Epiregulin is Up-regulated in pancreatic cancer and stimulates pancreatic cancer cell growth

Epiregulin belongs to the epidermal growth factor (EGF) family of polypeptides. Previous studies have underscored the important role of the EGF family of ligands and receptors in the pathology of pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). It is not known, however, whether epiregulin may also have a role in these diseases. Therefore, in the present study we investigated the expression and function of epiregulin in five pancreatic cancer cell lines and in PDAC and CP tissue samples. Epiregulin mRNA was present at high (MIA-PaCa-2 cells) or moderate levels (ASPC-1, CAPAN-1, and T3M4) in most cells, but was below detection levels in PANC-1 cells. All the cell lines exhibited a dose-dependent increase in growth in response to recombinant human epiregulin. Epiregulin mRNA levels were increased 2.1-fold in PDAC samples (P < 0.01) and 1.7-fold in CP samples (P < 0.01), when compared with the normal controls. There was no correlation between epiregulin mRNA levels and tumor stage or grade. By in situ hybridization, a moderate to intense epiregulin mRNA signal was present in most pancreatic cancer cells in PDAC. In contrast, only a weak (normal pancreas) to moderate (CP) signals were present in the ductal and acinar cells in CP. These findings suggest that epiregulin may contribute to the pathobiology of PDAC, and may also have a role in CP.     

Familial pancreatic cancer

Familial clustering is estimated in 5-10% of pancreatic cancers. In different countries Familial Pancreatic Cancer Registries have been established to investigate the epidemiology, and genetic background in these families and, to organize the screening programs for high-risk relatives and for follow-up. The largest such registry is found at Johns Hopkins University Hospital. Evaluating the available data revealed that familial pancreatic cancer is heterogeneous: it may occur in kindreds of pancreatic cancer patients, but it may also be associated with various familial cancer syndromes. Such syndromes include FAMMM-syndrome, hereditary breast cancer, Peutz-Jeghers syndrome, but other associations can also be taken into account. The germline mutations are also heterogeneous, and although they are not absolutely decisive, they significantly increase the risk of the affected persons, making the organ more susceptible for environmental carcinogens. High-risk family members should be screened for gene mutations (especially for BRCA2, STK11/LKB1, CDKN2A/p16, PRSS1 genes), and by using endoscopic ultrasound. These methods are useful for identifying the preneoplastic conditions, but of equal importance is the cessation of smoking. In Hungary there are no relevant data about the epidemiology of familial pancreatic cancer, but their number is estimated to be about 80-150 annually. Considering the very high (and continuously increasing) incidence, it seems to be necessary to register and screen these families. This review emphasizes the importance of these goals.     

Autophagy in pancreatic cancer

Pancreatic cancer, the fourth leading cause of cancer-related death in the United States, is resistant to current chemotherapies. Therefore, identification of different pathways of cell death is important to develop novel therapeutics. Our previous study has shown that triptolide, a diterpene triepoxide, inhibits the growth of pancreatic cancer cells in vitro and prevents tumor growth in vivo. However, the mechanism by which triptolide kills pancreatic cancer cells was not known, hence, this study aimed at elucidating it. Our study reveals that triptolide kills diverse types of pancreatic cancer cells by two different pathways; it induces caspase-dependent apoptotic death in some cell lines and death via a caspase-independent autophagic pathway in the other cell lines tested. Triptolide-induced autophagy requires autophagy-specific genes, atg5 or beclin 1, and its inhibition results in cell death via the apoptotic pathway, whereas inhibition of both autophagy and apoptosis rescues triptolide-mediated cell death. Our study shows for the first time that induction of autophagy by triptolide has a pro-death role in pancreatic cancer cells. Since triptolide kills diverse pancreatic cancer cells by different mechanisms, it makes an attractive chemotherapeutic agent for future use against a broad spectrum of pancreatic cancers.     

Bile, pancreatic cancer, and the activation of pancreatic juice

Bile and pancreatic juice vary in their trypsin inhibitor content. Activation of bile-pancreatic juice mixtures (1:1) occurred when the combined trypsin inhibitory capacity was low. No activation was seen with bile having a high trypsin inhibitor content. Pancreatic juice activated faster where more trypsin inhibitor complex was present. With calcium (25 mM), pancreatic secretions activated in a similar order as with the trypsin-inhibitor-free bile. We propose that activation occurs more readily where large amounts of the trypsin-inhibitor complex are present in pancreatic juice as a result of carcinoma or other etiologies.     

Human pancreatic cancer stem cells: implications for how we treat pancreatic cancer

Pancreatic cancer has the worst prognosis of any major malignancy, with an annual death rate that approximates the annual incidence rate. Delayed diagnosis, relative chemotherapy and radiation resistance and an intrinsic biologic aggressiveness all contribute to the abysmal prognosis associated with pancreatic cancer. Answers to the frustrating effort to find effective therapies for pancreatic cancer may be gained through a renewed perspective on tumorigenesis as a process governed by a select population of cells, termed cancer stem cells (CSCs). Cancer stem cells, like their normal counterparts, have the properties of self-renewal and multilineage differentiation and possess inherently heightened DNA damage response and repair mechanisms that make them difficult to eradicate. Initially discovered in leukemias, researchers have identified CSCs in several solid-organ malignancies including breast, brain, prostate, and colon cancers. We have recently identified a CSC population in human pancreatic cancers. These pancreatic CSC represent 0.5% to 1.0% of all pancreatic cancer cells and express the cell surface markers CD44, CD24, and epithelial-specific antigen. Pancreatic CSCs have been shown to be resistant to standard chemotherapy and radiation, and devising specific therapies to target this distinct cell population is likely needed to identify effective therapies to treat this dismal disease.     

Association between family cancer history and risk of pancreatic cancer

PurposeFamily history of pancreatic adenocarcinoma is an established risk factor for the disease. However, associations of pancreatic cancer with other familial cancers are less clear. We analyzed data from the Queensland Pancreatic Cancer Study (QPCS), an Australian population-based case-control study, to investigate associations between family history of various cancer types and risk of pancreatic cancer.Materials and methodsOur study included 591 pancreatic cancer patients and 646 controls, all of whom self-reported the histories of cancer in their first-degree relatives. We used logistic regression to estimate adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). Based on our results, we conducted a systematic literature review using the Medline (OVID) database to identify articles pertaining to the association between family history of melanoma and risk of pancreatic cancer. A meta-analysis including associations in five published studies, unpublished results from a study co-author and the QPCS results was then performed using the DerSimonian and Laird random-effects model.ResultsCases were more likely than controls to report a family history of pancreatic cancer (OR 2.20, 95% CI 1.16–4.19) and melanoma (OR 1.74, 95% CI 1.03–2.95), but not of breast, ovarian, respiratory, other gastrointestinal or prostate cancer. Meta-analysis of melanoma family history and pancreatic cancer risk yielded an OR of 1.22 (95% CI 1.00–1.51).ConclusionsOur results yield further evidence of increased risk of pancreatic cancer in those with family histories of the disease. We also provide suggestive evidence of an association between family history of melanoma and risk of pancreatic cancer.     

Troxacitabine prodrugs for pancreatic cancer

Troxacitabine is a cytotoxic deoxycytidine analogue with an unnatural L-configuration, which is activated by deoxycytidine kinase (dCK). The configuration is responsible for differences in the uptake and metabolism of troxacitabine compared to other deoxynucleoside analogues. The main drawback in the use of most nucleoside anticancer agents originates from their hydrophilic nature, which property requires a high and frequent dosage for an intravenous administration. To overcome this problem several troxacitabine prodrugs modified in the aminogroup with a linear aliphatic chain with a higher lipophilicity were developed. To determine whether these prodrugs have an advantage over Troxacitabine pancreatic cancer cell lines were exposed to Troxacitabine and the lipophilic prodrugs. The addition of linear aliphatic chains to troxacitabine increased sensitivity of pancreatic cancer cell lines to the drug > 100-fold, possibly due to a better uptake and retention of the drug.     

Proteomics in pancreatic cancer research

In this review, we give an overview of the actual role of proteomic technologies in the study of pancreatic cancers (PCs). We describe PC proteomics on the basis of sample origins, i.e. tissues, body fluids, and PC cell lines. As regards PC tissues, we report the identification of a number of candidate biomarkers of precursor lesions that may allow early diagnosis of this neoplasia. Moreover, we describe cytoskeletal and hypoxia-regulated proteins that confirm the involvement of cytoskeleton modifications and metabolism adaptations in carcinogenesis. We also discuss the most important biomarkers identified by proteomic analysis involved in local invasion and distant metastasis, and in the cross-talk between pancreatic tumor and the surrounding stroma. Furthermore, we report novel candidate biomarkers identified in serum, plasma, and pancreatic juice of cancer patients compared with cancer-free controls. Proteomic alterations in PC cell line models as compared to normal controls and studies on cell lines treated with drugs or new agents to understand their mechanism of pharmacological action or the onset of drug resistance are also presented. Finally, we discuss the recent improvements obtained in classical 2-DE and high-throughput proteomic strategies able to allow the overcoming of relevant proteomic drawbacks.     

Stromal biology of pancreatic cancer

The genetic paradigm of cancer, focused largely on sequential molecular aberrations and associated biological impact in the neoplastic cell compartment of malignant tumors, has dominated our view of cancer pathogenesis. For the most part, this conceptualization has overlooked the dynamic and complex contributions of the surrounding microenvironment comprised of non-tumor cells (stroma) that may resist, react to, and/or foster tumor development. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease in which a prominent tumor stroma compartment is a defining characteristic. Indeed, the bulk of PDAC tumor volume consists of non-neoplastic fibroblastic, vascular, and inflammatory cells surrounded by immense quantities of extracellular matrix, far exceeding that found in most other tumor types. Remarkably, little is known about the composition and physiology of the PDAC tumor microenvironment, in particular, the role of stroma in tumor initiation and progression. This review attempts to define key challenges, opportunities and state-of-knowledge relating to the PDAC microenvironment research with an emphasis on how inflammatory processes and key cancer pathways may shape the ontogeny of the tumor stroma. Such knowledge may be used to understand the evolution and biology of this lethal cancer and may convert these insights into new points of therapeutic intervention.     

Metabolism addiction in pancreatic cancer

Pancreatic ductal adenocarcinoma, an aggressively invasive, treatment-resistant malignancy and the fourth leading cause of cancer deaths in the United States, is usually detectable only when already inevitably fatal. Despite advances in genetic screening, mapping and molecular characterization, its pathology remains largely elusive. Renewed research interest in longstanding doctrines of tumor metabolism has led to the emergence of aberrant signaling pathways as critical factors modulating central metabolic networks that fuel pancreatic tumors. Such pathways, including those of Ras signaling, glutamine-regulatory enzymes, lipid metabolism and autophagy, are directly affected by genetic mutations and extreme tumor microenvironments that typify pancreatic tumor cells. Elucidation of these metabolic networks can be expected to yield more potent therapies against this deadly disease.     

Risk factors for pancreatic cancer

In the United States, the cumulative mortality or lifetime risk of dying from pancreatic cancer is about 1-2%, but although this form of cancer is rare, nearly all patients die from the disease within one to two years. Because of its lethality, pancreatic cancer now ranks fourth as a cause of death from cancer. There are country-specific differences in rates, perhaps explained by differences in life-style factors or diet. African-Americans in the USA have rates that are about 50% higher than Caucasians. Smoking is the major known risk factor for this cancer, explaining 20-30% of all cases. Another 5-10% of causes are caused by germline mutations, with mutations in BRCA2 being the most frequent. Two background diseases increase the risk of pancreatic cancer-pancreatitis, and diabetes. Major challenges presented by this cancer are: 1) determination of the molecular pathways that make this cancer so aggressive; 2) development of new modalities, perhaps based on proteomics, to enhance early detection.     

Carbohydrate markers of pancreatic cancer

Pancreatic cancer is the fourth most common cause of death from cancer in the world and the sixth in Europe. Pancreatic cancer is more frequent in males than females. Worldwide, following diagnosis of pancreatic cancer, <2% of patients survive for 5 years, 8% survive for 2 years and <50% survive for only approx. 3 months. The biggest risk factor in pancreatic cancer is age, with a peak of morbidity at 65 years. Difficulty in the diagnosis of pancreatic cancer causes a delay in its detection. It is one of the most difficult cancers to diagnose and therefore to treat successfully. Additional detection of carbohydrate markers may offer a better diagnosis of pancreatic cancer. Carbohydrate markers of cancer may be produced by the cancer itself or by the body in response to cancer, whose presence in body fluids suggests the presence and growth of the cancer. The most widely used, and best-recognized, carbohydrate marker of pancreatic cancer is CA 19-9 [CA (carbohydrate antigen) 19-9]. However, the relatively non-specific nature of CA 19-9 limits its routine use in the early diagnosis of pancreatic cancer, but it may be useful in monitoring treatment of pancreatic cancer (e.g. the effectiveness of chemotherapy), as a complement to other diagnostic methods. Some other carbohydrate markers of pancreatic cancer may be considered, such as CEA (carcinoembryonic antigen), CA 50 and CA 242, and the mucins MUC1, MUC2 and MUC5AC, but enzymes involved in the processing of glycoconjugates could also be involved. Our preliminary research shows that the activity of lysosomal exoglycosidases, including HEX (N-acetyl-β-D-hexosaminidase), GAL (β-D-galactosidase), FUC (α-L-fucosidase) and MAN (α-D-mannosidase), in serum and urine may be used in the diagnosis of pancreatic cancer.     

Immunoregulation in pancreatic cancer patients

Metastatic pancreatic cancer is one of the most aggressive cancer known in man yet specific antitumor immunity has been demonstrated in lymph nodes draining the sites of pancreatic tumors. Despite this immunity, pancreatic cancer patients suffer a quick demise. To further define tumor immunity in patients with metastatic pancreatic cancer, we sought to characterize helper T cell subsets, serum cytokines, cellular cytotoxicity that is both T-cell and non-T cell mediated, as well as known tumor-derived immunosuppressive products that may be present in their peripheral blood. Significantly heightened levels of interleukin 2 (IL-2), a Th1 cytokine, were found in patients before treatment with chemotherapy while serum IL-10, a Th2 cytokine, were at significantly lower levels than observed in normal donors tested between their fifth and seventh decades of life. IL-10 levels increased progressively with age as a serum-bound protein in normal, healthy donors tested between the ages of 24 through 61. An age associated progression of increased IL-10 levels was not observed in pancreatic cancer patients. Few patients had detectable serum levels of soluble fas ligand but approximately half had elevated levels of a tumor marker, detected with the CA-15.3 assay, known as soluble MUCIN 1 (MUC1). Cell mediated cytotoxicity including T-cell mediated killing of pancreatic tumor cell lines was detected in many patients. These data suggest that pancreatic cancer patients have activated type 1 helper T cells that can support development of cell-mediated immunity, and that their sera contain lowered levels of the "anti-inflammatory" type 2 cytokine, IL-10.     

Targeting pancreatic cancer stem cells for cancer therapy

Pancreatic cancer (PC) is the fourth most frequent cause of cancer death in the United States. Emerging evidence suggests that pancreatic cancer stem cells (CSCs) play a crucial role in the development and progression of PC. Recently, there is increasing evidence showing that chemopreventive agents commonly known as nutraceuticals could target and eliminate CSCs that have been proposed as the root of the tumor progression, which could be partly due to attenuating cell signaling pathways involved in CSCs. Therefore, targeting pancreatic CSCs by nutraceuticals for the prevention of tumor progression and treatment of PC may lead to the development of novel strategy for achieving better treatment outcome of PC patients. In this review article, we will summarize the most recent advances in the pancreatic CSC field, with particular emphasis on nutraceuticals that target CSCs, for fighting this deadly disease.