The hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha are activated in hypoxic tumor regions. However, their role in tumorigenesis remains controversial, as tumor growth promoter and suppressor activities have been ascribed to HIF-1alpha, while the role of HIF-2alpha remains largely unknown. Here, we show that overexpression of HIF-2alpha in rat glioma tumors enhances angiogenesis but reduces growth of these tumors, in part by increasing tumor cell apoptosis. Moreover, siRNA knockdown of HIF-2alpha reduced apoptosis in hypoxic human malignant glioblastoma cells. Furthermore, inhibition of HIF by overexpression of a dominant-negative HIF transgene in glioma cells or HIF-2alpha deficiency in teratomas reduced vascularization but accelerated growth of these tumor types. These findings urge careful consideration of using HIF inhibitors as cancer therapeutic strategies.

Adaptive responses to hypoxia in tumors are transcriptionally regulated by the hypoxia inducible factors (HIF-1α/HIF-2α), which are tightly controlled by the HIF-prolyl hydroxylases (PHD). Hypoxia induces expression of the PHD2 and PHD3 proteins in tumors but the pathobiological significance of these events is uncertain. Here, we show that PHD2 and PHD3 induction acts within a negative feedback loop to limit the hypoxic HIF response. In glioblastomas, PHD2 and PHD3 are hypoxia-inducible in vitro and expressed in hypoxic areas of tumors in vivo. Comparison with other PHDs revealed distinct cytoplasmatic and nuclear localization patterns of PHD2 and PHD3. Gain and loss of function experiments defined PHD2 and PHD3 as HIF target genes that remained operative even at low oxygen concentrations. We found that increased PHD levels could compensate for reduced oxygen availability to regulate the HIF response. This negative feedback loop protected tumor cells against hypoxia-induced cell death, functionally implicating this pathway in the control of the tumor-suppressive components of the HIF system in glioblastoma. Moreover, PHD inhibition facilitated cell death induction by staurosporine or tumor necrosis factor-related apoptosis-inducing ligand, hinting at a more general protective role of PHD in the regulation of cell viability. In summary, our findings recognize the PHD/HIF regulatory axis as a novel therapeutic target to disable a tumor's ability to adjust to hypoxic conditions and control cell survival, helping to potentially overcome therapeutic cell death resistance in glioblastomas. Cancer Res; 70(1); 357-66. ©2010 AACR.

ABSTR ACTBackground Some studies have already proposed an inverse association between vitamin D levels and breast density. As breast density is already considered an established risk factor for breast cancer, such a connection could offer a new starting point for the prevention of breast cancer. Material and MethodsTo investigate this suggested connection, a total of 412 pre-and 572 post-menopausal women for whom mammography was indicated were recruited into this cross-sectional study.In addition to a questionnaire-based interview on the patientʼs general and gynecological medical history, her eating habits and lifestyle, serum levels of 25-hydroxyvitamin D [25(OH)D], calcium, phosphate and creatinine were determined. Breast density was determined by mammography and categorized as 1 to 4 according to the ACR classification. In addition to performing descriptive analysis to get a better overview of the data, a number of multivariate regression models were developed to determine the impact of confounders and the connection between vitamin D and mammographic density.Results More than half of all participants had low levels of 25(OH)D (< 20 ng/ml) and only a small minority of women (5.7 %) had what are currently considered to be optimal serum levels of 25(OH)D of at least 30 ng/ml. The significant majority of the cohort had a medium mammographic density (n = 463 had ACR 2; n = 343 had ACR 3). Logistic regression analysis showed that lower 25(OH)D serum levels were associated significantly more often with high rather than medium breast density. This association remained, even after adjusting for other factors which influence breast density such as age, BMI and menopausal status (p = 0.032 for ACR 4 vs. ACR 2; p = 0.028 for ACR 4 vs. ACR 3).When the same analysis was done separately for pre-menopausal and post-menopausal women, BMI in both groups was found to be inversely correlated with breast density and this inverse correlation was highly significant. In post-menopausal women, age was found to be similarly

ScopeIncreasing the intake of satiety‐enhancing food compounds represents a promising strategy for maintaining a healthy body weight. Recently, satiating effects for the capsaicinoid nonivamide have been demonstrated. As various proteins and amino acids have also been demonstrated to decrease energy intake, oral glucose tolerance test (oGTT)‐based bolus interventions of 75 g glucose + 0.15 mg nonivamide (NV control) are tested with/without combination of a wheat protein hydrolysate (WPH: 2 g) and/or l‐arginine (ARG: 3.2 g) for their satiating effects in 27 moderately overweight male subjects.Methods and ResultsCompared to NV control intervention, ARG and WPH + ARG treatment both reduce (p < 0.01) total calorie intake from a standardized breakfast by –5.9 ± 4.15% and –6.07 ± 4.38%, respectively. For the WPH + ARG intervention, increased mean plasma serotonin concentrations (AUC: 350 ± 218), quantitated by ELISA, and delayed gastric emptying, assessed by 13C‐Na‐acetate breath test (−2.10 ± 0.51%, p < 0.05), are demonstrated compared to NV control. Correlation analysis between plasma serotonin and gastric emptying reveals a significant association after WPH ± ARG intervention (r = –0.396, p = 0.045).ConclusionCombination of WPH and ARG enhances the satiating effect of nonivamide, providing opportunities to optimize satiating food formulations by low amounts of the individual food constituents.