Modulations of glycerophosphorylcholine and phosphorylcholine in Friend erythroleukemia cells upon in vitro-induced erythroid differentiation: a 31P NMR study

AbstractA 31P NMR study has been carried out on Friend erythroleukemia cells (FLC) induced to undergo erythroid differentiation in vitro. Significant levels of glycerophosphorylcholine (GroPCho) and phosphorylcholine (P-Cho) were identified both in the untreated cells and in their PCA extracts. In FLC treated 4 days in vitro with either dimethylsulfoxide (DMSO) or hexamethylenebisacetamide (HMBA), the intracellular concentration of P-Cho was markedly increased, whereas that of GroPCho appeared to be significantly reduced. HMBA was more effective than DMSO in producing this effect. The concomitant modulations of GroPCho and P-Cho in differentiated FLC suggest the hypothesis that erythroid differentiation involves modifications of the regulatory mechanisms controlling biosynthesis and catabolism of phospholipids

Activation of phosphatidylcholinespecific phospholipase C in breast and ovarian cancer: Impact on mrs-detected choline metabolic profile and perspectives for targeted therapy

Elucidation of molecular mechanisms underlying the aberrant phosphatidylcholine cycle in cancer cells plays in favor of the use of metabolic imaging in oncology and opens the way for designing new targeted therapies. The anomalous choline metabolic profile detected in cancer by magnetic resonance spectroscopy and spectroscopic imaging provides molecular signatures of tumor progression and response to therapy. The increased level of intracellular phosphocholine (PCho) typically detected in cancer cells is mainly attributed to upregulation of choline kinase, responsible for choline phosphorylation in the biosynthetic Kennedy pathway, but can also be partly produced by activation of phosphatidylcholine-specific phospholipase C (PC-PLC). This hydrolytic enzyme, known for implications in bacterial infection and in plant survival to hostile environmental conditions, is reported to be activated in mitogen- and oncogene-induced phosphatidylcholine cycles in mammalian cells, with effects on cell signaling, cell cycle regulation, and cell proliferation. Recent investigations showed that PC-PLC activation could account for 20-50% of the intracellular PCho production in ovarian and breast cancer cells of different subtypes. Enzyme activation was associated with PC-PLC protein overexpression and subcellular redistribution in these cancer cells compared with non-tumoral counterparts. Moreover, PC-PLC coimmunoprecipitated with the human epidermal growth factor receptor-2 (HER2) and EGFR in HER2-overexpressing breast and ovarian cancer cells, while pharmacological PC-PLC inhibition resulted into long-lasting HER2 downregulation, retarded receptor re-expression on plasma membrane and antiproliferative effects. This body of evidence points to PC-PLC as a potential target for newly designed therapies, whose effects can be preclinically and clinically monitored by metabolic imaging methods

Triple-negative breast cancer: Present challenges and new perspectives

Contains fulltext : 83751.pdf (publisher's version ) (Open Access)21 p

Multicenter comparative multimodality surveillance of women at genetic-familial risk for breast cancer (HIBCRIT study): interim results.

PURPOSE: To prospectively compare clinical breast examination (CBE), mammography, ultrasonography (US), and contrast material-enhanced magnetic resonance (MR) imaging for screening women at genetic-familial high risk for breast cancer and report interim results, with pathologic findings as standard. MATERIALS AND METHODS: Institutional review board of each center approved the research; informed written consent was obtained. CBE, mammography, US, and MR imaging were performed for yearly screening of BRCA1 or BRCA2 mutation carriers, first-degree relatives of BRCA1 or BRCA2 mutation carriers, or women enrolled because of a strong family history of breast or ovarian cancer (three or more events in first- or second-degree relatives in either maternal or paternal line; these included breast cancer in women younger than 60 years, ovarian cancer at any age, and male breast cancer at any age). RESULTS: Two hundred seventy-eight women (mean age, 46 years +/- 12 [standard deviation]) were enrolled. Breast cancer was found in 11 of 278 women at first round and seven of 99 at second round (14 invasive, four intraductal; eight were <or=10 mm in diameter). Detection rate per year was 4.8% (18 of 377) overall; 4.3% (11 of 258) in BRCA1 or BRCA2 mutation carriers and first-degree relatives of BRCA1 or BRCA2 mutation carriers versus 5.9% (seven of 119) in women enrolled because of strong family history; and 5.3% (nine of 169) in women with previous personal breast and/or ovarian cancer versus 4.3% (nine of 208) in those without. In six (33%) of 18 patients, cancer was detected only with MR imaging. Sensitivity was as follows: CBE, 50% (95% confidence interval [CI]: 29%, 71%); mammography, 59% (95% CI: 36%, 78%); US, 65% (95% CI: 41%, 83%); and MR imaging, 94% (95% CI: 82%, 99%). Positive predictive value was as follows: CBE, 82% (95% CI: 52%, 95%); mammography, 77% (95% CI: 50%, 92%); US, 65% (95% CI: 41%, 83%); and MR imaging, 63% (95% CI: 43%, 79%). CONCLUSION: Addition of MR imaging to the screening regimen for high-risk women may enable detection of otherwise unsuspected breast cancers. (c) RSNA, 2007

Breast cancer in kurdish women of northern Iraq: incidence, clinical stage, and case control analysis of parity and family risk

<p>Abstract</p> <p>Background</p> <p>Breast cancer in the Middle-East occurs in relatively young women and frequently presents as advanced disease. A protective effect of multiparity is not apparent, and high familial risk is reported in some countries. This study investigates breast cancer rates and clinical stage related to age in the Kurdish region of Iraq and evaluates risk associated with parity and family history. Findings are compared with nearby countries and the West.</p> <p>Methods</p> <p>Sulaimaniyah Directorate of Health records identified 539 women diagnosed with breast cancer during 2006-2008. Clinical survey forms were completed on 296 patients and on 254 age-matched controls. Age specific incidence rates were calculated from Directorate of Health population estimates.</p> <p>Results</p> <p>Average patient age was 47.4 ± 11 years and 59.5% were pre-menopausal. Diagnosis was at clinical stage 1 for 4.1%, stage 2 for 43.5%, stage 3 for 26.0%, and stage 4 for 8.1% of patients. For 18.2%, stage was unknown. Annual breast cancer incidence rates per 100,000 women peaked at 168.9 at age 55 to 59 and declined to 57.3 at 60 and above. Patients had an average of 5.0 ± 3.3 children compared to 5.4 ± 3.5 for controls, <it>P </it>= 0.16. A first degree family member had breast cancer among 11.1% of patients and 2.1% of controls (<it>P </it>< 0.001) with > 50% of these patients and controls being ≥50 years old. No statistically significant relationship was found between tumor stage and age, <it>P </it>= 0.59.</p> <p>Conclusions</p> <p>In Kurdish Iraq, breast cancer is predominantly a disease of pre-menopausal women having multiple pregnancies. For younger patients, breast cancer incidence was similar to the West and possibly higher than many Middle-Eastern countries, but unlike the West, the estimated rates declined markedly in the elderly. The familial breast cancer risk for both older and younger women was within the general population risk of Western countries. Clinical stages were advanced and indicated delays in diagnosis that were unrelated to patient age.</p

Breast imaging technology: Imaging biochemistry - applications to breast cancer

The use of magnetic resonance spectroscopy (MRS) to investigate breast tumour biochemistry in vivo is reviewed. To this end, results obtained both from patients in vivo and from tumour extracts and model systems are discussed. An association has been observed between transformation and an increase in phosphomonoesters (PMEs) detected in the (31)P MRS spectrum, as well as an increase in choline-containing metabolites detected in the (1)H spectrum. A decrease in PME content after treatment is associated with response to treatment as assessed by tumour volume. Experiments in model systems aimed at understanding the underlying biochemical processes are presented, as well as data indicating the usefulness of MRS in monitoring the uptake and metabolism of some chemotherapeutic agents

Failure patterns and survival outcomes in triple negative breast cancer (TNBC): a 15 year comparison of 448 non-Hispanic black and white women

Purpose: Triple negative breast cancer (TNBC) is a distinct subtype of breast cancer with unique pathologic, molecular and clinical behavior. It occurs more frequently in young blacks and has been reported to have a shorter disease-free interval. We undertook this study to analyze the demographic characteristics, failure patterns, and survival outcomes in this disease. Methods: A total of 448 non-Hispanic black and white women were identified over a 15 year period from 1996 to 2011. Demographic and clinical information including age, race, menopausal status, stage, tumor characteristics, and treatments were collected. Fisher’s exact test and multivariable Cox regression were used to compare failure patterns and survival outcomes between races. Results: 49 % (n = 223) were black. 59 % patients were between 41 and 60 years, with 18 % ≤40 years. 57 % were premenopausal and 89 % had grade 3 tumors. Stage II (47 %) was most frequent stage at diagnosis followed by stage III (28 %). 32 % had lymphovascular invasion. Adjusting for age, stage, and grade, there was no difference in survival outcomes (OS, DFS, LFFS, and DFFS) between the two races. 62 (14 %) patients failed locally either in ipsilateral breast or chest wall, and 19 (4 %) failed in the regional lymphatics. Lung (18 %) was the most frequent distant failure site with <12 % each failing in brain, liver and bones. Conclusion: Failure patterns and survival outcomes did not differ by race in this large collection of TNBC cases. Lung was the predominate site of distant failure followed by brain, bone, and liver. Few patients failed in the regional lymphatics

Detection of polyol accumulation in a new ovarian carcinoma cell line, CABA I: a1H NMR study

Ovarian carcinomas represent a major form of gynaecological malignancies, whose treatment consists mainly of surgery and chemotherapy. Besides the difficulty of prognosis, therapy of ovarian carcinomas has reached scarce improvement, as a consequence of lack of efficacy and development of drug-resistance. The need of different biochemical and functional parameters has grown, in order to obtain a larger view on processes of biological and clinical significance. In this paper we report novel metabolic features detected in a series of different human ovary carcinoma lines, by 1H NMR spectroscopy of intact cells and their extracts. Most importantly, a new ovarian adenocarcinoma line CABA I, showed strong signals in the spectral region between 3.5 and 4.0 p.p.m., assigned for the first time to the polyol sorbitol (39±11 nmol/106 cells). 13C NMR analyses of these cells incubated with [1-13C]-D-glucose demonstrated labelled-sorbitol formation. The other ovarian carcinoma cell lines (OVCAR-3, IGROV 1, SK-OV-3 and OVCA432), showed, in the same spectral region, intense resonances from other metabolites: glutathione (up to 30 nmol/106 cells) and myo-inositol (up to 50 nmol/106 cells). Biochemical and biological functions are suggested for these compounds in human ovarian carcinoma cells, especially in relation to their possible role in cell detoxification mechanisms during tumour progression