Pancreatic Adenocarcinoma
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Pancreatic Adenocarcinoma

Pancreatic carcinoma is one of the most enigmatic and aggressive malignant diseases. Neoplasms of the pancreas encompass a wide spectrum of benign and malignant tumors. Pancreatic adenocarcinoma, the malignant neoplasm of the exocrine duct cells, accounts for more than ninety percent of all pancreatic tumors (Ref.1). Pancreatic ductal adenocarcinoma evolves from a progressive cascade of cellular, morphological and architectural changes from normal ductal epithelium through pre-neoplastic lesions termed PanIN (Pancreatic Intraepithelial Neoplasia). These PanIN lesions are in turn associated with somatic alterations in canonical oncogenes and tumor suppressor genes. Pancreatic cancer like many other tumors over-expresses the RTKs (Receptor Tyrosine Kinases), EGFR (Epidermal Growth Factor Receptor) and/or its family members (like Her2) and TGF-BetaRs (Transforming Growth Factor-Beta Receptors). The expression of RTKs and their ligands, basically growth factors, is an early event in the development of pancreatic cancer (PanIN-1A and PanIN-1B stages). After ligand binding, these receptors both homo- and heterodimerize and become active. Activation involves trans-phosphorylation of Tyrosine residues by their intrinsic Tyrosine kinase activity. Phosphotyrosine residues generate docking sites for other signaling molecules harboring either Src  Homology-2 or Phosphotyrosine-interacting domains. The activation of RTKs triggers a signaling cascade, which involves SOS (Son of Sevenless), Src  (v-Src Avian Sacroma (Schmidt-Ruppin A-2) Viral Oncogene), GRB2 (Growth Factor Receptor-Bound Protein-2), and MAPKs (Mitogen-Activated Protein Kinases) activation, ultimately resulting in a cellular proliferative response. Activation of these pathways regulates proliferation thereby contributing to cellular transformation (Ref.2 & 3).

As pancreatic cancer progresses, additional alterations of the KRas  (Kirsten-Ras) pathway occur via different mechanisms. KRas  is activated by RTK induced-GEFs (Guanine Nucleotide Exchange Factors), which in turn activates Raf -MEK1/2 (MAPK/ERK Kinase)-ERK (Extracellular Signal-Regulated Kinase)-Elk1 (ETS-domain protein Elk1) pathway by first localizing Raf to the plasma membrane, initiating the mitogenic cascade and G0-G1 phase transition that results in cell proliferation and anti-apoptosis. In addition, the GEFs -induced activation of Rho family GTPases (Rho , Rac and CDC42  (Cell Division Cycle-42)) activate their downstream effectors, which are either kinases such as MEK 1/2 and PI3K  (Phosphatidylinositol-3-Kinase) that further enhance ERKs -Elk1 and Akt (v-Akt Murine Thymoma Viral Oncogene Homolog)-NF-KappaB (Nuclear Factor-KappaB) mediated transcription process. NF-KappaB  controls VEGF  (Vascular Endothelial Growth Factor), MMP (Matrix Metalloproteinase), Bcl2  (B-Cell CLL/Lymphoma-2), BclXL  (Bcl2 Related Protein Long Isoform), CcnD1  (Cyclin-D1), COX2  (Cyclooxygenase-2) and Survivin  gene transcription to regulate tumor growth, tissue invasion and anti-apoptosis. During PanIN-2 and PanIN-3 stages, EGFR signaling plays important role and its aberrant expression enhance tumor growth, invasion and motility. After ligand binding, EGFR dimerizes, either as a homodimer or heterodimer with other members of the EGFR family like  Her2 (Ref.3 & 4). EGFR is then auto-phosphorylated or trans-phosphorylated at specific tyrosine residues for its activation, resulting in the activation of multiple downstream signaling cascades, including PI3K -Akt -HSP90 (Heat Shock Protein-90KD), and the Notch1  (Notch Homolog-1) pathway, ultimately leading to increased cellular proliferation and prevention of programmed cell death through NF-KappaB  activation (Ref.5).

Under normal physiological conditions, activation of EGFR/ErbB (v-ErbB Avian Erythroblastic Leukemia Viral Oncogene Homolog) receptors is controlled by spatial and temporal expression of their ligands in the pancreas, like TGF-Alpha  (Transforming Growth Factor-Alpha), HBEGF  (Heparin-Binding EGF) and EGF  (Epidermal Growth Factor). There are at least 16 different EGF family ligands that bind ErbB receptors. Alterations in these receptors influence NF-KappaB-mediated gene transcription and the crosstalk between EGFR/ Her2Notch1  and NF-KappaB  pathways are key regulators of cellular events, such as proliferation and apoptosis. Therefore, inactivation of EGFR- and Notch1-mediated cell growth inhibition and induction of apoptosis by ERRP (EGFR-Related Protein) may be partly mediated via inactivation of NF-KappaB  activity (Ref.3 & 6). For signal propagation, the cytoplasmic domains of EGFR/ Her2 receptor are also associated with JAKs (Janus Kinases). Activation of JAKs occurs upon ligand-mediated receptor multimerization as two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs . This phosphotyrosine permits the dimerization of STATs through interaction with a conserved SH2 domain. Phosphorylated STATs then enter the nucleus and subsequently control the G0-G1 phase transition. Apart from these alcohol metabolized by CYP2E1 (Cytochrome P450 Family-2 Subfamily-E Polypeptide-1) results in generation of ROS (Reactive Oxygen Species), 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 leads to the formation of DNA adduct and initiation of pancreatic carcinogenesis. Novel avenues by which EGFRs can be inactivated may represent a promising strategy for the development of novel and selective anti-cancer therapies (Ref.7).

Further manifestations of pancreatic tissue pseudostratifications and papillary foldings and eventual progression to pancreatic adenocarcinoma and metastasis occur mainly due to inactivation of TGF-Beta  (Transforming Growth Factor-Beta)/TGF-BetaRs , p53SMAD4  (Sma and MAD (Mothers Against Decapentaplegic) Related Protein-4)/DPC4 (Deleted in Pancreatic Carcinoma-4) and BRCA2  (Breast Cancer-2) genes. TGF-Beta  signaling acts as a tumor suppressor in normal cells and at early stages of carcinogenesis, whereas it switches into a tumor promoter during tumor progression. The growth inhibitory effects of TGF-Beta  are frequently mediated through the induction of CKIs (CDK (Cyclin Dependent Kinase) Inhibitors) like p15(INK4B); p21(CIP1); p27(KIP1) and down regulation of CDKs and Cyclins like CcnD, CcnECDK2  and CDK4. These along with other CKIs like p16(INK4A), p18(INK4C) and p19(INK4D) are critical for the regulated progression through the cell cycle and therefore maintain the Rb  (Retinoblastoma) protein in the hypophosphorylated state, which prevents the transcription factor E2F (E2F Transcription Factor) from inducing the aberrant expression of genes required for G1-S phase transition. DPC4/SMAD4 tumor suppressor gene along with SMAD2/3 and E2Fs plays a critical role in signal transduction through the TGF-Beta  superfamily of cell surface receptors. They may act through p15(INK4B) to inhibit CDK4  interaction with CcnD1  and inactivation of this gene promotes progression from the G1-S restriction. TGF-Beta  expression is therefore considered as a positive prognostic factor in pancreatic adenocarcinoma (Ref.8 & 9). The INK4 family of CKIs comprises of multiple gene products which repress cell cycle progression at G1-S phase. Loss of these gene products then favors cell cycle progression at G1-S. p16(INK4A), which is altered in a significant percentage of human tumors inhibits the interaction of CcnD1  with CDK4. This CcnD1-CDK4 complex phosphorylates Rb  preventing the formation of E2F-Rb complex. This phosphorylation step frees E2F to act as a transcription factor with the resultant progression of the cell cycle to S phase. Loss of p16(INK4A) activity results in the elimination of these inhibitory effects at the level of CcnD1-CDK4 interaction, thereby promoting cell cycle progression. Loss or decreased activity of p16(INK4A) occur through a variety of mechanisms but mainly through homozygous deletion at this locus. In some tumors point mutations in the p16(INK4A) coding sequence are more frequent than deletions while in some, inactivation of the p16(INK4A) promoter by methylation are common (Ref.10).

A second INK4 family member closely linked to p16(INK4A), is p15(INK4B), located 30 kb downstream from the p16(INK4A) gene and is deleted in most tumors with p16(INK4A) deletions. p15(INK4B) is up-regulated by TGF-Beta and inhibits the formation of activated CDK4  in the same manner as p16(INK4A). Another putative tumor suppressor gene is imbedded in the p16(INK4A) locus, p14(ARF), derives in part from an alternate reading frame in the p16(INK4A) gene. It utilizes the same second exon as p16(INK4A) with a separate first exon and promoter. p14(ARF) is therefore inactivated in all tumors with p16(INK4A) gene deletions and in many but not all tumors with p16(INK4A) point mutations. The biologic significance of the unusual genetic organization of the p16(INK4A) locus is unclear. p14(ARF) binds to the MDM2  (Mouse Double Minute-2) protein and thereby inhibit its interaction with DNA damage induced-p53. Normally, MDM2  regulates p53  by binding to it and accelerating its degradation and blocking its effects on gene transcription. Over expression and/or gene amplification of MDM2  in some types of tumors (but not in pancreatic adenocarcinoma) results in functional loss of normal p53  function and a transformed phenotype. Loss of p14(ARF) then mimics the effects of MDM2  over-expression by permitting MDM2  to freely interact with p53  and down regulating it. Consequently, most homozygous deletions at this locus result in the coordinate loss of three gene products involved in regulating the G1-S checkpoint with potentially synergistic facilitation of cell cycle progression. No other single genetic target has the potential to result in this number of genetic alterations, targeting and single cellular pathway. Similarly, the human tumor suppressor p53  gene mutations are common in pancreatic adenocarcinoma and serve a critical role at the G1-S phase transition by blocking cell entry into S phase in response DNA damage (may be mainly due generation of ROS as a result of heavy alcohol intake or smokimg). The p53  gene has been proposed to exert an inhibitory effect on CDK4  directly and indirectly through p21(CIP1) (Ref.10 & 11). Wild-type p53  is also necessary for the efficient activation of apoptosis in sensitive cells in response to DNA damage, a mechanism counteracted by the tumor suppressor gene, BRCA2. Germline BRCA2  gene mutations therefore lead to sporadic pancreatic carcinomas. BRCA2  mutations are generally characterized by ‘allelic’ or ‘phenotypic’ heterogeneity (Ref.12).

Pancreatic cancer is considered an ‘orphan’ cancer because of its relative low incidence and is intimately related to processes like digestion and absorption. Numerous inherited germ line mutations are associated with pancreatic cancer, yet despite the many germ line mutations now known to cause pancreatic cancer, only about ten percent or less of pancreatic cancers are caused by an inherited disorder. Although anti-inflammatory drugs (NSAIDS) and Aspirin are known to reduce the risk of several malignant and non-malignant pancreatic diseases, still pancreatic cancer remains as one of the deadliest tumors with long-term survival rates close to zero in all regions of the world. Efforts to prevent pancreatic cancer must emphasize on alcohol and smoking cessation. An additional measure which may be effective is avoiding obesity, either by dietary measures or by a combination of diet and exercise (Ref.13).