The dismal prognosis of pancreatic adenocarcinoma (PA) is due in part due to a lack of molecular information regarding disease development. Established cell lines remain a useful tool for investigating these molecular events. Here we present a review of available information on commonly used PA cell lines as a resource to help investigators select the cell lines most appropriate for their particular research needs. Information on clinical history, in vitro and in vivo growth characteristics, phenotypic characteristics, such as adhesion, invasion, migration and tumorigenesis, and genotypic status of commonly altered genes (KRAS, p53, p16, and SMAD4) was evaluated. Identification of both consensus and discrepant information in the literature suggests careful evaluation before selection of cell lines and attention be given to cell line authentication.

SUMMARY Chronic pancreatitis is a well-known risk factor for pancreatic ductal adenocarcinoma (PDA) development in humans, and inflammation promotes PDA initiation and progression in mouse models of the disease. However, the mechanistic link between inflammatory damage and PDA initiation is unclear. Using a Kras-driven mouse model of PDA, we establish that the inflammatory mediator Stat3 is a critical component of spontaneous and pancreatitis-accelerated PDA precursor formation and supports cell proliferation, metaplasia associated inflammation, and MMP7 expression during neoplastic development. Furthermore, we show that Stat3 signaling enforces MMP7 expression in PDA cells and that MMP7 deletion limits tumor size and metastasis in mice. Finally, we demonstrate that serum MMP7 level in human PDA patients correlated with metastatic disease and survival.

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Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN–PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Although Brg1-null IPMN–PDA develops rapidly, it possesses a distinct transcriptional profile compared with PanIN-PDA driven by mutant Kras and hemizygous p53 deletion. IPMN–PDA also is less lethal, mirroring prognostic trends in PDA patients. In addition, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, this study implicates Brg1 as a determinant of context-dependent Kras-driven pancreatic tumorigenesis and suggests that chromatin remodelling may underlie the development of distinct PDA subsets.

Objectives To assess the relationship between telomere length and adiposity, using dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI), in addition to conventional anthropometric proxies including body mass index (BMI) and cardiovascular disease risk factors. Methods A cross-sectional sample of 309 non-Hispanic white participants in the Fels Longitudinal Study aged 8 to 80 yr (52% female) was included. Average telomere length was measured by quantitative PCR. Results Telomere length was negatively correlated with age (r = −0.32, P < 0.0001) and had numerous significant correlations with established cardiovascular disease risk factors including waist circumference (r = −0.33), apolipoprotein B (r = −0.26), systolic blood pressure (r = −0.28), and fasting serum glucose (r = −0.15); all P < 0.0025. In back-ward selection linear regression models of telomere length, adiposity measures were consistently retained in the best models; BMI, waist circumference, hip circumference, total body fat, and visceral adipose tissue volume were all inversely associated with telomere length at the nominal P < 0.05 level or lower, independent of age, sex, systolic blood pressure, and fasting serum lipid, lipoprotein, and glucose concentrations. The negative association of BMI with telomere length was stronger among younger than older participants (P for interaction, 0.03). Conclusions Individuals with higher total and abdominal adiposity have lower telomere length, a marker of cellular senescence, suggesting obesity may hasten the aging process. Longitudinal studies are required to establish the causal association of early life adiposity with biological aging.

Pancreatic cancer is the fourth most common cause of cancer mortality in the United States, with 5 year survival rates for patients with resectable tumors ranging from 15 - 20%. However, most patients present with distant metastases, are not resectable, and have a 5-year survival of close to 0%. This demonstrates a need for improved screening to identify pancreatic cancer while the tumor is localized and amenable to surgical resection. Studies of patients with pancreatic tumors incidentally diagnosed demonstrate longer median survival as compared with tumors discovered only when the patient is symptomatic, suggesting that early detection may improve outcome. Recent evidence from genomic sequencing indicates a 15 year interval for genetic progression of pancreatic cancer from initiation to the metastatic stage, suggesting a sufficient window for early detection. Still, many challenges remain in implementing effective screening. Early diagnosis of pancreatic cancer relies on developing screening methodologies with highly sensitive and specific biomarkers and imaging modalities. It also depends on a better understanding of the risk factors and natural history of the disease in order to accurately identify high risk groups that would be best served by screening. This review summarizes our current understanding of the biology of pancreatic cancer relevant to methods available for screening. At this time, given the lack of proven benefit in this disease, screening efforts should probably be undertaken in the context of prospective trials.

Inheritable missense mutations in small molecular weight heat-shock proteins (HSP) with chaperone-like properties promote self-oligomerization, protein aggregation, and pathologic states such as hypertrophic cardiomyopathy in humans. We recently described that human mutant αB-crystallin (hR120GCryAB) overexpression that caused protein aggregation cardiomyopathy (PAC) was genetically linked to dysregulation of the antioxidant system and reductive stress (RS) in mice. However, the molecular mechanism that induces RS remains only partially understood. Here we define a critical role for the regulatory nuclear erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein (Keap1) pathway--the master transcriptional controller of antioxidants, in the pathogenesis of PAC and RS. In myopathic mice, increased reactive oxygen species signaling during compensatory hypertrophy (i.e., 3 months) was associated with upregulation of key antioxidants in a manner consistent with Nrf2/antioxidant response element (ARE)-dependent transactivation. In transcription factor assays, we further demonstrate increased binding of Nrf2 to ARE during the development of cardiomyopathy. Of interest, we show that the negative regulator Keap1 was predominantly sequestrated in protein aggregates (at 6 months), suggesting that sustained nuclear translocation of activated Nrf2 may be a contributing mechanism for RS. Our findings implicate a novel pathway for therapeutic targeting and abrogating RS linked to experimental cardiomyopathy in humans. Antioxid.