The Impact of Lifestyle on Sperm Function, Telomere Length, and IVF Outcomes.

Many risk factors can potentially influence sperm quality. Telomeres confer stability on the chromosome and their dysfunction has been implicated in conditions such as cancer, aging, and lifestyle. The impact of lifestyle on sperm cell telomeres is unclear. The objectives of this study were to evaluate the impact of lifestyle behaviors on telomere length in sperm and to follow the correlation with pregnancy outcomes in patients undergoing in vitro fertilization (IVF). In this prospective observational study, sperm was analyzed for telomere length (TL). Men were asked to report lifestyle behaviors including occupation (physical or sedentary), smoking duration and amount, physical activity, dietary habits, and where they keep their cellular phone (bag, pants, or shirt pocket). Correlations among semen analysis, TL, men's habits, and embryo quality and pregnancy outcomes were evaluated. Among 34 patients recruited, 12 had longer TL and 13 shorter TL. Sperm motility was negatively correlated with TL (Pearson correlation = -.588, p = .002). Smoking adversely affected native sperm motility (53% motility in nonsmokers vs. 37% in smokers; p = .006). However, there was no significant impact on TL. The group with longer telomeres demonstrated significant association with healthy diet (10/12 vs. 6/13; p = .05) and a trend toward more sports activity, weekly (16/84 vs. 7/91; p = .04) compared with the shorter telomeres group. This study suggests that lifestyle, healthy diet, and sports activity are associated with long telomeres in sperm. Sperm quality is also influenced by patients' habits. The study strongly recommends maintaining a healthy lifestyle to preserve general health and fertility.

The expression of heparanase in term and preterm human placentas.

PURPOSE: Heparanase is an endo-ß-glucuronidase that cleaves side chains of heparan-sulfate proteoglycans, an integral constituent of the extra cellular matrix. The abundance of heparanase in placental trophoblast cells implies its role in the processes of placentation and trophoblast invasion. This study aims to explore the involvement of heparanase in parturition and preterm deliveries (PTD). METHODS: Sixteen human placentas were collected following singleton spontaneous onset term vaginal deliveries (n = 6), spontaneous onset preterm vaginal deliveries (n = 7) and term elective cesarean sections (n = 3). Placentas were excluded in case of any maternal chronic illness, pregnancy or delivery complications apart from PTD. Placental tissue samples were dissected, homogenized and proteins were extracted. Additionally, cryosections were prepared from the placental tissues. Heparanase expression was evaluated utilizing western blot analysis and immunofluorescence staining using heparanase specific antibodies. Heparanase expression was compared between the study groups qualitatively and quantitatively. RESULTS: Western blot analysis results demonstrated higher expression of both pro-heparanase and heparanase in PTD placentas compared to term vaginal placentas. Accordingly, immunofluorescence staining shows elevated heparanase expression in PTD placentas compared to term vaginal placentas (5.1 ± 0.92 vs. 1.2 ± 0.18, p < .005). Expression level of heparanase was higher in term cesarean section placentas as compared to term vaginal deliveries placentas, but did not reach statistical significance (1.8 ± 0.39 vs. 1.2 ± 0.18, p = .06). CONCLUSION: This study demonstrates for the first time that preterm vaginal deliveries are associated with higher expression of heparanase in placental tissue. This may imply a direct effect of heparanase on preterm labor. Further studies should evaluate the functional role by which heparanase influence preterm delivery.

ZYG11A Is Expressed in Epithelial Ovarian Cancer and Correlates With Low Grade Disease.

The insulin-like growth factors (IGF) are important players in the development of gynecological malignancies, including epithelial ovarian cancer (EOC). The identification of biomarkers that can help in the diagnosis and scoring of EOC patients is of fundamental importance in clinical oncology. We have recently identified the ZYG11A gene as a new candidate target of IGF1 action. The aim of the present study was to evaluate the expression of ZYG11A in EOC patients and to correlate its pattern of expression with histological grade and pathological stage. Furthermore, and in view of previous analyses showing an interplay between ZYG11A, p53 and the IGF1 receptor (IGF1R), we assessed a potential coordinated expression of these proteins in EOC. In addition, zyg11a expression was assessed in ovaries and uteri of growth hormone receptor (GHR) knock-out mice. Tissue microarray analysis was conducted on 36 patients with EOC and expression of ZYG11A, IGF1R and p53 was assessed by immunohistochemistry. Expression levels were correlated with clinical parameters. qPCR was employed to assess zyg11a mRNA levels in mice tissues. Our analyses provide evidence of reduced ZYG11A expression in high grade tumors, consistent with a putative tumor suppressor role. In addition, an inverse correlation between ZYG11A and p53 levels in individual tumors was noticed. Taken together, our data justify further exploration of the role of ZYG11A as a novel biomarker in EOC.

IGF1R Axis Inhibition Restores Dendritic Cell Antitumor Response in Ovarian Cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. The insulin-like growth factor (IGF) system plays a key role in regulating growth and invasiveness in several malignancies, including ovarian cancer. IGF1R targeting showed antiproliferative activity of EOC cells. However, clinical studies failed to show significant benefit. EOC cells suppress antitumor immune responses by inducing dendritic cell (DC) dysfunction. The IGF1 axis can regulate DC maturation. The current study evaluated involvement of the IGF1 axis in DC differentiation in EOC. Studies were conducted on EOC and on a human monocyte cell line. Tissue microarray analysis (TMA) was performed on 36 paraffin blocks from EOC patients. Expression of IGF1R, p53, Ki67, BRCA1, and DC markers was evaluated using immunohistochemistry. Co-culture of EOC cells with DC pretreated with IGF1R inhibitor blocked cancer cell migration. TMA demonstrated higher rate of IGF1R protein expression in patients with advanced (76.9%) as compared to early (40%) EOC. A negative correlation between IGF1R protein expression and the CD1c marker was found. These findings provide evidence that IGF1R axis inhibition could be a therapeutic strategy for ovarian cancer by restoring DC-mediated antitumor immunity.

[THE PROLIFERATIVE EFFECT OF DENDRITIC CELLS IN OVARIAN CANCER AND THE RELATIONSHIP WITH THE IGF SIGNALING PATHWAY].

INTRODUCTION: Epithelial ovarian cancer (EOC) is the principal cause of death from gynecologic cancer in developed countries. While surgery and chemotherapy can improve survival, the mortality and morbidity rates remain significantly high. The insulin-like growth factor (IGF) axis has been shown to play an important part in carcinogenesis of several human malignancies. Preclinical studies reported a significant anti-proliferative activity of IGF1 receptor (IGF1R) inhibitors in ovarian malignancies, however, clinical studies have shown variable response rates. Recent data indicate that immunotherapy could hold promise in improving EOC treatment. Dendritic cells (DCs) which are antigen presenting cells evoke a positive immune response. Moreover, a recent study shows that IGF treatment can inhibit DC maturation. AIMS: To investigate the involvement of IGF1R signaling in DCs and the effect of combined DCs and IGF1R inhibitor treatment on EOC cells growth. METHODS: HL-60 leukemic cells were differentiated to DCs and ligand induced phosphorylated IGF1R levels were measured by Western blotting. Next, inhibition of IGF1R in DCs was applied and the effect of this inhibition on EOC cell lines ES2 and SKOV3 was examined using the migration assay method. RESULTS: The differentiation of HL-60 into DCs was associated with decreased levels of both IGF1R phosphorylation and total IGF1R protein. In addition, in-vitro growth assays (scratch assay) demonstrated an increased growth of both ES2 and SKOV3 cells into the scratch zone when co-cultured with DCs which were not pre-treated with IGF1R inhibitor as compared to treated DCs. CONCLUSIONS: Preliminary data suggest that DC differentiation is associated with IGF1R signaling downregulation. Moreover, inhibition of IGF1R signaling in DCs might decrease EOC growth.

Oncogenic fusion proteins adopt the insulin-like growth factor signaling pathway.

The insulin-like growth factor-1 receptor (IGF1R) has been identified as a potent anti-apoptotic, pro-survival tyrosine kinase-containing receptor. Overexpression of the IGF1R gene constitutes a typical feature of most human cancers. Consistent with these biological roles, cells expressing high levels of IGF1R are expected not to die, a quintessential feature of cancer cells. Tumor specific chromosomal translocations that disrupt the architecture of transcription factors are a common theme in carcinogenesis. Increasing evidence gathered over the past fifteen years demonstrate that this type of genomic rearrangements is common not only among pediatric and hematological malignancies, as classically thought, but may also provide a molecular and cytogenetic foundation for an ever-increasing portion of adult epithelial tumors. In this review article we provide evidence that the mechanism of action of oncogenic fusion proteins associated with both pediatric and adult malignancies involves transactivation of the IGF1R gene, with ensuing increases in IGF1R levels and ligand-mediated receptor phosphorylation. Disrupted transcription factors adopt the IGF1R signaling pathway and elicit their oncogenic activities via activation of this critical regulatory network. Combined targeting of oncogenic fusion proteins along with the IGF1R may constitute a promising therapeutic approach.

TMPRSS2-ERG fusion protein regulates insulin-like growth factor-1 receptor (IGF1R) gene expression in prostate cancer: involvement of transcription factor Sp1.

Prostate cancer is a major health issue in the Western world. The most common gene rearrangement in prostate cancer is the TMPRSS2-ERG fusion, which results in aberrant expression of the transcription factor ERG. The insulin-like growth factor-1 receptor (IGF1R) plays a key role in cell growth and tumorigenesis, and is overexpressed in most malignancies, including prostate cancer. In this study we show that TMPRSS2-ERG mediates its tumorigenic effects through regulation of IGF1R gene expression. Silencing of T-ERG in VCaP cells resulted in downregulation of both IGF1R and Sp1, a critical IGF1R regulator. Co-immunoprecipitation assays revealed a physical interaction between transcription factors ERG and Sp1, with potential relevance in IGF1R gene regulation. In addition, transactivation of the IGF1R gene by ERG was mediated at the level of transcription, as indicated by results of promoter assays. To identify new co-activators of the TMPRSS2-ERG fusion protein we performed mass spectrometry-based proteomic analyses. Among other interactors, we identified AP-2 complex subunit mu (AP2M1) and caveolin-1 (CAV1) in association with ERG in cell nuclei. These proteins play a mechanistic role in IGF1R internalization. Our analyses are consistent with a potential novel function of TMPRSS2-ERG as a major regulator of IGF1R gene expression. Results may impinge upon ongoing efforts to target the IGF1R in the clinics.