Biomedical subjects

C E Lewis

Publications and source records attributed to C E Lewis.

At least 19 recordsLinked to original sources

PubMed2006

Visceral adipose tissue: relationships between single slice areas at different locations and obesity-related health risks.

BACKGROUND: Visceral adipose tissue (VAT) is widely recognized as conveying the highest health risk in humans among the currently measurable adipose tissue compartments. A recent study indicated that the traditionally measured VAT area at L(4)-L(5) is not the VAT area with the highest correlation with total VAT volume. At present, it is unknown whether the area with the highest correlation is also the most strongly associated with obesity-related health risk. OBJECTIVE: The study aim was to establish which VAT slice area(s) are most strongly associated with obesity-related health risk indicators. DESIGN: The subjects were a convenience sample of healthy adults who completed whole-body magnetic resonance imaging (MRI) scans. The correlations, with appropriate adjustments, were examined between individual MRI slice VAT areas and fasting serum/plasma triglycerides (TG), high-density lipoprotein cholesterol (HDL), glucose, insulin and blood pressure. RESULTS: The sample consisted of 283 healthy men (age (mean+/-s.d.) 41.9+/-15.8 years; BMI, 26.0+/-3.2 kg/m(2); VAT, 2.7+/-1.8 L) and 411 women (age, 48.1+/-18.7 years; BMI 27.0+/-5.4 kg/m(2); VAT, 1.7+/-1.2 L). After adjusting for age, race, menopause status, scan position and specific blood analysis laboratory, VAT area at L(4)-L(5) had lower correlations with most metabolic risk factors including serum/plasma TG, HDL, glucose, insulin and blood pressure than VAT volume in both men and women. The VAT areas 10 and 15 cm above L(4)-L(5) in men had higher or equal correlations with health risk measures than VAT volume. In women, the VAT area 5 cm above or below L(4)-L(5) and total VAT volume had similar correlations with health risk measures. CONCLUSIONS: An appropriately selected single slice VAT area is an equally reliable phenotypic marker of obesity-related health risk as total VAT volume. However, in both men and women the VAT slice area at the traditional L(4)-L(5) level is not the best marker of obesity-related health risk.

Abdomen↗

PubMed2006

Genotype-by-sex interaction in the aetiology of type 2 diabetes mellitus: support for sex-specific quantitative trait loci in Hypertension Genetic Epidemiology Network participants.

AIMS/HYPOTHESIS: While there are sex-related differences in both the prevalence of type 2 diabetes mellitus and disease risk factors, there is only limited research on sex-specific influences on type 2 diabetes aetiology within the same study population. Thus, we assessed genotype-by-sex interaction using a liability threshold model in an attempt to localise sex-specific type 2 diabetes quantitative trait loci (QTLs). SUBJECTS, MATERIALS AND METHODS: Hypertensive siblings and their offspring and/or parents in the Hypertension Genetic Epidemiology Network of the Family Blood Pressure Program were recruited from five field centres. The diabetic phenotype was adjusted for race, study centre, age and non-linear age effects. In total, 567 diabetic individuals were identified in 385 families. Variance component linkage analyses in the combined sample and stratified by sex and race were performed (SOLAR program) using race-specific marker allele frequencies derived from a random sample of participants at each centre. RESULTS: We observed a QTL-specific genotype-by-sex interaction (p=0.009) on chromosome 17 at 31 cM, with females displaying a robust adjusted logarithm of odds (LOD) of 3.0 compared with 0.2 in males and 1.3 in the combined sample. Three additional regions demonstrating suggestive evidence for linkage were detected: chromosomes 2 and 5 in the female sample and chromosome 22 (adjusted LOD=1.9) in the combined sample. CONCLUSIONS/INTERPRETATION: These findings suggest that multiple genes may regulate susceptibility to type 2 diabetes, demonstrating the importance of considering the interaction of genes and environment in the aetiology of common complex traits.

Adult↗

PubMed2006

Endogenous sex steroids, weight change and rates of hip bone loss in older men: the MrOS study.

INTRODUCTION: Lower levels of endogenous sex steroids or declines in these hormones may contribute to the increased rates of bone loss observed in older adults experiencing weight loss. We hypothesized that among older men with weight loss, higher rates of bone loss at the hip would be observed in men with lower baseline bioavailable sex steroids or those with greater declines in these hormones. METHODS: To test this hypothesis, body weight, hip bone mineral density (BMD) using dual energy x-ray absorptiometry and endogenous sex steroids in paired serum samples by sensitive immunoassays were measured at a baseline and at a second examination that was held an average of 1.8 years later in 1267 older men enrolled in the Osteoporotic Fractures in Men (MrOS) study. RESULTS: Men experiencing weight loss had higher rates of hip bone loss than those with stable weight or weight gain within each quartile of baseline sex steroid level [p values for test of trend across weight change categories <0.010 within each quartile of bioavailable estradiol and testosterone and <0.060 within each quartile of sex hormone-binding globulin (SHBG)]. Results were similar when a change in sex steroids was substituted for baseline sex steroids in the analyses. Among men with weight loss, the rate of decline in total hip BMD showed a stepwise increase in magnitude with decreasing baseline bioavailable estradiol (p value for trend <0.040), with increasing baseline SHBG (p value for trend<0.030) and with greater decreases in bioavailable testosterone from baseline (p value for trend <0.001). CONCLUSIONS: These findings support the hypothesis that the impact of weight loss in older men on rates of hip bone loss may be increased by the presence of a sex steroid insufficiency.

Absorptiometry, Photon↗

PubMed2006

Gene therapy for prostate cancer: current strategies and new cell-based approaches.

Prostate cancer is the most commonly diagnosed cancer in adult males in the Western world. It accounts for one in ten cancer cases and is the second leading cause of cancer death in men, after lung cancer. A number of curative treatments are available for patients with localized prostate cancer such as radical prostatectomy, radiotherapy, or brachytherapy. However, a proportion of these men will develop progressive disease, and some will present de novo with advanced and metastatic prostate cancer, which is amenable to palliation only with androgen-withdrawal therapy. Most of these patients will eventually develop hormone refractory disease which is incurable, and for whom gene therapy, if feasible may develop as an alternative treatment option. In this review we discuss the gene therapy vectors and strategies that are currently in use, new cell-based approaches, discuss their advantages and disadvantages, and review the potential or proven pre-clinical and clinical efficacy in prostate cancer models/patients.

Adult↗

PubMed2006

Changes in risk factors for cardiovascular disease by baseline weight status in young adults who maintain or gain weight over 15 years: the CARDIA study.

OBJECTIVES: To examine whether changes in cardiovascular disease (CVD) risk factors differ by baseline weight status among young adults who maintained or gained weight. DESIGN: Longitudinal cohort study. SUBJECTS: White and African Americans who either maintained (+/-5 pounds; n=488) or gained (>5 pounds; n=2788) weight over 15 years. MEASUREMENTS: Anthropometrics and CVD risk factors were measured at baseline (1985-1986) and follow-up. Participants were classified as normal weight (body mass index (BMI) 18.5-24.9 kg/m2) or overweight (BMI >or=25 kg/m2) at baseline. Multivariable models were stratified by ethnicity and weight change category. RESULTS: Normal weight maintainers tended to have more favorable risk factors at baseline and follow-up than overweight maintainers. Size and direction of 15-year changes in risk factors were similar by weight status, except that in white normal weight maintainers changes in high-density lipoprotein (HDL)-cholesterol (3.3 mg/dl (95% confidence interval (CI): 0.4, 6.3)) and triglycerides (-14.7 mg/dl (-25.8, -3.7)) were more favorable. Weight gain was associated with unfavorable changes in risk factors. Weight gainers normal weight at baseline had less adverse changes in glucose, blood pressure, HDL-cholesterol (whites only) and triglycerides (African Americans only) than overweight gainers. However, normal weight African-American weight gainers had more adverse changes in total (3.1 mg/dl (0.2, 6.1)) and low-density lipoprotein-cholesterol (3.4 mg/dl (0.6, 6.3)). CONCLUSIONS: Baseline weight status does not appear to influence the size or direction of risk factor changes among adults who maintained their weight over 15 years. In contrast, weight gain was associated with changes in some risk factors differentially by baseline weight status.

Adolescent↗

PubMed2006

Macrophages promote angiogenesis in human breast tumour spheroids in vivo.

An in vivo model has been established to study the role of macrophages in the initiation of angiogenesis by human breast tumour spheroids in vivo. The extent of the angiogenic response induced by T47D spheroids implanted into the dorsal skinfold chamber in nude mice was measured in vivo and compared to that induced by spheroids infiltrated with human macrophages prior to implantation. Our results indicate that the presence of macrophages in spheroids resulted in at least a three-fold upregulation in the release of vascular endothelial growth factor (VEGF) in vitro when compared with spheroids composed only of tumour cells. The angiogenic response measured around the spheroids, 3 days after in vivo implantation, was significantly greater in the spheroids infiltrated with macrophages. The number of vessels increased (macrophages vs no macrophages 34+/-1.9 vs 26+/-2.5, P<0.01), were shorter in length (macrophages vs no macrophages 116+/-4.92 vs 136+/-6.52, P<0.008) with an increased number of junctions (macrophages vs no macrophages 14+/-0.93 vs 11+/-1.25, P<0.025) all parameters indicative of new vessel formation. This is the first study to demonstrate a role for macrophages in the initiation of tumour angiogenesis in vivo.

Animals↗

PubMed2006

Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

BACKGROUND: Previous genotype-phenotype association studies of fibrinogen have been limited by incomplete knowledge of genomic sequence variation within and between major ethnic groups in FGB, FGA, and FGG. METHODS: We characterized the linkage disequilibrium patterns and haplotype structure across the human fibrinogen gene locus in European- and African-American populations. We analyzed the association between common polymorphisms in the fibrinogen genes and circulating levels of both 'functional' fibrinogen (measured by the Clauss clotting rate method) and total fibrinogen (measured by immunonephelometry) in a large, multi-center, bi-racial cohort of young US adults. RESULTS: A common haplotype tagged by the A minor allele of the well-studied FGB-455 G/A promoter polymorphism (FGB 1437) was confirmed to be strongly associated with increased plasma fibrinogen levels. Two non-coding variants specific to African-American chromosomes, FGA 3845 A and FGG 5729 G, were each associated with lower plasma fibrinogen levels. In European-Americans, a common haplotype tagged by FGA Thr312Ala and several other variant alleles across the fibrinogen gene locus was strongly associated with decreased fibrinogen levels as measured by functional assay, but not by immunoassay. Overall, common polymorphisms within the three fibrinogen genes explain < 2% of the variability in plasma fibrinogen concentration. CONCLUSIONS: In young adults, fibrinogen multi-locus genotypes are associated with plasma fibrinogen levels. The specific single nucleotide polymorphism and haplotype patterns for these associations differ according to population and also according to phenotypic assay. It is likely that a substantial proportion of the heritable component of plasma fibrinogen concentration is due to genetic variation outside the three fibrinogen genes.

Adolescent↗

PubMed2005

Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families.

AIMS/HYPOTHESIS: The heritability of fasting serum insulin and glucose concentrations in non-diabetic members of multiplex hypertensive families is unknown. METHODS: We calculated the familial aggregation of fasting serum glucose and insulin concentrations and performed a genome-wide scan to assess whether quantitative trait loci contribute to these phenotypes in 2,412 non-diabetic individuals from 1,030 families enrolled in the Hypertension Genetic Epidemiology Network (HyperGEN) in the Family Blood Pressure Program. RESULTS: The heritability (+/-SE) of fasting serum insulin was 0.47+/-0.085 in European Americans and 0.28+/-0.08 in African Americans (p<0.0001 for both), after adjusting for age, sex, and BMI. A genome-wide scan for fasting serum insulin yielded a maximum log of the odds (LOD) score of 2.36 on chromosome 5 at 20 cM (p=0.0004) in European Americans, and an LOD score of 2.28 on chromosome 19 at 11 cM (p=0.0004) in African Americans. The heritability of fasting serum glucose was 0.5109+/-0.08 in the former and 0.29+/-0.09 in the latter (p<0.0003 for both) after adjusting for age, sex and BMI. A genome-wide scan for fasting serum glucose revealed a maximum LOD score of 2.07 on chromosome 5 at 26 cM (p=0.0009) in European Americans. CONCLUSIONS/INTERPRETATION: These analyses demonstrate the marked heritability of fasting serum insulin and glucose concentrations in families enriched for the presence of members with hypertension. They suggest that genes associated with fasting serum insulin concentration are present on chromosomes 19 and 5, and that genes associated with fasting serum glucose concentration are on chromosome 5, in families enriched for hypertension.

Adult↗

PubMed2005

Biological inferences from a mathematical model of comedo ductal carcinoma in situ of the breast.

The growth of a tumour in a duct is examined in order to model ductal carcinoma in situ (DCIS) of the breast, the earliest known stage of breast cancer. Interactions between the expansive forces created by tumour cell proliferation and the stresses that develop in the compliant basement membrane are studied using numerical and analytical techniques. Particular attention focuses on the impact that proteolytic enzymes have on the tumour's progression. As the tumour expands and the duct wall deforms, the tumour cells are subjected to mechanical and nutritional stresses caused by high pressures and oxygen deprivation. Such stresses may stimulate the cells to produce proteolytic enzymes that degrade the duct wall, making it more compliant and prone to penetration by the tumour cells. We use our model to compare these two hypotheses for enzyme production and find that mechanical stress is likely the dominant mechanism, with the wall deforming most at the centre of the duct. We then discuss the biological implications of our theoretical results and suggest possible directions for future work.

Animals↗

PubMed2005

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: the HyperGEN study.

OBJECTIVE: To conduct a full genome search for genes potentially influencing two related phenotypes: body mass index (BMI, kg/m2) and percent body fat (PBF) from bioelectric impedance in men and women. DESIGN: A total of 3383 participants, 1348 men and 2035 women; recruitment was initiated with hypertensive sibpairs and expanded to first-degree relatives in a multicenter study of hypertension genetics. MEASUREMENTS: Genotypes for 387 highly polymorphic markers spaced to provide a 10 cM map (CHLC-8) were generated by the NHLBI Mammalian Genotyping Service (Marshfield, WI, USA). Quantitative trait loci for obesity phenotypes, BMI and PBF, were examined with a variance components method using SOLAR, adjusting for hypertensive status, ethnicity, center, age, age2, sex, and age2 x sex. As we detected a significant genotype-by-sex interaction in initial models and because of the importance of sex effects in the expression of these phenotypes, models thereafter were stratified by sex. No genotype-by-ethnicity interactions were found. RESULTS: A QTL influencing PBF in women was detected on chromosome12q (12q24.3-12q24.32, maximum empirical LOD score=3.8); a QTL influencing this phenotype in men was found on chromosome 15q (15q25.3, maximum empirical LOD score=3.0). These QTLs were detected in African-American and white women (12q) and men (15q). QTLs influencing both BMI and PBF were found over a broad region on chromosome 3 in men. QTLs on chromosomes 3 and 12 were found in the combined sample of men and women, but with weaker significance. CONCLUSION: The locations with highest LOD scores have been previously reported for obesity phenotypes, indicating that at least two genomic regions influence obesity-related traits. Furthermore, our results indicate the importance of considering context-dependent effects in the search for obesity QTLs.

Adult↗

PubMed2004

The transcription factors hypoxia-inducible factor 1alpha and Ets-1 colocalize in the hypoxic synovium of inflamed joints in adjuvant-induced arthritis.

OBJECTIVE: To determine the relationship between hypoxia and the expression of Ets-1 and hypoxia-inducible factor 1alpha (HIF-1alpha) in both normal and inflamed joints. Adjuvant-induced arthritis (AIA) was used as the model system, since it mirrors many aspects of the pathology of rheumatoid arthritis. METHODS: Adjuvant arthritis was induced in a group of 10 female Lewis rats. A second group of 10 uninjected female Lewis rats served as naive controls. When a maximum clinical joint score was achieved in the AIA group, all 20 rats were injected with the specific hypoxic cell marker Hypoxyprobe-1 and subsequently killed. Hypoxyprobe-1 adducts, Ets-1, and HIF-1alpha were localized in the joints of the hind feet from these groups using immunohistochemistry. RESULTS: Compared with the joints from control rats, inflamed joints contained markedly more cells with Hypoxyprobe-1 adduct immunoreactivity, Ets-1-immunoreactive nuclei, and nuclear immunoreactivity for both Ets-1 and HIF-1alpha. CONCLUSION: Our results demonstrate the presence of hypoxia in inflamed joints in this experimental model of arthritis. The colocalization of Ets-1 and HIF-1alpha in these hypoxic areas suggests that hypoxia may induce Ets-1 and HIF-1alpha expression during joint inflammation.

Animals↗

PubMed2004

Excess gains in weight and waist circumference associated with childbearing: The Coronary Artery Risk Development in Young Adults Study (CARDIA).

OBJECTIVE: To examine the association of childbearing with weight and waist circumference (WC) changes, we compared women with and without pregnancies or births during follow-up. STUDY DESIGN: A multicenter, longitudinal observational study over 10 years. Comparison groups defined by the number of pregnancies and births during follow-up: P0 (0 pregnancies; nongravid), P1 (1+ miscarriages or abortions; 'short' pregnancies), B1 (1 birth), and B2 (2+ births). Mean changes in weight and WC for P1, B1 and B2 groups vs P0 were examined separately by race (black and white), baseline parity (nulliparous and parous) and baseline weight status (normal weight; BMI <25 kg/m(2) and overweight; BMI >/=25 kg/m(2)). SUBJECTS: A population-based sample of 2070 women aged 18-30 y at baseline (1053 black subjects and 1017 white subjects) from Birmingham, Alabama, Chicago, Illinois, Minneapolis, Minnesota, and Oakland, California were examined five times between 1985-1986 and 1995-1996. MEASUREMENTS: Weight and WC measurements were obtained using standardized protocol at baseline and examinations at years 2, 5, 7 and 10. Sociodemographic, reproductive, and behavioral attributes were assessed at baseline and follow-up examinations. RESULTS: Gains in weight and WC associated with pregnancy and childbearing varied by race (P<0.001), baseline parity (P<0.05) and overweight status (P<0.001). Among overweight nulliparas, excess gains in weight (black subjects: 3-5 kg, white subjects: 5-6 kg) and WC (black subjects: 3-4 cm, white subjects: 5-6 cm) were associated with 'short' pregnancies and one or more birth(s) during follow-up compared to no pregnancies (P<0.01 and 0.001). Among normal weight nulliparas, excess gains in weight (about 1 kg) and WC (2-3 cm) were associated with follow-up birth(s) (P<0.05). Among women parous at baseline, no excess weight gains were found, but excess WC gains (2-4 cm) were associated with follow-up births. CONCLUSION: Substantial excess weight gain is associated with both short pregnancies and a first birth in women overweight prior to initiation of childbearing. Excess weight gain was not associated with higher order births. Increases in waist girth were cumulative with both first and higher order births among overweight as well as normal weight women. Interventions to prevent obesity should be targeted at women who are overweight prior to initiation of childbearing. The impact of excess WC gains associated with childbearing on women's future health risk should be evaluated further.

Adolescent↗

PubMed2004

Blood pressure and pulse responses to three stressors: associations with sociodemographic characteristics and cardiovascular risk factors.

Cardiovascular reactivity is hypothesized to increase the risk of hypertension and other CVD-related conditions. However, studies to date are inconclusive. We compared the association of blood pressure and pulse responses to three stressors (postural challenge, handgrip test, mental arithmetic) with sociodemographic characteristics and CVD risk factors. We included 782 participants from the Hypertension Genetic Epidemiology Study. Blood pressure and pulse responses to stressors were defined as the difference between post- and pre-stress measurements. Stepwise regression analyses examined change in SBP and pulse in response to stressors as a function of sociodemographic and CVD risk factors. Age, race, and gender were forced into models and other variables (education, BMI, waist circumference, resting SBP and DBP, cigarette smoking, LDL and HDL cholesterol, glucose, and antihypertensive medications (beta-blockers, calcium channel blockers, diuretics, ace inhibitors)) were retained if P<0.10. Age was a significant predictor of SBP response to all stressors. The SBP response to a change in posture was not related to other variables. The SBP response to mental arithmetic was significantly higher among men, those with larger waists, higher SBP, beta-blocker users, and lower among smokers. SBP response to the handgrip was significantly higher among those with higher SBP and beta-blocker users. Similarly, the association of the pulse response to the risk factors varied considerably across the stressors. Overall, the socio-demographic and CVD risk factors accounted for between 9 and 14% of the variance in the SBP response to the stressors and from between 4 and 12% of the variance in the pulse response to the three stressors. The associations between sociodemographic and CVD risk factors and the SBP and pulse response to stress were modest and inconsistent across stressors. The findings suggest that cardiovascular reactivity is a concept that needs to be defined in reference to specific stressors so that mechanisms leading to responses can be better understood.

Adult↗

PubMed2003

Modelling the early growth of ductal carcinoma in situ of the breast.

The growth of a tumour in a rigid walled cylindrical duct is examined in order to model the initial stages of tumour cell expansion in ductal carcinoma in situ (DCIS) of the breast. A nutrient-limited growth model is formulated, in which cell movement is described by a Stokes flow constitutive relation. The effects on the shape of the tumour boundary of the material properties (i.e. the viscosity) and the extent to which the cells adhere to the duct wall are studied using numerical and asymptotic methods. It is shown how stable, non-planar, interface configurations result and that, during these initial stages, before the duct wall has been breached, few cells die and a nutrient-rich model is usually sufficient to capture the behaviour. Finally, we discuss the relevance of this approach to DCIS and suggest possible avenues for further work.

Apoptosis↗

PubMed2003

The impact of weight change on cardiovascular disease risk factors in young black and white adults: the CARDIA study.

OBJECTIVE: To quantify the relation between weight change and change in blood pressure, lipids and insulin levels, and determine if this relation differs by race or initial level of obesity. DESIGN: Longitudinal cohort study. SETTING AND PARTICIPANTS: Community-based sample of 3325 black and white men and women aged 18-30 y from four centers followed for 10 y. Women pregnant at baseline or 10th year exam and persons without a recorded weight at both exams were excluded. Participants whose baseline BMI was >or=25 kg/m(2) were classified as overweight. Height, weight, HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), fasting triglycerides, fasting insulin, and blood pressure were measured at baseline and Year 10. RESULTS: The mean (s.d.) of weight gained over 10 y was 10.5 (10.0) kg (black men), 11.7 (11.0) (black women), 7.7 (8.0) (white men), and 7.2 (10.0) (white women). An increase in weight was associated with adverse changes in all factors in all race-sex groups. For example, a 9.1 kg (20-lb) weight increase in persons not overweight at baseline predicted an increase in LDL-C ranging from 0.23 mmol/l in black women to 0.28 mmol/l in black men and a decrease in HDL-C from 0.09 mmol/l (white women) to 0.11 mmol/l (white men) (all P<0.0001). The estimated change in triglycerides was greater in white than in black participants (P<0.02); no other racial differences were found. Changes in triglycerides (P<0.00001) and fasting insulin (P=0.004) were greater in men than in women. Only for LDL-C was a weight change-associated increase significantly different (greater, P<0.001) for nonoverweight persons than for those overweight at baseline. None of these associations were highly specific. Mean levels of LDL-C, HDL-C, and systolic blood pressure improved among all those who lost or did not gain weight. CONCLUSIONS: A 10 y weight gain in young adults of both races and sexes tends to confer adverse changes in their levels of LDL-C, HDL-C, triglycerides, fasting insulin, and blood pressure. This effect occurs regardless of initial weight, age, race, or gender.

Adolescent↗

PubMed2003

Mathematical modelling of comedo ductal carcinoma in situ of the breast.

The growth of a tumour in a cylindrical duct with compliant walls is examined in order to model the early stages of ductal carcinoma in situ (DCIS) of the breast, the earliest known stage of breast cancer. A nutrient-limited growth model is formulated, in which cell movement is described by a Stokes flow constitutive relation. The interactions between the expansive forces created by tumour cell proliferation and the stresses that develop in the compliant basement membrane are studied using asymptotic and numerical methods. In this way we show how the duct wall deforms as the tumour grows and also how the progression of the tumour along the duct depends upon the stiffness of the wall. By varying key parameters we determine how treatment, protease production and the inclusion of the surrounding stroma affect the growth. Finally, we discuss the biological relevance of our results and suggest possible directions for future work.

Basement Membrane↗

PubMed2002

Regulation of a rat VL30 element in human breast cancer cells in hypoxia and anoxia: role of HIF-1.

Novel approaches to cancer gene therapy currently exploit tumour hypoxia to achieve transcriptional targeting using oxygen-regulated enhancer elements called hypoxia response elements. The activity of such elements in hypoxic cells is directly dependent on upregulation of the hypoxia-inducible transcription factor-1 However tumours also contain areas of anoxia, which may be considered a more tumour-selective transcriptional stimulus than hypoxia for targeting gene therapy to tumours. Another element, from the rat virus-like retrotransposon, VL30 (termed the "secondary anoxia response element") has been reported to be more highly inducible in rat fibroblasts under anoxia than hypoxia. To investigate anoxia as a potential transcriptional target in human tumours, we have examined secondary anoxia response element inducibility in two human breast cancer cell lines, MCF-7 and T47D, under anoxia, hypoxia and normoxia. In both cell types, the trimerised secondary anoxia response element showed greater inducibility in anoxia than hypoxia (1% and 0.5% O(2)). The anoxic response of the secondary anoxia response element was shown to be dependent on hypoxia-inducible transcription factor-1 and the presence of a hypoxia-inducible transcription binding site consensus (5'-ACGTG-3'). Mutational analysis demonstrated that the base immediately 5' to this modulates the anoxic/hypoxic induction of the secondary anoxia response element, such that TACGTG>GACGTG>>CACGTG. A similar correlation was found for erythropoietin, phosphoglycerate kinase 1, and aldolase hypoxia response elements, which contain these respective 5' flanking bases.

Animals↗

PubMed2002

Fibrinogen E fragment selectively disrupts the vasculature and inhibits the growth of tumours in a syngeneic murine model.

We recently demonstrated that a fragment of human fibrinogen, fibrinogen E fragment, inhibits the migration and differentiation of human endothelial cells in vitro. Here we show that it exerts similar effects on murine endothelial cells in vitro, and selectively disrupts tumour endothelium in vivo, causing widespread intravascular thrombosis and retarding the growth of CT26 tumours in a syngeneic murine model.

Adenocarcinoma↗