Immune target and Immune response in pancreatic cancer

Cancer is fundamentally a gene associated disease, it has become increasingly clear that some genomic instability and aberrant gene expression lead to biologic behaviour abnormality in tumor cells. In pancreatic cancer, Several genes have high mutation rate in different phase, so the tumor cell may express abnormal antigens that make them immunologically distinct and potential targets for the host immune system.

K-Ras: The mutation of K-ras oncogene (homologous to the ras gene of Kirsten murine sarcoma virus) occurs in 75-100% of pancreatic cancer(6). With the progression from minimally dysplasia epithelium(PanIN 1A, 1B) to more severe dysplasia(PanIN 2, 3) and invasive cancer(7), the mutation rate of K-ras oncogene is increaseing successively, denotes k-ras oncogene plays a very important role in tumor origination and progression®.

Picture 1. Associated genes in pancreatic cancer progression. from Paula Ghaneh, et al. Biology and management of pancreatic cancer. Gut 2007;56:1134-1152.

K-ras gene encodes a 21 kDa membrane-bound guanosine triphosphate(GTP) -binding protein. Before localization at cell membrane, K-ras protein must be farnesylated or geranylgeranylated on the same cysteine residue, it is involved in the transduction of signal from growth factor receptors and other signal inputs, as an upstream activator, it will activat several signaling pathways including Raf/MEK/ERK, P13K/Akt and RalEGF/Ral(9)to regulate gene expression and prevent apoptosis. The mutation of the K-ras oncogene, which occers mostly at codon 12 but also occasionally at codon 13 and 61, will lead to impaired GTPhosphatase(GTPase) activity, resulting in lock the protein locked in GTP-bound state and thus activating downstream signalling cascades(10). According to the META Analyse, point mutation occurred in codon 12 mainly divided into several types, the wild type GGT is replaced by GAT(47%), GTT(28%), CGT(15%), TGT(7%), AGT(2%) and GCT(1%). so in the protein, the 12th amino acid Guanine is replaced by Aspartic acid, Valine, Arginine, Cysteine, Alanine, Serine(11). The K-RAS function changes due to the abnormality in protein structure. The mutation also provide the epitope which might be the target in immunotherapy.

MUC1: Mucins are large glycoproteins with carbohydrate content and marked diversity both in the apoprotein and in the oligosaccharide moieties(12). MUC1 is a heavily glycosylated type I membrane protein with several extracellular tandem repeat domains, which is expressed by nearly all human glandular epithelial and its expression is limited to the apical membrane of the cells. In pancreatic cancer, MUC1 expression is upregulated with an expression pattern over the entire cell surface(13). The core peptide of MUC1 not only serves as a counter-receptor for myelin-associated glycoprotein in pancreatic cancer and is related to perineural invasion(14), but also block death receptor-mediated apoptosis by binding to caspase 8 and FADD(15). MUC1 molecular has sialic acid-containing oligosaccharides in a highly O-glycosylated tandem-repeat domain, the structure has wide range and a large molecular weight(16). Although the core protein of MUC1 is similar in both normal and tumor cells, there is a remarkable diversity in oligosaccharide moieties between normal and cancer cells(17).

Mesothelin: Mesothelin is a 40-kDa glycosyl phosphatidylinositol anchored cell surface protein and is a c-terminus menbrane-bound form of a 69-kDa precursor protein encoded by the Mesothelin gene(MSLN). Normally, mesothelin is only expressed on mesothelial cells which lining peritoneal, pleural and pericardial cavities(18). The biologic functions are not clearly understood. Some early studies have shown mesothelin playing role in tumor adhesion and dissemination(19). In pancreaticobiliary adenocarcinomas, the expression rate of mesotheline is 100%, whereas none in normal pancreas and chronic pancreatitis(20).

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