Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG-EGFR/ErbB4 autocrine loop.

Tumor progression is intrinsically tied to the clonal selection of tumor cells with acquired phenotypes allowing to cope with a hostile microenvironment. Hypoxia-inducible factors (HIFs) master the transcriptional response to local tissue hypoxia, a hallmark of solid tumors. Here, we report significantly longer patient survival in breast cancer with high levels of HIF-2α. Amphiregulin (AREG) and WNT1-inducible signaling pathway protein-2 (WISP2) expression was strongly HIF-2α-dependent and their promoters were particularly responsive to HIF-2α. The endogenous AREG promoter recruited HIF-2α in the absence of a classical HIF-DNA interaction motif, revealing a novel mechanism of gene regulation. Loss of AREG expression in HIF-2α-depleted cells was accompanied by reduced activation of epidermal growth factor (EGF) receptor family members. Apparently opposing results from patient and in vitro data point to an HIF-2α-dependent auto-stimulatory tumor phenotype that, while promoting EGF signaling in cellular models, increased the survival of diagnosed and treated human patients. Our findings suggest a model where HIF-2α-mediated autocrine growth signaling in breast cancer sustains a state of cellular self-sufficiency, thereby masking unfavorable microenvironmental growth conditions, limiting adverse selection and improving therapy efficacy. Importantly, HIF-2α/AREG/WISP2-expressing tumors were associated with luminal tumor differentiation, indicative of a better response to classical treatments. Shifting the HIF-1/2α balance toward an HIF-2-dominated phenotype could thus offer a novel approach in breast cancer therapy.

Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis.

Hypoxia-elicited adaptations of tumor cells are essential for tumor growth and cancer progression. Although ample evidence exists for a positive correlation between hypoxia-inducible factors (HIFs) and tumor formation, metastasis and bad prognosis, the function of the HIF-α protein stability regulating prolyl-4-hydroxylase domain enzyme PHD2 in carcinogenesis is less well understood. In this study, we demonstrate that downregulation of PHD2 leads to increased tumor growth in a hormone-dependent mammary carcinoma mouse model. Tissue microarray analysis of PHD2 protein expression in 281 clinical samples of human breast cancer showed significantly shorter survival times of patients with low-level PHD2 tumors over a period of 10 years. An angiogenesis-related antibody array identified, amongst others, amphiregulin to be increased in the absence of PHD2 and normalized after PHD2 reconstitution. Cultivation of endothelial cells in conditioned media derived from PHD2-downregulated cells resulted in enhanced tube formation that was blocked by the addition of neutralizing anti-amphiregulin antibodies. Functionally, amphiregulin was regulated on the transcriptional level specifically by HIF-2 but not HIF-1. Our data suggest that PHD2/HIF-2/amphiregulin signaling has a critical role in the regulation of breast tumor progression and propose PHD2 as a potential tumor suppressor in breast cancer.

Onconeuronal cerebellar degeneration-related antigen, Cdr2, is strongly expressed in papillary renal cell carcinoma and leads to attenuated hypoxic response.

The onconeuronal cerebellar degeneration-related antigen Cdr2 is associated with paraneoplastic syndromes. Neoplastic expression of Cdr2 in ovary and breast tumors triggers an autoimmune response that suppresses tumor growth by developing tumor immunity, but culminates in cerebellar degeneration when Cdr2-specific immune cells recognize neuronal Cdr2. We identified Cdr2 as a novel interactor of the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1 and provide evidence that Cdr2 might represent a novel important tumor antigen in renal cancer. Strong Cdr2 protein expression was observed in 54.2% of papillary renal cell carcinoma (pRCC) compared with 7.8% of clear-cell RCC and no staining was observed in chromophobe RCC or oncocytoma. High Cdr2 protein levels correlated with attenuated HIF target gene expression in these solid tumors, and Cdr2 overexpression in tumor cell lines reduced HIF-dependent transcriptional regulation. This effect was because of both attenuation of hypoxic protein accumulation and suppression of the transactivation activity of HIF-1alpha. pRCC is known for its tendency to avascularity, usually associated with a lower pathological stage and higher survival rates. We provide evidence that Cdr2 protein strongly accumulates in pRCC, attenuates the HIF response to tumor hypoxia and may become of diagnostic importance as novel renal tumor marker.

[Acute cholecystitis and gallbladder neoplasms: the experience of 2215 cases]. / Colecistite acuta e neoplasia della colecisti: esperienza su 2215 casi.

The authors have retrospectively analysed 2215 surgical procedures for gallbladder stones. The global incidence of gallbladder neoplasm has been 5%. This rate rises to 11% considering female patients over 60 years old. In this group, a gallbladder carcinoma was contemporary present in 17.4% of acute cholecystitis. Cholecystectomy may be suggested in every patients with gallstones, even asymptomatic, particularly if some risk factors are present.

[Hypertonic saline solutions in resuscitation in hemorrhagic shock. An experimental study]. / Le soluzioni saline ipertoniche nel recupero dallo shock emorragico. Studio sperimentale.

The aim of the study was to evaluate the use of hypertonic solutions in restoring intravascular volume in a model of hemorrhagic shock. Eighteen pigs underwent general anesthesia and were instrumented with a carotid catheter to record mean arterial pressure (MAP), a pulmonary artery catheter for pulmonary arterial pressure (MPAP) and cardiac output (CO) monitoring and an electromagnetic flowmeter around the abdominal supraceliac aorta for aortic flow measurement (Vaor). Oxygen delivery (DO2) and oxygen consumption (VO2) data were calculated by standard formulas. The animals were hemorrhaged to a MAP of 45 mmHg, held for 1 hour. They were resuscitated during the following hour until the aortic flow regained its basal value, using three different solutions: normotonic saline (NS = NaCl 0.9%), hypertonic saline (HS = NaCl 7.5%), hypertonic saline added with dextran (HSDX = NaCl 7.5% + 6% dextran 70). An hour of autologous blood transfusion and a two hours follow-up concluded the experiment. Volumes infused were remarkably lower administering HS (13.70 +/- 1.44 ml/kg) and HSDX (9.11 +/- 1.20 ml/kg) compared to NS (90.32 +/- 24.83 ml/kg). MAP, CO and DO2 values resulted significantly higher in the HSDX animals, with lower MPAP levels. During the two hours follow-up only the animals reinfused with HSDX maintained hemodynamic and oxygen transport values at normal levels. We conclude that the administration of hypertonic saline solutions during hemorrhagic shock allows the saving of infusion volumes, thus diminishing the occurrence of interstitial edema formation. The adding of dextran to the solution prolongs the hemodynamic effects.