ALDH expression marks pancreatic cancer cells that have stem cell and mesenchymal features. The enhanced clonogenic growth and migratory properties of ALDH-positive pancreatic cancer cells suggest that they play a key role in the development of metastatic disease that negatively affects the overall survival of patients with pancreatic adenocarcinoma.

Background Pancreatic cancer is a near uniformly lethal disease and a better understanding of the molecular basis of this malignancy may lead to improved therapeutics. The Axl receptor tyrosine kinase is implicated in cellular transformation and tumor progression, although its role in pancreatic cancer has not been previously documented. Results Axl labeling was present in 54 of 99 (55%), and was absent in 45 of 99 (45%) cases, respectively. Axl expression in pancreatic cancer was significantly associated with lymph node metastases (p < 0.01), and a shorter median survival (12 versus 18 months, p < 0.01), than in tumors with negative labeling. Stable knockdown of Axl resulted in significant reduction in cell viability (p < 0.001), anchorage independent growth (p = 0.0031), as well as attenuation of migratory (p < 0.001) and invasive properties (p < 0.005), compared to vector-transfected cells. Profound inhibition of p42/p44 MAP kinase and PI-3kinase/Akt effector pathways was observed in MIAPaCa-2 cells with loss of Axl function. The reduction in invasion and migration upon Axl knockdown was mirrored by a decrease in the amounts of activated (GTP-bound) GTPase proteins Rho and Rac, significant downregulation in transcript levels of the epithelial mesenchymal transition (EMT)-associated transcription factors slug, snail and twist, and significant decrease in matrix metalloproteinase MMP-9 mRNA levels. Materials The immunohistochemical expression of Axl protein was assessed in a panel of 99 archival pancreatic cancers. Endogenous Axl expression was stably downregulated by lentiviral short hairpin shRNA directed against AXL mRNA in MIAPaCa-2 cells, and the effects on cell viability, anchorage independent growth, invasion, migration and intracellular effector pathways was assessed, by comparing to lentiviral vector-transfected cells. Conclusion Expression of Axl tyrosine kinase in pancreatic cancers confers an adverse prognostic influence, and represents a new therapeutic target in this malignancy.

Recent evidence suggests that blockade of aberrant Hedgehog signaling can be exploited as a therapeutic strategy for pancreatic cancer. Our previous studies using the prototype Hedgehog small-molecule antagonist cyclopamine had shown the striking inhibition of systemic metastases on Hedgehog blockade in spontaneously metastatic orthotopic xenograft models.

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Purpose: Aberrant activation of the Notch signaling pathway is commonly observed in human pancreatic cancer, although the mechanism(s) for this activation has not been elucidated. Experimental Design: A panel of 20 human pancreatic cancer cell lines was profiled for the expression of Notch pathway-related ligands, receptors, and target genes. Disruption of intracellular Notch signaling, either genetically by RNA interference targeting NOTCH1 or pharmacologically by means of the g-secretase inhibitor GSI-18, was used for assessing requirement of Notch signaling in pancreatic cancer initiation and maintenance. Results: Striking overexpression of Notch ligand transcripts was detectable in the vast majority of pancreatic cancer cell lines, most prominently JAGGED2 (18 of 20 cases, 90%) and DLL4 (10 of 20 cases, 50%). In two cell lines, genomic amplification of the DLL3 locus was observed, mirrored by overexpression of DLL3 transcripts. In contrast, coding region mutations of NOTCH1 or NOTCH2 were not observed. Genetic and pharmacologic inhibition of Notch signaling mitigated anchorage-independent growth in pancreatic cancer cells, confirming that sustained Notch activation is a requirement for pancreatic cancer maintenance. Further, transient pretreatment of pancreatic cancer cells with GSI-18 resulted in depletion in the proportion of tumor-initiating aldehyde dehydrogenase^expressing subpopulation and was associated with inhibition of colony formation in vitro and xenograft engraftment in vivo, underscoring a requirement for the Notch-dependent aldehyde dehydrogenase^expressing cells in pancreatic cancer initiation. Conclusions: Our studies confirm that Notch activation is almost always ligand dependent in pancreatic cancer, and inhibition of Notch signaling is a promising therapeutic strategy in this malignancy.Pancreatic cancer is an almost uniformly lethal disease with an overall 5-year survival of f5%, and this dire prognosis has not markedly improved over the last few decades (1). In the United States, f34,000 individuals succumb to this malignancy each year. To date, the only potentially curative therapeutic option is complete surgical resection, but unfortunately, the majority of patients are diagnosed at a locally advanced or distant metastatic stage, thus precluding surgical cure (2). Currently available treatment options for advanced pancreatic cancer, such as gemcitabine, have had minimal effect in ameliorating survival. Identification of aberrant signaling pathways that can also form the substrate for targeted therapies has thus become an area of foremost priority.The reactivation of embryonic signal transduction pathways, such as Notch and Hedgehog, have been reported in a variety of human cancers (3, 4); further, the availability of potent smallmolecule inhibitors has meant that these pathways can be targeted in these cancers, as we and others have recently shown

Aim: Following implementation of Improvement Outcome Guidance (IOG), pancreatic cancer surgery is now mostly performed in major pancreatic referral centers. This may have affected selection for surgery and outcome. We report the effect on workload and mortality rate of centralizing pancreatic surgery for a population of about 3.5 millions to a single Centre. Method: We reviewed activity in 2003 and 2007 (before and after implementation of IOG). Pancreatic surgery was done in 3 hospitals in 2003. In 2007 centralization affected 2.3M population form January, and an additional 1.2M from April 2007. Before centralization the surgical HDU was expanded from 3 to 8 beds. Results: In 2003, there were 67 pancreatic procedures of all types performed by 7 surgeons. In 2007 102 patients diagnosed with a neoplasm were deemed operable, and underwent laparotomy. Only one patient on a cancer pathway failed to meet the 62 day target. Two patients were found to be inoperable, and had palliative bypass. Three surgeons performed 100 resections. A further 10 patients had pancreatic necrosectomy. Of the elective resections 94% were managed in surgical HDU (level 2 critical care). Neo-adjuvant treatment was attempted in 12 borderline pancreatic cancers, 4 were successfully resected, 3 are currently receiving chemotherapy, and in 5 cases there was no improvement and palliative chemoYradio therapy was stopped. Conclusion: Centralization has increased the numbers of patients in this Network offered pancreatic resection for tumor. This has enabled new approaches such as laparoscopic distal pancreatectomy and neoadjuvant treatment for borderline resectable tumors. The inoperability rate is low. Despite wider indications for surgery, the mortality rate has fallen. We conclude that centralization has enabled more patients to benefit from safe surgery for pancreatic neoplasm. emerged as a treatment for pancreatic cancer. One decade has elapsed since its institution. The aim of the study is to detect whether adjuvant G improves survival. Methods: A prospective surgical database from 1985 to 2007 with 1637 records was reviewed and identified 579 patients who underwent resection for PDAC. Median, mean and 1, 3, and 5 year survival were calculated for the entire group; by decades regardless of adjuvant treatment; and by treatment with or without G. Results: The 1, 3 and 5 year survival of resected patients (579) was 66, 26 and 15% respectively, with a mean of 30.8 mo. No significant differences were identified over two decades. Patients who received G (n = 199, 34.5%) compared to NG (n = 379, 65.6%) had a statistically significant increase in survival at 1(80 vs. 55%), 3(35 vs. 20%) and 5(20 vs. 12%) years, with a mean of 37 vs. 27.6 (p G 0.0001). G improved survival in patients with tumors that were moderately differentiated (mean 36.5 vs. 25.5, p G 0.0007), Flavanoids are important components of many fruits and vegetables and are believed to have preventive and therapeutic effects in various human malignancies. We hypothesize that flavanoids may...

Introduction-Pancreatic ductal adenocarcinoma (i.e., pancreatic cancer) is an almost universally lethal disease. The identification of precursor lesions of pancreatic cancer provides an opportunity for early detection and potential therapeutic intervention before the development of invasive cancer.

Pancreatic intraepithelial neoplasia (PanIN) lesions are the most common non-invasive precursors of pancreatic adenocarcinoma. We postulated that accumulating DNA damage within the PanIN epithelium activates checkpoint mechanisms. Tissue microarrays were constructed from 81 surgically resected primary pancreatic adenocarcinomas, and an independent set of 58 PanIN lesions (31 PanIN-1, 14 PanIN-2, and 13 PanIN-3). Immunohistochemical labeling was performed using anti- γH2AXSer139, anti-phosphoATMSer1981, anti-phosphoChk2Thr68, and anti-p53. A “histologic score” combining area and intensity of labeling in the nuclear compartment was determined for each lesion. A progressive increase in γH2AXSer139 labeling, consistent with escalating DNA damage, was observed in the non-invasive precursor lesions (scores of 4.34, 6.21, and 7.50, respectively for PanIN-1, -2, and -3), compared to pancreatic ductal epithelium (score 2.36) (ANOVA, P<0.0001). In conjunction, activation of the ATM-Chk2 checkpoint pathway was observed in all histological grades of PanIN lesions. Specifically, pATMSer1981 histologic scores for PanIN-1, PanIN-2, and PanIN-3 were 4.83, 5.14, and 7.17, respectively, versus 2.33 for ductal epithelium (ANOVA, P<0.0001); the corresponding scores for pChk2Thr68 were 5.43, 7.64, and 5.44 in PanINs-1, -2, and -3, respectively, versus 2.75 in ductal epithelium (ANOVA, P<0.0001). In contrast, absent to minimal nuclear p53 was observed in ductal epithelium, and in PanINs-1 and 2 (histologic score of 0-1.86), with a significant upregulation (corresponding to mutational inactivation) seen only at the stage of PanIN-3 and invasive neoplasia (histologic score of 4.00 and 4.22). Nuclear p53 accumulation in cancers was associated with attenuation of the ATM-Chk2 checkpoint and a restitution of “baseline” levels. To conclude, activation of the ATM-Chk2 checkpoint pathway is commonly observed in PanINs, likely in response to the accumulating DNA damage from events such as oncogene mutations and telomere dysfunction. Loss of p53 function appears to be a critical determinant for bypassing this checkpoint and the subsequent progression to invasive adenocarcinoma.