Intraepithelial Neoplasia of Pancreas
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Intraepithelial Neoplasia of Pancreas

Pancreatic ductal adenocarcinoma is the most common pancreatic neoplasm and as its name suggests it arises from ductal epithelial cells of the pancreas. Other subtypes of pancreatic neoplasms include benign and malignant cystic lesions, mucin producing tumor, acinar cell carcinoma, adenosquamous carcinoma, lymphomas and sarcomas. Pancreatic ductal adenocarcinoma evolves from a progressive cascade of cellular, morphological and architectural changes from normal ductal epithelium through preneoplastic lesions termed PanIN (Pancreatic Intraepithelial Neoplasia). These PanIN lesions are in turn associated with somatic alterations in canonical oncogenes and tumor suppressor genes. The molecular pathogenesis of human pancreatic ductal adenocarcinoma involves the temporal and spatial accumulation of genetic alterations, influenced undoubtedly by environmental exposures. The alterations that occur in canonical oncogenes, tumor suppressor genes and DNA mismatch repair genes, are largely due to LOH (Loss of Heterozygosity), point mutations, overexpression, and imbalance in immunohistochemistry (Ref.1). The major factors that trigger pancreatic cancer and enhance its pathogenesis includes, long-term heavy alcohol consumption, chain smoking, chewing tobacco, PAHs (Polycyclic Aromatic Hydrocarbons) and heterocyclic amines, to mention a few. Long-term heavy alcohol consumption leads to chronic pancreatitis, and the progression of pancreatitis may lead to co-morbidities, including malabsorption, diabetes and pancreatic cancer. During pancreatitis, alcohol and its metabolites cause similar molecular-cellular mechanisms that are common to inflammatory processes, such as generation of ROS (Reactive Oxygen Species), NF-KappaB (Nuclear Factor-KappaB), COX2 (Cyclooxygenase-2), and various cytokines; loss of tumor suppression function; and stimulation of oncogene expression (Ref.2).

Alcohol, especially in combination with smoking, is an established risk factor for upper gastrointestinal tract cancer. Alcohol consumption, therefore, is classified as a human carcinogen. The pancreas metabolizes ethanol by means of oxidative and non-oxidative pathways to generate metabolites, such as Acetaldehyde and FAEEs (Fatty Acid Ethyl Esters). The major oxidative enzyme system uses either ADHs (Alcohol Dehydrogenases) or the Cytochrome-P450 system (especially CYP2E1 (Cytochrome P450 Family-2 Subfamily-E Polypeptide-1)), whereas the non-oxidative pathway uses the FAEE Synthase enzyme pathway. The metabolites generated by both oxidative and non-oxidative mechanisms are injurious to both exocrine and endocrine pancreas. Acetaldehyde is known to injure pancreatic tissues through its genotoxicity and adduct formation (Ref.2). Alcohol metabolized by CYP2E1 results in generation of ROS, which initiates tissue injuries through activation of NF-KappaB and heightened transcription of pro-inflammatory cytokines. These pathways interact with carcinogens involved in smoking and dietary pro-carcinogens, which, in turn, convert to ultimate carcinogens. The activated carcinogen lead to the formation of DNA adduct and initiation of pancreatic carcinogenesis. The non-oxidative pathway of ethanol metabolism is involved in the formation of FAEEs. The accumulation of FAEEs occurs in the pancreas after exposure to ethanol. This increases the fragility of pancreatic lysosomes to release endogenous hydrolases, which are capable of converting Trypsinogen to Trypsin and thereby predisposing to autodigestive injuries and pancreatitis. The injurious effect of ethanol on the pancreas are mediated through the sensitization of exocrine acinar cells to Cholecystokinin-induced pancreatic activation of Zymogens and the potentiation of the effect of Cholecystokinin on the activation of transcription factors, including NF-KappaB and AP-1 (Activation Protein-1), generated by both non-oxidative and oxidative pathways. All these mechanisms interact throughout, leading to pancreatic injury and the inflammatory process and, ultimately, to both acute and chronic damage. In addition to the direct effect of alcohol, various predisposing factors, such as genetics, smoking, high-fat diets, infections, and compromised immune functions (leading to uncontrolled bacteria and virus growth), may render the pancreas more susceptible to alcohol-induced tissue injury (Ref.2 & 3).

The molecular pathogenesis of human pancreatic ductal adenocarcinoma involves both the temporal and spatial accumulation of genetic alterations of oncogenes, tumor suppressor genes and DNA mismatch repair genes, influenced undoubtedly by the etiologic factors like cigarette-smoking, high-fat diet and alcohol, which leads to progressive nuclear hyperchromasia and atypia, change of the cuboidal to columnar epithelium, loss of epithelial cell polarity, papillary foldings, and shedding of cells into the lumen with progression through the PanIN stages. Each histopathologic stage is associated with genetic alterations at the molecular level. Of paramount importance are the KRas, p16(INK4A), p14(ARF), Her2, EGFR (Epidermal Growth Factor Receptor), p53SMAD4  (Sma and MAD (Mothers Against Decapentaplegic) Related Protein-4)/DPC4 (Deleted in Pancreatic Carcinoma-4), BRCA2 (Breast Cancer-2 Gene) and TGF-Beta (Transforming Growth Factor-Beta)/TGF-BetaR (Transforming Growth Factor-Beta-Receptor) that are frequently mutated in PanIN lesions. Single point mutations, which occur in codons 12 and 13, activate the oncogenic potential of KRas during PanIN-1A and PanIN-1B stages. Subsequently PanIN-2 and PanIN-3 tumors harbor either biallelic inactivation of p16(INK4A), p14(ARF), Her2/EGFR overexpression, BRCA2  mutations or LOH of the SMAD4/DPC4-p53 gene locus. The rapid acceleration of PanIN lesions and formation of pancreatic ductal adenocarcinomas with metastatic lesions also witness TGF-Beta/TGF-BetaR gene mutations. TGF-Beta signaling acts as tumor suppressor in normal cells and at early stages of carcinogenesis, whereas it switches into a tumor promoter during tumor progression. The LOH of chromosomes 9p, 17p and 18q are therefore instrumental to such loss of cell growth control (Ref.4,5 & 6). Mechanisms underlying the interactive effects of alcohol and the predisposing factors, in pancreatic carcinogenesis require further investigation. However, the protective effect of fruit and vegetable intake provide certain phytonutrients, such as isothiocyanates, polyphenols, and flavonoids, to act as antioxidants to counteract the by-products of the oxidative metabolites from alcohol. In addition, how insulin and other islet cell growth factors interact with the various molecular-cellular levels affected by alcohol and its metabolites needs further elucidation. Because pancreatic carcinogens, from intraepithelial neoplasia stage to invasive carcinoma, take years to develop and the development of pancreatic cancer due to chronic pancreatitis is cumulative, therefore an appropriate cancer prevention and screening strategy needs to be developed to prevent pancreatic cancer arising from either alcoholic or non-alcoholic pancreatitis. A collaborative research effort might offer the best promise in the future to address the complexity of alcohol and pancreatic diseases and be used to advance the knowledge of why alcohol and its metabolites are carcinogens (Ref.7).