The German National Case Collection for familial PancreaticCancer (FaPaCa) was established in 1999 to prospectively collect FPC families [9, 10]. Screening re- sults of the majority of IAR, in particular MRI, EUS and pathological findings, were recently reported [19, 20]. As previously suggested, the diagnosis of FPC was based on the presence of two or more FDR, with a confirmed diagnosis of PDAC, and without evidence of any other inherited tumor syndrome . FPC families were in- cluded based on a three-generation family pedigree and confirmation of all cancer diagnoses in the family by re- view of medical and pathological records, death certif- icates, and by revision of the pathology slides whenever available. Members of families fulfilling the criteria of FPC were offered mutational analyses of the BRCA1/2, PALB2 and CDKN2a genes as previ- ously described [20, 36, 37].
activation has been currently contentious and confusing. In 1990s, differential effects of IL-4 or IL-13 compared to IFN-γ and/or lipopolysaccharide (LPS) on macrophage gene expression were described. The macrophages acti- vated by IL-4 or IL-13 were termed to be “alternative activation,” and the ones activated by IFN-γ and/or LPS were termed to be “classical activation” . Mill et al. proposed the terminology M1 for classical activated mac- rophages, and M2 for alternative activated macrophages in 2000 . M2 was further defined into M2a, M2b, M2c for different activation scenarios . Diversity of terminology of macrophages activated by different sig- nals have impeded researches significantly. To tackle this issue, an international consensus nomenclature system was proposed in 2014 . M1- and M2-polarized TAMs are only extremes of a continuum in a universe of func- tional states and most of the TAMs are in the continuum changeable status between M1 and M2 . Activation of TAMs from tumor microenvironment of various tumors include hypoxia [66, 67], metabolic products of cancer cells (e.g., lactic acid) [59, 68], COX-2 , cytokines (e.g., TGF-β, CSF-1, GM-CSF), interleukins (IL-4, IL-10, IL-13) and plasma cells and immune complexes, damage associated molecular patterns (DAMPs), such as high- mobility group box1 protein (HMGB1), extracellular ATP, and degraded extracellular matrix components pro- duced by cancer cells or stromal cells . Signal path- ways involved in M1 polarization include NF-Kappa B, STAT1, and IRF5, whereas IRF4, STAT6, MYC, PPARγ and KLF4 have been reported to promote M2 polariza- tion [46, 65, 71]. Once activated, TAMs exert different functions to affect the malignant behaviors of cancers, which predominantly promote the invasiveness of cancer cells. The high infiltrations of TAMs, especially the M2 polarization TAMs, in tumor tissue predicted poor prog- nosis of many cancers, including pancreaticcancer.
In addition to PA.3, smaller studies have evaluated erlotinib in other settings and combinations for advanced pancreaticcancer. A phase II study presented at the annual meeting of ASCO in 2005 evaluated the combination of capecitabine and erlotinib as a second-line regimen in 28 patients with metastatic pancreaticcancer after failure of front line therapy with gemcitabine (Blaszkowsky et al 2005). This study reported a well-tolerated toxicity proﬁ le as well as a promising median survival of 6.7 months. Three patients (11%) were assessed as having a partial response and an additional 16 (57%) demonstrated stable disease. Another phase II study presented at the annual meeting of ASCO in 2006 randomized 58 previously untreated patients with advanced pancreaticcancer to treatment arms consisting of bevacizumab (B) and gemcitabine (C) plus either erlotinib (E) or cetuximab (C) (Kindler et al 2006). Preliminary analysis suggested activity of both regimens (GBE and GBC) with overall responses of 21% and 19%, respectively; similar six-month survival rates (38% and 41%); and minimal differ- ences in toxicity proﬁ les. A separate phase I study of erlotinib and gemcitabine in combination with bevacizumab is now underway (Gomez-Martin et al 2007). Erlotinib may also have very modest activity as a single agent or in combina- tion with bevacizumab for patients who have progressed on prior chemotherapy (Epelbaum et al 2007; Ko et al 2007).
2 μ M). Lapatinib also demonstrated some activity in three K- Ras mutated pancreaticcancer cell lines which displayed resistance to erlotinib. Drug effect/combination index (CI) isobologram analysis was used to study the interactions of lapatinib with gemcitabine, cisplatin and 5’deoxy-5’fluorour- idine. Concentration-dependent anti-proliferative effects of lapatinib in combination with chemotherapy were observed. To evaluate the potential effect of lapatinib in pancreaticcancer tumours, and to identify a subset of patient most likely to benefit from lapatinib, expression of EGFR and HER2 were investigated in 72 pancreaticcancer tumour specimens by immunohistochemistry. HER2 membrane expression was ob- served in only 1 % of cases, whereas 44 % of pancreatic
Another lncRNA related to HOX gene is the lncRNA termed HOXA transcript at the distal tip (HOTTIP). HOTTIP can promote H3 lysine 4 trimethylation by binding with WD repeat containing protein 5(WDR5) . Similar to HOTAIR, HOTTIP is over-expressed in PC cell lines. The expression level of 757 genes was decreased and that of 514 genes was increased when HOTTIP was knocked down. Among these down- regulated genes, Aurora kinase A (AURKA), acting as a cell growth regulator, could maintain Panc-1 cell growth, inhibit apoptosis and promote migration, and these regulatory effects were independent of WDR5. However, siHOTTIP decreased the proportion of cells in S phase and increased of the proportion of cells in G 2 /M phase, while siAURKA decreased the percentage of cells in G0/G1 phase and increased the percentage of cells in S/G2 phase in Panc-1 PC cell line. This difference indicates that the mechanism of HOTTIP in promoting Panc-1 pancreaticcancer cell proliferation and survival through AURKA is more complex than we imagine. In hepatocellular carcinoma (HCC), the expression of HOXA locus gene was co-regulated by HOTTIP and WDR5/ mixed lineage leukemia 1 (MLL1) complex . Unlike liver cancer cells, HOXA13 is not the downstream target of HOTTIP, but other HOX genes, such as HOXA10, HOXB2, HOXA9 and HOXA1 are increased by HOTTIP.
Abstract: Early detection of pancreatic ductal adenocarcinoma (PDAC) requires further examination after selecting cases with risk factors for the condition, such as family history, hereditary pancreatic carcinoma syndrome, intraductal papillary mucinous neoplasms, or chronic pancreatitis. The Japan Study Group on the Early Detection of PancreaticCancer has investigated and clarified the clinicopathological features for the early diagnosis of PDAC. Further approaches for the early diagnosis of PDAC are warranted.
Initially, we investigated the morphological changes induced by the combination of harmine and gemcitabine in BxPC-3 and PANC-1 cells. Figure 3A showed that a large proportion of pancreaticcancer cells treated with harmine plus gemci- tabine were detached from the culture dishes, whereas the remaining adherent cells showed loss of adhesion, shrink- age, and rounding, which are typical morphological changes associated with apoptosis. Subsequently, we investigated the apoptotic effect of harmine, gemcitabine, and harmine plus gemcitabine in PANC-1 and BxPC-3 cells. As shown in Figure 3B, according to Annexin V positivity, the percen- tages of apoptotic PANC-1 cells were as follows: vehicle control, 7.33%±0.18%; gemcitabine, 35.60%±1.56% (har- mine vs harmine plus gemcitabine, P=0.0032); harmine, 19.75%±1.34% (gemcitabine vs harmine plus gemcitabine, P=0.0015); and harmine plus gemcitabine, 74.63%±2.72%. Harmine enhanced gemcitabine induced apoptosis by in both PANC-1 and BxPC-3 cells (Figure 3B). We also found that the cleavage of PARP and activation of caspase- 3 were enhanced following treatment with harmine plus gemcitabine versus either single-agent treatment in pancrea- tic cancer cells (Figure 3C). Thus, we concluded that har- mine induces apoptosis and enhances gemcitabine induced apoptosis in pancreaticcancer cells.
Pancreaticcancer (PC) has one of the worst prognoses of any major malignancy (6.7% 5-year survival) . De- spite recent improvements in surgical and chemotherapeutic approaches, PC continues to have a poor prognosis due to the lack of early symptoms, which results in advanced stage and metastatic states of PC patients and makes their malignancy inoperable. Moreover, drug-resistance is also a main reason for the dismal prognosis with an average overall median survival of 4 - 6 months in PC patients  . Nowadays, PC is the fifth most common cause of cancer death yearly in the United States and seventh cancer death in China  . According to the report of Nation Cancer Institute (NIH), the number of new cases of PC was 12.3 per 100,000 men and women per year during 2007-2011, while 10.9 per 100,000 men and women dead of PC every year during
Pancreaticcancer is highly resistant to chemotherapy  and several clinical trials are ongoing to improve its treatment . Our data suggests that UHRF1 is a potentially important target for pancreaticcancer drugs, due to its multiple effects on pancreaticcancer cells; the growth- inhibitory effect of UHRF1 depletion on pancreaticcancer cell lines as well as the effect in restoring the expression of TSGs that are commonly silenced by their promoter methylation (with a greater effect noted when UHRF1 siRNA was combined with the DNMT1 inhibitor 5-aza- deoxycytidine. Restoring the function of TSGs using epigenetic drugs has shown promise for cancer therapy [163-165]. Our novel discovery (upregulation of KEAP1 and downregulation of NRF2 by targeting UHRF1 by siRNA in pancreaticcancer cells) makes UHRF1 an interesting drug target in pancreaticcancer. It has been reported that targeting NRF2 by siRNA causes a decrease in proliferation and an increase in cell resistance to certain drugs [128, 166]. Targeting NRF2 alone resulted in a decrease in chemo-resistance to cancer therapy, but this could be a double-edged sword due to its ability to protect against cancer initiating insults in normal cells [167, 168]. Our results show the dual effect of UHRF1 depletion on the KEAP1/NRF2 pathway. This is an important finding, especially as UHRF1 depletion appears to inhibiting NRF2 through regulating KEAP1 promoter methylation; this might be an advantage in pancreaticcancer treatment, by sensitizing the cells to chemotherapy .
Heterogeneity in the risk estimates for our study was assessed using the Q statistic and the I 2 statistic. We considered statistically significant heterogeneity at the P = 0.05 level of association. I 2 was used because it describes the percentage of variability in point estimates that is due to heterogeneity rather than sampling error. A value of I 2 of 50% or more was considered to be notably heterogeneous. To investigate whether one single study unduly influenced the pooled estimates, sensitivity analyses also were conducted to compare pooled risk estimates after systematically excluding each study in turn. Finally, we conducted stratified analyses by sex, smoking status, and BMI, as they are established risk factors of pancreaticcancer, as well as folate intake, since alcohol can influence folate metabolism and DNA methylation. Tests for interactions were conducted by including the cross-product terms for alcohol (continuous) and the stratified variables in the logistic regression models (using BMI ≤ 25 and >25; never, former, and current smoker; low and high folate based on median cutpoint).
imaging, 2 year screening intervals are suf ﬁ cient and safe. Therefore, we now consider extending the screening intervals to 24 months in IAR with an unremarkable pancreas at baseline screening. This approach is also underscored by the results of a quantitative analysis of the timing of the genetic evolution of PDAC, that indicate a time span of at least one decade between the occurrence of the cancer initiating mutation and cancer for- mation, providing a broad window of opportunity for the early detection of pancreaticcancer. 30 Recent studies suggest, however, that once a PDAC becomes detectable, clinical progres- sion from low-stage to advanced-stage disease is rapid. 31 Thus, intensifying screening at baseline by using MRI plus EUS to exclude the presence of clinically detectable PDAC, and to de-escalate screening intensities and intervals thereafter appears as an option to be discussed.
A two-stage case-control study was conducted to examine the association between six candidate U2-depedent spliceosome genes (SRSF1, SRSF2, SF3A1, SF3B1, SF1 and PRPF40B) and pancreaticcancer (PC). Subjects with one or two T alleles at rs2074733 in SF3A1 had a lower risk of PC compared to those with two C alleles in combined two populations (OR: 0.59, 95% confidence interval: 0.48–0.73, False discovery rate (FDR)-P = 1.5E-05). Moreover, the presence of the higher-risk genotype at rs2074733 plus smoking or drinking had synergic effects on PC risk. These findings illustrate that RNA splicing-related genes appear to be associated with the occurrence of PC, and show synergic interactions with smoking and drinking in the additive model. In the future, our novel findings should be further confirmed by functional studies and independent large-scale population studies.
Pancreaticcancer worry and concern was assessed by four items adapted from Lerman and colleagues . Three items referred to the time period “during the past month” and queried: “How often have you thought about your chances of getting pancreaticcancer?” “How often have thoughts about your chances of getting pan- creatic cancer affected your mood?” and “How often have thoughts about your chances of getting pancreaticcancer affected your ability to perform your daily activ- ities?” Response options included “not at all or rarely,” “sometimes,” “often,” and “a lot”. A fourth item queried: “How concerned are you about getting pancreatic can- cer?” to which participants responded using a 4-point Likert-type scale ranging from (1) “extremely concerned” to (4) “not at all concerned”. Cronbach’s alpha for these items was 0.78, demonstrating acceptable internal consistency. For multivariable analysis, responses were categorized as “concerned” (“extremely”/“moderately”) or “not concerned” (“mildly”/“not at all”) for ease of interpretation.
73. Yu S, Lu Z, Liu C, Meng Y, Ma Y, Zhao W, et al. miRNA- 96 suppresses KRAS and functions as a tumor suppressor gene in pancreaticcancer. Cancer research. 2010;70(14):6015-25. 74. Vogt M, Munding J, Grüner M, Liffers S-T, Verdoodt B, Hauk J, et al. Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas. Virchows Archiv. 2011;458(3):313-22. 75. Torrisani J, Bournet B, Du Rieu MC, Bouisson M, Souque A, Escourrou J, et al. let-7 MicroRNA transfer in pancreaticcancer-derived cells inhibits in vitro cell proliferation but fails to alter tumor progression. Human gene therapy. 2009;20(8):831-44.
Pancreaticcancer is one of the leading causes of cancer-related death in the United States and survival outcomes remain dismal despite significant advances in molecular diagnostics and therapeutics in clinical practice. The micro- environment of pancreaticcancer carries unique features with increased desmoplastic reaction and is infiltrated by regulatory T cells and myeloid-derived suppressor cells which negatively impact the effector immune cells. Current evidence suggests that stellate cell-induced hypovascular stroma may have direct effects on aggressive behavior of pancreaticcancer. Preclinical studies suggested improvement in drug delivery to cancer cells with stroma modifying agents. However these findings so far have not been confirmed in clinical trials. In this article, we elaborate current- state-of-the science of the pancreaticcancer microenvironment and its impact on molecular behavior of cancer cells, chemotherapy resistance and druggability of stroma elements in combination with other agents to enhance the efficacy of therapeutic approaches.
In the near future a retrospective analysis is planned with merged data from the collaborating registries. Differences in age, gender, incidence, tumour stage and differences in treat- ment can be identified. Also elderly patients are included in the EURECCA projects and consequently care patterns for the elderly pancreaticcancer patients can be analysed. The aggressive tumour biology and the late onset of complaints and consequently the late presentation of patients, result in high percentages of advanced stage disease and less thera- peutic options. Only (borderline) resectable patients, the smallest group, are expected to be discussed in the tumour boards. Locally advanced pancreaticcancer patients, as well as metastasized patients are often directed to the medical oncologist. In future registry or audit structures of all stages should be combined to have a clear view of the medical deci- sion making, clinical care pathways and treatment strategies in the different collaborating countries. By calculating with the date of diagnosis and date of surgery, waiting times for surgery or start of neoadjuvant treatment can be calculated. If patients are treated, neoadjuvant therapies impact on path- ological responses, so it is very important to stratify for clin- ical stage before therapy starts. Pre-treatment TNM stages
The tumor microenvironment is a complex mixture of tumor cells, inflammatory cells, blood vessels, and mesenchymal cells. In pancreaticcancer, this microenvironment has an excess of fibroblasts and extracellular matrix, and is known as desmoplasia. This feature is one of the challenges of pancreaticcancer, as its presence signals a more aggressive and metastatic tumor. Palladin, an actin-binding protein with roles in cell adhesion, motility, and contractility, is overexpressed and mutated in a form of familial pancreaticcancer, and overexpressed in sporadic pancreatic adenocarcinoma. Evidence points to palladin being overexpressed in the activated fibroblasts of the tumor microenvironment, a subset of cells that phenotypically resemble wound healing fibroblasts and are more motile, secretory, and contractile than normal fibroblasts. Tumors are increasingly being compared to “wounds that will not heal,” since many of the same molecular programs are induced in both situations. Palladin is also upregulated in activated fibroblasts in wound healing, which leads to the conclusion that palladin may be a part of the wound healing signature found in more aggressive tumors, and could be playing an integral role in these tumor-associated
References to the sources of information used to write this booklet and an acknowledgement of the health professionals who reviewed it are available on our website – www.pancreaticcancer.org.uk/diet PancreaticCancer UK makes every effort to make sure that its services provide up-to-date, unbiased and accurate information about pancreaticcancer. We hope that this information will add to the medical advice you have received and help you to take part in decisions related to your treatment and care. Please do continue to talk to your doctor, specialist nurse or other members of your care team if you are worried about any medical issues.
(Table 1) [58, 59]. This gene encodes nuclear receptor subfamily 5 group A member 2 (NR5A2), sometimes referred to as liver receptor homolog-1 (LRH-1). NR5A2 is a transcription factor that plays important roles in multiple aspects of pancreatic development and function, including cholesterol synthesis, bile acid homeostasis, steroidogenesis and in regulating stem- ness [62-64]. Likewise, NR5A2 is an important regu- lator of exocrine function in the adult pancreas where it regulates the expression of a number of acinar spe- cific genes . Nr5a2 is required for early embryonic development and mice that lack both copies of Nr5a2 die at embryonic day 7 . However, heterozygous Nr5a2 mice are viable and exhibit increased rates of pancreatic acinar to ductal metaplasia (ADM) and impaired recovery after chemically induced acute pancreatitis [67, 68]. Furthermore, Nr5a2 haploinsuf- ficiency cooperates with pancreatitis in a mouse model driven by oncogenic KRAS, increasing the number of preneoplastic PanIN (Pancreatic Intraepi- thelial Neoplasia) lesions and driving their progres- sion toward PDAC [67, 68]. Thus, NR5A2 appears to be important for maintaining homeostasis in the exo- crine pancreas and promote the regeneration of func- tional acinar cells from metaplastic duct-like cells after inflammation caused by pancreatitis, and protect the pancreas from KRAS driven pre-neoplastic changes. Although the mechanism by which variants on chr1q32.1 mediate risk of pancreaticcancer is not clear, the mouse studies described above indicate that the underlying mechanism may involve negative regulation of NR5A2 gene expression or function,