Detection of oncogenes in chronic pancreatitis

BACKGROUND: The pathogenesis of chronic pancreatitis (CP) remains poorly understood. Recently, molecular biology has identified the genetic background for many patients with hereditary CP. In addition, a number of studies have focused on the detection of proto-oncogenes and tumour suppressor gene mutations in the pathogenesis of CP. So far, the use of these mutations (with the exception of mutations causing hereditary CP), as diagnostic and prognostic markers is still controversial. DISCUSSION: It is well known that the risk of pancreatic cancer in patients with CP, especially the hereditary form, is high. At present, there is insufficient evidence to show a clear relationship between the development of pancreatic cancer and certain mutations. New biotechnological methods, such as DNA array expression analysis, expand our knowledge of the molecular pathogenesis of this disease and may help to develop specific diagnostic, prognostic and therapeutic tools. However, until long-term studies examine the safety and efficacy of certain genetic markers, long-term follow-up of patients with CP who harbour mutations is needed.     

MicroRNAs as emerging biomarkers and therapeutic targets for pancreatic cancer

Despite tremendous efforts from scientists and clinicians worldwide, pancreatic adenocarcinoma (PDAC) remains a deadly disease due to the lack of early diagnostic tools and reliable therapeutic approaches. Consequently, a majority of patients (80%) display an advanced disease that results in a low resection rate leading to an overall median survival of less than 6 months. Accordingly, robust markers for the early diagnosis and prognosis of pancreatic cancer, or markers indicative of survival and/or metastatic disease are desperately needed to help alleviate the dismal prognosis of this cancer. In addition, the discovery of new therapeutic targets is mandatory to design effective treatments. In this review, we will highlight the translational studies demonstrating that microRNAs may soon translate into clinical applications as long-awaited screening tools and therapeutic targets for PDAC.     

Experimental animal models of pancreatic carcinogenesis and metastasis

Pancreatic cancer is a lethal disease characterized by early metastasis, local invasion, and resistance to conventional therapies. To understand its etiology and eventually make prevention of it possible and effective, appropriate carcinogenesis models will certainly help us understand the effects of environmental and genetic elements on pancreatic carcinogenesis. The development of new treatment strategies to control cancer metastasis is of immediate urgency. Fulfillment of this task relies on our knowledge of the cellular and molecular biology of pancreatic cancer metastasis and the availability of biologically and clinically relevant model systems. Many of the existing pancreatic cancer carcinogenesis and metastasis animal models are described in this review. The advantages and disadvantages of each model and their clinical implications are discussed, and special attention is focused on experimental therapeutic strategies targeting pancreatic cancer metastasis.     

Experimental animal models in pancreatic carcinogenesis: lessons for human pancreatic cancer

The silent course of pancreatic cancer and its explosive fatal outcome have hindered studies of tumor histogenesis and the identification of early biochemical and genetic alterations that could help to diagnose the disease at a curable stage and develop therapeutic strategies. Experimental animal models provide important tools to assess risk factors, as well as preventive and therapeutic possibilities. Although several pancreatic cancer models presently exist, only models that closely resemble human tumors in morphological, clinical, and biological aspects present useful media for preclinical studies. Because an estimated 70% of human tumors are induced by carcinogens and because a significant association has been found between cigarette smoking and pancreatic cancer, chemically induced models are of particular value. Moreover, in such models the etiology, modifying factors, effects of diets, and naturally occurring products can be studied and early diagnostic, preventive, and therapeutic possibilities sought out. Many of the existing models are described in this review, and the advantages and shortcomings of each model and their clinical implications are discussed.     

Detection of small pancreatic cancers: Diagnostic potential of tumor markers,oncogenes, and tumor-suppressor genes

The development of the monoclonal antibody technique has made it possible to use various tumor markers, such as CA 19-9, to detect pancreatic cancer. Although it has been reported that these markers are not sensitive or specific enough to detect small pancreatic cancers, nearly 70% of small pancreatic cancers (<4.0 cm) release pancreatic-cancer associated antigens. In addition, the use of serum tumor markers and ultrasound (US) as screening tools in the outpatient clinic is very effective in detecting pancreatic cancer, including small pancreatic cancers. Recently, observations of carcinogenesis in the pancreas in humans and in experimental models have suggested several cellular pathways for carcinoma of the pancreas. There is increasing evidence that pancreatic cancer results from an accumulation of dominant and recessive mutations in oncogenes and tumor-suppressor genes. Identification of the mutations that occur in pancreatic cancer may provide important information concerning the early stage of this disease. Although there are currently no methods of detecting the premalignant stages of pancreatic cancer, the study of genetic markers may play a central role in the development of techniques for the early detection of pancreatic cancer in the future. (For more detailed information on genetic changes in pancreatic cancer, see: PG Terhune and DS Longnecker, Do Oncogene and Tumor Suppressor Gene Abnormalities Vary with Type of Carcinoma of the Pancreas? J Hep Bil Pancr Surg (1995) 2:1–7.)     

Novel gene therapy approaches to pancreatic cancer

One of the most lethal human malignancies, pancreatic adenocarcinoma has remained a therapeutic challenge. Historically, the only curable treatment modalities available to patients with this disease have included pancreaticoduodenectomy with adjuvant chemoradiation. Few patients, however, have resectable disease at the time of presentation, and even for those who are offered this radical course of treatment, post-surgical survival is dismally short. Recently, however, advances in the understanding of the molecular biology of pancreatic cancer have enabled researchers to investigate novel gene therapy approaches to the treatment of this disease. In this paper, we review the common genetic mutations found in pancreatic adenocarcinomas, discuss strategies for the manipulation of genetic targets, and assess current progress in the field of gene therapy as it relates to pancreatic cancer.     

Pancreatic cancer: early detection, diagnosis, and screening

Pancreatic cancer, pancreatic ductal adenocarcinoma, is one of the most lethal malignancies, and researchers have therefore intensified efforts directed at its early detection and management. Early detection includes an effective screening program, as pancreatic cancer is known to evolve from precursor lesions, which can be identified using currently available diagnostic modalities. A recent multicenter trial (the CAPS 3 trial) demonstrated that screening of asymptomatic individuals at high risk for pancreatic cancer frequently detects small cystic pancreatic lesions, including curable, noninvasive high-grade neoplasms. In that study, endoscopic ultrasound and magnetic resonance imaging were better at detecting pancreatic lesions than was computed tomography. On the other hand, effective screening modalities (e.g., imaging studies with measurement of biomarkers) are lacking for individuals at normal to moderate risk for this disease. Therefore, pancreatic cancer screening strategies should include identification of the population at high risk for this cancer and intensive application of screening tools with adequate sensitivity to detect early-stage disease.     

Adenocarcinoma of the pancreas--past, present and future

Adenocarcinoma of the pancreas has always been a disease with a dismal prognosis. Almost every patient with this cancer dies of the tumor. Over the years there has been extensive advancement in the understanding of etiology, molecular biology, diagnosis and treatment of this disease. Presently, surgical resection is the only potentially curative option available for these patients. It is now clear that surgery alone cannot increase the survival of these patients. With the understanding of molecular biology of pancreatic cancer new management strategies are under a preclinical stage of development. These new diagnostic and therapeutic modalities hopefully will improve the outcome of patients with pancreatic cancer.     

Targeting tight junctions during epithelial to mesenchymal transition in human pancreatic cancer

Pancreatic cancer continues to be a leading cause of cancer-related death worldwide and there is an urgent need to develop novel diagnostic and therapeutic strategies to reduce the mortality of patients with this disease. In pancreatic cancer, some tight junction proteins, including claudins, are abnormally regulated and therefore are promising molecular targets for diagnosis, prognosis and therapy. Claudin-4 and -18 are overexpressed in human pancreatic cancer and its precursor lesions. Claudin-4 is a high affinity receptor of Clostridium perfringens enterotoxin (CPE). The cytotoxic effects of CPE and monoclonal antibodies against claudin-4 are useful as novel therapeutic tools for pancreatic cancer. Claudin-18 could be a putative marker and therapeutic target with prognostic implications for patients with pancreatic cancer. Claudin-1, -7, tricellulin and marvelD3 are involved in epithelial to mesenchymal transition (EMT) of pancreatic cancer cells and thus might be useful as biomarkers during disease. Protein kinase C is closely related to EMT of pancreatic cancer and regulates tight junctions of normal human pancreatic duct epithelial cells and the cancer cells. This review focuses on the regulation of tight junctions via protein kinase C during EMT in human pancreatic cancer for the purpose of developing new diagnostic and therapeutic modalities for pancreatic cancer.     

Advances in pancreatic cancer research: Moving towards early detection

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer. Substantial progress has been made in the understanding of the biology of pancreatic cancer, and advances in patient management have been significant. However, most patients (nearly 80%) who present with locally advanced or metastatic disease have an extremely poor prognosis. Survival is better for those with malignant disease localized to the pancreas, because surgical resection at present offers the only chance of cure. Therefore, the early detection of pancreatic cancer may benefit patients with PDAC. However, its low rate of incidence and the limitations of current screening strategies make early detection difficult. Recent advances in the understanding of the pathogenesis of PDAC suggest that it is possible to detect PDAC in early stages and even identify precursor lesions. The presence of new-onset diabetes mellitus in the early phase of pancreatic cancer may provide clues for its early diagnosis. Advances in the identification of novel circulating biomarkers including serological signatures, autoantibodies, epigenetic markers, circulating tumor cells and microRNAs suggest that they can be used as potential tools for the screening of precursors and early stage PDAC in the future. However, proper screening strategies based on effective screening methodologies need to be tested for clinical application.     

Pancreatic cancer today

Carcinoma of the exocrine pancreas remains a challenging disease with poor prognosis mainly due to advanced stage by the time of presentation, the early systemic dissemination and its extraordinary local tumor progression. Surgery has little more to offer in improvement of curative percentage of disease and some progress has been made in the medical management of pancreatic cancer with the introduction and use of new chemical agents and with combined immunochemotherapy and chemoradiotherapy. The purpose of this review article is to focus on all recent advances in the management of pancreatic cancer. We review the current trial literature emphasizing the risk factors, the molecular biology of the tumor, and the therapeutic approach.     

Circulating tumor DNA as a liquid biopsy target for detection of pancreatic cancer

Most pancreatic cancer patients present with advanced metastatic disease, resulting in extremely poor 5-year survival, mainly because of the lack of a reliable modality for early detection and limited therapeutic options for advanced disease. Therefore, there is a need for minimally-invasive diagnostic tools for detecting pancreatic cancer at an early stage, when curative surgery and also novel therapeutic approaches including precision medicine may be feasible. The “liquid biopsy” addresses these unmet clinical needs based on the concept that simple peripheral blood sampling and detection of circulating tumor DNA (ctDNA) could provide diagnostic information. In this review, we provide an overview of the current status of blood-based tests for diagnosis of pancreatic cancer and the potential utility of ctDNA for precision medicine. We also discuss challenges that remain to be addressed in developing practical ctDNA-based liquid biopsy approaches for early diagnosis of pancreatic cancer.     

Molecular mechanisms of pancreatic cancer.

Pancreatic cancer is a deadly disease with no effective therapy short of surgical resection. Unfortunately, only a minority of patients are candidates for potential curative surgery as the tumor spreads early to extrapancreatic sites. Patients with metastatic pancreatic cancer survive less than 1 year following diagnosis. The current challenge for both clinicians and scientists is to translate the growing body of knowledge of the molecular basis of this disease into effective strategies for early diagnosis and systematic treatment. Molecular studies of pancreatic cancer have revealed that this cancer is associated with several genetic mutations. Although our knowledge of the molecular alterations in pancreatic cancer has grown significantly, there is still much to learn. It is clear that oncogenes, tumor suppressor genes, growth factors and DNA mismatch repair genes all play a role in pancreatic tumorigenesis. However, a better understanding of the relative contribution of each of these molecular alterations is necessary and will aid the development of more effective diagnostic and therapeutic strategies to deal with this deadly and aggressive cancer.     

Translational research in pancreatic cancer. Highlights from the "44th ASCO Annual Meeting". Chicago, IL, USA. May 30 - June 3, 2008

Pancreatic cancer is an international problem because of its increasing incidence worldwide. The incidence and age-adjusted mortality rates are almost equal, underscoring the aggressive nature of the disease. Although efforts are being made to unveil the principles governing the initiation and progression of this cancer, and to identify the factors that confer its particular aggressiveness, the exact succession of molecular events underlying the development of this devastating malignancy has remained unsolved. The management of pancreatic cancer is, therefore, an ongoing challenge. Many translational studies were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) this year. The author summarizes few of them including: polymorphisms of genes involved in gemcitabine metabolism correlate with prognosis in patients receiving neoadjuvant therapy for pancreatic cancer, diagnostic performance of MUC1 for pancreatic ductal adenocarcinoma, and use of whole genome expression analysis of pancreatic adenocarcinoma to predict prognosis after surgery. Pancreatic cancer remains a dismal disease and early diagnostic markers and therapeutic targets are urgently needed.     

Pancreatic cancer

Pancreatic cancer remains a major unsolved health problem, with conventional cancer treatments having little impact on disease course. Almost all patients who have pancreatic cancer develop metastases and die. The main risk factors are smoking, age, and some genetic disorders, although the primary causes are poorly understood. Advances in molecular biology have, however, greatly improved understanding of the pathogenesis of pancreatic cancer. Many patients have mutations of the K-ras oncogene, and various tumour-suppressor genes are also inactivated. Growth factors also play an important part. However, disease prognosis is extremely poor. Around 15-20% of patients have resectable disease, but only around 20% of these survive to 5 years. For locally advanced, unresectable, and metastatic disease, treatment is palliative, although fluorouracil chemoradiation for locally advanced and gemcitabine chemotherapy for metastatic disease can provide palliative benefits. Despite pancreatic cancer's resistance to currently available treatments, new methods are being investigated. Preoperative chemoradiation is being advocated, with seemingly sound reasoning, and a wider role for gemcitabine is being explored. However, new therapeutic strategies based on the molecular biology of pancreatic cancer seem to hold the greatest promise.     

Genetic counseling and testing for germline p16 mutations in two pancreatic cancer-prone families

The mortality from pancreatic cancer coincides closely with its incidence, indicating a dismal outlook. Hereditary factors probably account for approximately 5%-10% of the pancreatic cancer burden. The molecular genetic etiology of pancreatic cancer is only beginning to be identified. We describe our genetic counseling experience with 2 large families prone to pancreatic cancer-malignant melanoma in which p16 (CDKN2) germline mutations had been identified. Members of each family underwent intensive counseling before and at the time of disclosure of p16 germline mutation findings. Two non-cancer-affected siblings from each of the 2 families had p16 mutations identified in DNA from their peripheral blood lymphocytes. In each case, a parent affected with pancreatic cancer also harbored the p16 mutation identified in DNA from their respective tumor blocks. The sibling pairs stated that they would seriously consider prophylactic pancreatectomy if biomarkers or imaging findings suggested a precancerous state. Our experience highlights limited options for managing these families and emphasizes the need for better tools to diagnose pancreatic cancer at a curable stage.     

Pancreatic cell lines: a review

Pancreatic cancer has an extremely poor prognosis and lacks early diagnostic and therapeutic possibilities, mainly because of its silent course and explosive fatal outcome. The histogenesis of the disease and early biochemical and genetic alterations surrounding carcinogenesis are still controversial. In vitro studies offer a useful tool to study physiologic, pathophysiologic, differentiation, and transformation processes of cells and to understand some of these shortcomings. The extreme difficulties in isolating individual pancreatic cells and their purification by maintaining their native characteristics have limited research in this area. This review is intended to present and discuss the current availability of rodent and pancreatic cell lines, their differences as well as the difficulties, limitations, and characteristics of these cultured cells. Discussed are in vitro models; ductal, islet, and acinar cell culture; cell differentiation; cell transformation, including genetic and chromosomal alterations; as well as tumor cell markers. Also addressed are the advantages and problems associated with the cell culture in humans and rodents. Advancements in tissue culture technique and molecular biology offer steady progress in this important line of research. The improved methods not only promise the establishment of beta-cell cultures for the treatment of diabetes, but also for studying sequential genetic alterations during pancreatic carcinogenesis and in understanding the tumor cell origin.     

Pancreatic cancer stem cell biology and its therapeutic implications

Pancreatic cancer remains one of the most difficult malignancies to treat. Significant developments in our understanding of pancreatic cancer biology have occurred over the past decade. One of the key advances has been the formulation of the cancer stem cell model of tumor growth and subsequent experimental proof of pancreatic cancer stem cell existence. Cancer stem cells contribute to pancreatic tumor growth and progression and are at least partially responsible for the relative resistance of the tumor to systemic chemotherapy and radiation. Significant questions remain about how the mutational profile of the tumor, the tumor microenvironment, and normal pancreatic developmental pathways contribute to pancreatic cancer stem cell biology. Answers to these questions will likely yield new therapeutic approaches for this deadly disease.     

Pankreaskarzinom

Therapy for pancreatic adenocarcinoma is still one of the unsolved problems of modern medicine. The molecular genesis of pancreatic cancer is characterized by mutations in oncogenes and tumor suppressors as well as epigenetic changes. These alterations result is apoptosis resistance, which causes resistance to cytotoxic chemotherapies. Interestingly, the EGFR system and angiogenesis have been identified as therapeutic targets for which molecular therapeutic tools already exist. Here, we review current phase III trials and some phase II trials which are of particular interest. Recent success in the treatment of other tumor entities resistant to cytotoxic therapies gives hope of therapeutic progress in pancreatic cancer.     

Epigenetics and pancreatic cancer:Pathophysiology and novel treatment aspects

An improvement in pancreatic cancer treatment represents an urgent medical goal.Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades.Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations,such as mutations of K-ras,and especially epigenetic dysregulation of tumor-associated genes,such as silencing of the tumor suppressor p16ink4a,are hallmarks of pancreatic cancer.Here,we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation,histone acetylation or miRNA(microRNA)expression,and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition,morphological pattern formation,or cancer stem cell regulation during carcinogenesis from PanIN(pancreatic intraepithelial lesions)to invasive cancer and resistance development.Epigenetic drugs,such as DNA methyltransferases or histone deactylase inhibitors,have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development.Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.