Decreased blood flow with increased metabolic activity: a novel sign of pancreatic tumor aggressiveness.

Department of Radiology, Division of Nuclear Medicine, Saint Louis University, St. Louis, Missouri.
Clinical Cancer Research (Impact Factor: 8.19). 12/2009; 16(1):367; author reply 567. DOI: 10.1158/1078-0432.CCR-09-2512
Source: PubMed

ABSTRACT To the Editor: Nghi Nguyen, Khalid Taalab, Medhat Osman. We read with great interest the recent article by Komar et al. (1), in which the authors evaluated blood flow (BF) using oxygen-15-labeled water and standardized uptake values (SUV) using (18)F-fluorodeoxyglucose positron emission tomography in patients with pancreatic tumors, and correlated these findings with patient survival. Ten patients with pancreatic cancer were divided into two subgroups, using survival at 12 months as the cutoff. Because of the very small sample size (5 patients in each patient subgroup), the unpaired Student's t test applied in the study was inappropriate. Typically, unpaired Student's t test is used for samples with normal distribution. A nonparametric test such as the Mann-Whitney-Wilcoxon test would have been more appropriate because it would not require a normal distribution of the data (2). The P value, however, would have remained statistically significant when using the Mann-Whitney-Wilcoxon test (P = 0.015) instead of the unpaired Student's t test (P = 0.022). The prognosis in patients with pancreatic cancer depends largely on the extent of disease based on tumor-node-metastasis (TNM) staging. Therefore, it would be important to correlate the TNM staging with the SUV/BF ratio. Of the 10 pancreatic cancer patients evaluated, however, TNM staging was not provided in four of these patients because of insufficient data or other reasons. TNM staging was available in the remaining six patients, which, however, would be limited for a proper statistical analysis. It was not clear how much the SUV/BF ratio would correlate with the TNM staging in this study. The study contained pancreatic cancer lesions of 2.5 cm and greater. Therefore, it was not clear whether the prognostic marker of increased metabolism and associated decreased blood perfusion could be applicable for pancreatic lesions less than 2.5 cm in size. The authors suggested that decreased blood flow with associated increased fluorodeoxyglucose metabolism indicated a novel sign of pancreatic tumor aggressiveness. This statement was not convincing because the aforementioned insufficiencies that involved the very small sample size, the lack of lesions less than 2.5 cm in size, and the missing correlation between SUV/BF and TNM staging. Further studies are required to validate these findings. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Receptors for purines and pyrimidines are expressed throughout the cardiovascular system. This study investigated their functional expression in porcine isolated pancreatic arteries. Pancreatic arteries (endothelium intact or denuded) were prepared for isometric tension recording and preconstricted with U46619, a thromboxane A2 mimetic; adenosine-5'-diphosphate (ADP), uridine-5'-triphosphate (UTP) and MRS2768, a selective P2Y2 agonist, were applied cumulatively, while adenosine-5'-triphosphate (ATP) and αβ-methylene-ATP (αβ-meATP) response curves were generated from single concentrations per tissue segment. Antagonists/enzyme inhibitors were applied prior to U46619 addition. ATP, αβ-meATP, UTP and MRS2768 induced vasoconstriction, with a potency order of αβ-meATP > MRS2768 > ATP ≥ UTP. Contractions to ATP and αβ-meATP were blocked by NF449, a selective P2X1 receptor antagonist. The contraction induced by ATP, but not UTP, was followed by vasorelaxation. Endothelium removal and DUP 697, a cyclooxygenase-2 inhibitor, had no significant effect on contraction to ATP but attenuated that to UTP, indicating actions at distinct receptors. MRS2578, a selective P2Y6 receptor antagonist, had no effect on contractions to UTP. ADP induced endothelium-dependent vasorelaxation which was inhibited by MRS2179, a selective P2Y1 receptor antagonist, or SCH58261, a selective adenosine A2A receptor antagonist. The contractions to ATP and αβ-meATP were attributed to actions at P2X1 receptors on the vascular smooth muscle, whereas it was shown for the first time that UTP induced an endothelium-dependent vasoconstriction which may involve P2Y2 and/or P2Y4 receptors. The relaxation induced by ADP is mediated by P2Y1 and A2A adenosine receptors. Porcine pancreatic arteries appear to lack vasorelaxant P2Y2 and P2Y4 receptors.
    Purinergic Signalling 12/2013; 10(2). DOI:10.1007/s11302-013-9403-2 · 3.51 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The P2Y14 receptor is the newest member of the P2Y receptor family; it is Gi/o protein-coupled and is activated by UDP and selectively by UDP-glucose and MRS2690 (7-10 fold more potent than UDP-glucose). This study investigated whether the P2Y14 receptor is functionally expressed in porcine isolated pancreatic arteries. Pancreatic arteries were prepared for isometric tension recording and UDP-glucose, UDP and MRS2690 applied cumulatively after preconstriction with U46619, a thromboxane A2 mimetic. Levels of phosphorylated MLC2 were assessed with Western blotting. Levels of cAMP were assessed using a competitive enzyme immunoassay kit. Concentration-dependent contraction with a rank order of potency of MRS2690 (10-fold) > UDP-glucose ≥ UDP was observed; contraction was reduced by PPTN, a selective antagonist of P2Y14 receptor, which did not affect the response to UTP. Contraction to UDP-glucose was not affected by MRS2578, a P2Y6 receptor selective antagonist. In the presence of U46619 and forskolin, which increases cAMP levels, contraction to UDP-glucose was enhanced. In addition, UDP-glucose and MRS2690 inhibited forskolin-stimulated cAMP levels. Removal of the endothelium and inhibition of endothelium-derived contractile agents (thromboxane A2 , prostaglandin F2α and endothelin-1) inhibited contractions. Y-27632, nifedipine and thapsigargin also reduced contraction to the agonists. UDP-glucose and MRS2690 increased MLC2 phosphorylation, which was blocked by PPTN. These data identify a novel vasocontractile role of P2Y14 receptors in porcine pancreatic arteries. P2Y14 -mediated contraction involves cAMP-dependent mechanisms, an elevation of Ca(2+) levels, activation of RhoA/ROCK signalling, and MLC2 in porcine pancreatic arteries. It also involves a release of thromboxane A2 , prostaglandin F2α and endothelin-1.
    British Journal of Pharmacology 10/2013; 171(3). DOI:10.1111/bph.12473 · 4.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. Most drugs that pass preclinical tests fail in these patients, emphasizing the need of improved preclinical models to test novel anticancer strategies. Here we developed four orthotopic mouse models employing primary human PDAC cells genetically engineered to express Firefly- and Gaussia-luciferase, simplifying the ability to monitor tumor growth and metastasis longitudinally in individual animals with MRI and high-frequency ultrasound. In these models we conducted detailed histopathological and immunohistochemical analyses on paraffin-embedded pancreatic tissues and metastatic lesions in liver, lungs and lymph nodes. Genetic characteristics were compared to the originator tumor and primary tumor cells using array-based comparative genomic hybridization, employing frozen specimens obtained by laser microdissection. Notably, the orthotopic human xenografts in these models recapitulated the phenotype of human PDACs, including hypovascular and hypoxic areas. Pursuing genomic and immunohistochemical evidence revealed an increased copy number and overexpression of c-Met in one of the models, we examined the preclinical efficacy of c-Met inhibitors in vitro and in vivo. In particular, we found that crizotinib decreased tumor dimension, prolonged survival and increased blood and tissue concentrations of gemcitabine, synergizing with a cytidine deaminase-mediated mechanism of action. Together, these more readily imaged orthotopic PDAC models displayed genetic, histopathological and metastatic features similar to their human tumors of origin. Moreover, their use pointed to c-Met as a candidate therapeutic target in PDAC and highlighted crizotinib and gemcitabine as a synergistic combination of drugs warranting clinical evaluation for PDAC treatment.
    Cancer Research 10/2013; 73(22). DOI:10.1158/0008-5472.CAN-13-0837 · 9.28 Impact Factor