l'angiogenèse des carcinomes NBT-II

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Targets of Fibroblast Growth Factor 1 (FGF-1) and FGF-2 Signaling Involved in the Invasive and Tumorigenic Behavior of Carcinoma Cells

Fibroblast growth factor (FGF)-1 and -2 have potent biological activities implicated in malignant tumor development. Their autocrine and nonautocrine activity in tumor progression of carcinoma was investigated in the NBT-II cell system. Cells were manipulated to either produce and be autocrine for FGF-1 or -2 or to only produce but not respond to these factors. The autocrine cells are highly invasive and tumorigenic and the determination of specific targets of FGF/fibroblast growth factor receptor (FGFR) signaling was assessed. In vitro studies showed that nonautocrine cells behave like epithelial parental cells, whereas autocrine cells have a mesenchymal phenotype correlated with the overexpression of urokinase plasminogen activator receptor (uPAR), the internalization of E-cadherin, and the redistribution of β-catenin from the cell surface to the cytoplasm and nucleus. uPAR was defined as an early target, whereas E-cadherin and the leukocyte common antigen-related protein-tyrosine phosphatase (LAR-PTP) were later targets of FGF signaling, with FGFR1 activation more efficient than FGFR2 at modulating these targets. Behavior of autocrine cells was consistent with a decrease of tumor-suppressive activities of both E-cadherin and LAR-PTP. These molecular analyses show that the potential of these two growth factors in tumor progression is highly dependent on specific FGFR signaling and highlights its importance as a target for antitumor therap

Early Effects of Combretastatin A4 Phosphate Assessed by Anatomic and Carbogen-Based Functional Magnetic Resonance Imaging on Rat Bladder Tumors Implanted in Nude Mice

Combretastatin A4 phosphate (CA4P) causes rapid disruption of the tumor vasculature and is currently being evaluated for antivascular therapy. We describe the initial results obtained with a noninvasive multi-parametric magnetic resonance imaging (MRI) approach to assess the early effects of CA4P on rat bladder tumors implanted on nude mice. MRI (4.7 T) comprised a fast spin-echo sequence for growth curve assessment; a multislice multiecho sequence for T(2) measurement before, 15 minutes after, and 24 hours after CA4P (100 mg/kg); and a fast T(2w)* gradient-echo sequence to assess MR signal modification under carbogen breathing before, 35 minutes after, and 24 hours after CA4P. The tumor fraction with increased T(2w)* signal intensity under carbogen (T(+)) was used to quantify CA4P effect on functional vasculature. CA4P slowed tumor growth over 24 hours and accelerated necrosis development. T(+) decrease was observed already at 35 minutes post-CA4P. Early T(2) increase was observed in regions becoming necrotic at 24 hours post-CA4P, as confirmed by high T(2) and histology. These regions exhibited, under carbogen, a switch from T(2w)* signal increase before CA4P to a decrease post-CA4P. The combination of carbogen-based functional MRI and T(2) measurement may be useful for the early follow-up of antivascular therapy without the administration of contrast agents

Multiple-target tracking of 3D fluorescent objects based on simulated annealing

International audienceThis paper presents a framework for tracking fluorescent objects imaged with 3D+time video-microscopy. The proposed technique solves the NP-hard problem of the multi-frame object correspondence. For this purpose, we use the simulated annealing algorithm for its flexibility for feature correspondence and its ability to give results in a very short time. Our approach takes into account events like "split", 'merge", "birth" and "death". These "evolutionary events" are motivated by biological and physical considerations. We demonstrate the performance of the proposed algorithm on images of carcinoma NBT-II cells expressing fluorescent LAR-PTP, a tyrosine phosphatase possibly involved in tumor progression

Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth.

CONTEXT: A sex difference in the progression of prolactin (PRL) tumors has been disputed for years. OBJECTIVE: To compare tumor characteristics and postoperative clinical course between men and women, and correlate data with estrogen receptor alpha (ERα (ESR1)) expression status. DESIGN, PATIENTS, AND METHODS: Eighty-nine patients (59 women and 30 men) operated on for a prolactinoma and followed for at least 5 years were selected. Tumors were classified into five grades according to their size, invasion, and proliferation characteristics. The ERα expression was detected by immunohistochemistry and a score (0-12) calculated as the product of the percentage of positive nuclei and the staining intensity. RESULTS: We found a significant preponderance of high-grade tumors among men and a lower surgical cure rate in men (23%) than in women (71%). Patients resistant to medical treatment were mainly men (7/8), six of whom showed tumor progression despite postoperative medical treatment, which led to multiple therapies and eventually death in three. The median score for ERα expression was 1 in men (range, 0-8) and 8 in women (range, 0-12) (P<0.0001). The expression of ERα was inversely correlated with tumor size (r=-0.59; P<0.0001) and proliferative activity. All dopamine agonist-resistant tumors and all grade 2b (invasive and proliferative) tumors (from ten men and four women) were characterized by low ERα expression. CONCLUSIONS: PRL tumors in men are characterized by lower ERα expression, which is related to higher tumor grades, resistance to treatment, and an overall worse prognosis

Clinical, pathological and molecular factors of aggressiveness in lactotroph tumours.

The behaviour of lactotroph tumours varies between benign tumours, those cured by treatment, and that of aggressive tumours, and carcinomas with metastasis. Identification of clinical, pathological and molecular factors is essential for the early identification of patients that may have such aggressive tumours. Plasma prolactin levels and tumour size and invasion, per se, are not prognostic factors. However, tumours appearing at a young age ( 2) are correlated to invasion and proliferation, but, taken alone, their prognostic value is debatable. Based on a 5-tiered clinicopathological classification, and taking into account invasion and proliferation, a grade 2b (aggressive) lactotroph tumour has a 20× risk of progression compared to a grade 1a (benign) tumour. Moreover, lactotroph tumours are the second-most frequent aggressive and malignant tumour. Other factors, such as the expression of growth factors (vascular endothelial growth factor [VEGF] and epidermal growth factor [EGF]), the genes regulating invasion, differentiation and proliferation, adhesion molecules (E-cadherin), matrix metalloproteinase 9, and chromosome abnormalities (chromosomes 11, 19, and 1), have also been correlated with aggressiveness. Currently, clinical signs, a prognostic classification, and molecular and genetic markers may all help the clinician in the early identification of aggressive lactotroph tumours and enable stratification of their management

Pituitary carcinomas and aggressive pituitary tumours: merits and pitfalls of temozolomide treatment.

International audiencePituitary carcinomas are rare, accounting for about 0*2% of all pituitary tumours. They represent a challenge to clinical practice in both diagnosis and treatment. They may present initially as typical pituitary adenomas, with a delayed appearance of aggressive signs, or as aggressive tumours from the outset. Predicting the pituitary tumour behaviour remains difficult: increased mitotic, Ki-67 and P53 indices might be associated with tumour aggression. The treatment of pituitary carcinomas and aggressive pituitary tumours includes surgery, adjuvant medical treatment, external beam radiotherapy and chemotherapy. Until recently, the treatment of pituitary carcinomas was mainly palliative and did not seem to increase overall survival. Recent case reports have detailed the successful use of temozolomide, an orally administered alkylating agent used to treat malignant gliomas, in the management of pituitary carcinomas and aggressive pituitary tumours. The outcome of treatment might depend on the expression of O (6) -methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme that potentially interferes with drug efficacy. This review describes the clinical presentation and response to temozolomide in 44 patients with pituitary carcinomas or aggressive pituitary tumours reported in the literature. The results suggest that temozolomide should be considered a drug of major importance in the therapeutic algorithm of aggressive pituitary tumours and pituitary carcinomas. Because of the inconsistency of published data, MGMT expression should probably not be taken as a reason to deny these patients the potential benefit of temozolomide treatment, taking into account the paucity of other available treatments