microRNAs (miRs) modulate the expression levels of mRNAs and proteins and can thus contribute to cancer initiation and progression. In addition to their intracelluar function, miRs are released from cells and shed into the circulation. We postulated that circulating miRs could provide insight into pathways altered during cancer progression and may indicate responses to treatment. Here we focus on pancreatic cancer malignant progression. We report that changes in miR expression patterns during progression of normal tissues to invasive pancreatic adenocarcinoma in the p48-Cre/LSL-KrasG12D mouse model mirrors the miR changes observed in human pancreatic cancer tissues. miR-148a/b and miR-375 expression were found decreased whereas miR-10, miR-21, miR-100 and miR-155 were increased when comparing normal tissues, premalignant lesions and invasive carcinoma in the mouse model. Predicted target mRNAs FGFR1 (miR-10) and MLH1 (miR-155) were found downregulated. Quantitation of nine microRNAs in plasma samples from patients distinguished pancreatic cancers from other cancers as well as non-cancerous pancreatic disease. Finally, gemcitabine treatment of control animals and p48-Cre/LSL-KrasG12D animals with pancreatic cancer caused distinct and up to 60-fold changes in circulating miRs that indicate differential drug effects on normal and cancer tissues. These findings support the significance of detecting miRs in the circulation and suggests that circulating miRs could serve as indicators of drug response.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths worldwide with less than a 6% 5-year survival rate. PDAC is associated with poor prognosis based on the late stage diagnosis of the disease. Current diagnostic tests lack the sensitivity and specificity to identify markers of early staging. Metabolomics has provided biomarkers for various diseases, stressors, and environmental exposures. In this study we utilized the p48-Cre/LSL-KrasG12D mouse model with age-matched wild type mice. This model shows malignant progression to PDAC analogous to the human disease stages via early and late pancreatic intra-epithelial neoplasia (PanIN) lesions.ResultsSerum was collected from mice with early PanIN lesions (at 3-5 months) and with late PanIN or invasive PDAC lesions (13-16 months), as determined by histopathology. Metabolomics analysis of the serum samples was conducted through UPLC-TOFMS (Ultra Performance Liquid Chromatography coupled to Time-of-flight Mass Spectrometry). Multivariate data analysis revealed distinct metabolic patterns in serum samples collected during malignant progression towards invasive PDAC. Animals with early or late stage lesions were distinguished from their respective controls with 82.1% and 81.5% accuracy, respectively. This also held up for randomly selected subgroups in the late stage lesion group that showed less variability between animals. One of the metabolites, citrate, was validated through tandem mass spectrometry and showed increased levels in serum with disease progression. Furthermore, serum metabolite signatures from animals with early stage lesions identified controls and animals with late stage lesions with 81.5% accuracy (p<0.01) and vice-versa with 73.2% accuracy (p<0.01).ConclusionsWe conclude that metabolomics analysis of serum samples can identify the presence of early and late stage pancreatic cancer.

Tumor necrosis factor-α (TNFα) inhibitor therapy has signified an important milestone in the fight against many rheumatological disorders and inflammatory bowel disease (IBD). Cutaneous adverse events caused by this class of medications are well known but relatively uncommon. Most reactions are mild and rarely warrant treatment withdrawal. Henoch-Schönlein purpura (HSP) is a disease with cutaneous vasculitis, arthritis, and gastrointestinal and renal involvement that is usually seen in children, though the worst complications are typically seen in adults. We present a case of HSP complicating adalimumab treatment in a patient with ulcerative colitis who had achieved endoscopic remission. We review similar cases reported in the literature and discuss the consequences of these autoimmune diseases.

Anaplastic lymphoma kinase (ALK) is a transmembrane tyrosine kinase receptor that has an increased expression in various tumors and areas of active angiogenesis. In pancreatic tissues of mice with endogenously expressed mutant KrasG12D under embryonic acinar promoter p48, we detected ALK expression in pre maligant pancreatic intra-epithelial neoplastic ducts (PanIN) as well as malignant adenocarcinoma (PDAC). We have developed an antagonistic mouse monoclonal IgG antibody to the ALK receptor (anti-ALK IgG). To determine the antibody's binding efficacy, we used a quantum dot labeled anti-ALK IgG for the fluorescent visualization of pancreatic allografts in nude mice. Intravenously injected Qdot labeled anti-ALK IgG concentrated in allograft areas more than a Qdot labeled control antibody. In a prospective treatment study, we treated KrasG12D mice to determine the antibody's efficacy at preventing the progression from early to late PanIN and ultimately PDAC. Mice of three different age cohorts were treated with the antibody inta-peritoneal for six weeks. Upon completion of antibody treatment, the pancreata of mice were histologically examined for the appearance of early PanIN, late PanIN, or PDAC. Anti-ALK IgG treatment was most effective at preventing the progression of late PanIN to PDAC, with 8.3% of antibody treated mice harboring PDAC compared to 33.3% of saline treated control mice. Metastasis was also prevented in mice treated with antibody. Anti-ALK IgG treatment did not prevent the progression of early or late PanINs better than control treatment. Preliminary experiments have determined a change in microRNA expression in the pancreatic tissues of mice treated with antibody compared to controls and during different stages of pancreatic cancer progression. Expression of miR-375 decreased approximately 100 fold in PanIN and PDAC tissues compared to control tissues, but this decrease was not seen in PanIN tissues of mice treated with anti-ALK IgG. Reports have shown miR-375's role in pancreas development and the regulation of glucose homeostasis, and that its expression decreased in certain cancers. These data suggest miR-375 is necessary for normal physiological pancreatic activity and has a possible tumor suppressive role, and that anti-ALK IgG can help maintain this function. MiR- 22, 141, 148a, 148b, and 301a also had similar expression patterns in PanIN tissues and controls when pancreata were from mice treated with antibody. Another group of microRNAs, including miR- 10, 16, 21, 100, 155, and 199 showed little change in expression in antibody or control treated mice. These changes in microRNA expression suggest a response to antibody treatment at the genetic level, which may provide further insights into the functional mechanism of anti-ALK IgG's efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 721.

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