Role of S128R polymorphism of E‐selectin in colon metastasis formation

Abstract

The extravasation of cancer cells is a key step of the metastatic cascade. Polymorphisms in genes encoding adhesion molecules can facilitate metastasis by increasing the strength of interaction between tumor and endothelial cells as well as impacting other properties of cancer cells. We investigated the Ser128Arg (a561c at the nucleotide level) polymorphism in the E-selectin gene in patients with metastatic colon cancer and its functional significance. Genotyping for a561c polymorphism was performed on 172 cancer patients and on an age-matched control population. The colon cancer group was divided into groups with (M 1 ) and without observable metastasis (M 2 ). For in vitro functional assays, Huvec transfected cells expressing wild-type (WT) or the S128R variant of E-selectin were established to study in vitro binding ability and signal transduction processes of T84 colon cancer cell line. Our results demonstrated that the Arginine 128 allele was more prevalent in the M 1 group than in the M 2 group or normal controls (p < 0.005; odds ratio, 1.56; 95% confidence interval (CI) 1.16-1.92; p < 0.001, odds ratio 5 1.65; CI 5 1.24-1.99, respectively). In vitro, S128R E-selectin transfected Huvec cells, supported increased adhesion as well as increased cellular signaling of T84 cancer cells compared to WT E-selectin and mock-transfected Huvec cells. These findings suggest that the E-selectin S128R polymorphism can functionally affect tumor-endothelial interactions as well as motility and signaling properties of neoplastic cells that may modulate the metastatic phenotype. ' 2007 Wiley-Liss, Inc.Key words: E-selectin; colon cancer; genetic polymorphisms; metastasis; cell signaling Metastasis is the main cause of death for cancer patients. Metastatic dissemination is a complex process, depending on the ability of malignant cells to escape from the primary tumor, penetrate and flow through the bloodstream, adhere to the vascular bed and then invade and proliferate in the organ parenchyma.1 Interactions of blood-borne carcinoma cells and the microvasculature are essential prerequisites for metastasis to occur. These processes involve mechanical contact and transient attachment, which are mediated by endothelial surface adhesion molecules and their ligands on the neoplastic cells.2 Factors mediating these interactions are therefore viewed as important determinants of the metastatic phenotype. Among the molecules mediating tumor-endothelium interactions are selectins. [3][4][5][6][7] The selectins are a small family of intercellular adhesion molecules with 3 members: E-, P-and Lselectin. They share a mosaic structure consisting of an amino-terminal domain followed by an epidermal growth factor (EGF)-like domain, a variable number of complement regulatory repeats, a transmembrane domain and a short cytoplasmic domain. E-selectin (ELAM-1) is expressed by endothelial cells, which are activated by cytokines released during the inflammatory process and plays an important role in neutrophil extravasation into injured tissues as w...

Analysis of E‐Selectin S128R gene polymorphism in pancreatic cancer

“…The most compelling evidence for the role of E‐selectin polymorphism in malignancy comes from previous genotype and allele frequencies' studies showing that this specific polymorphism is associated with the susceptibility to metastasis formation in colon cancer 26, 27. In the current study, we attempted to determine whether an association exists between this E‐selectin gene variant and pancreatic cancer.…”

“…In general, genetic polymorphisms in leukocyte‐ and endothelial‐cell‐adhesion molecules have been defined and studied extensively in diseases with multifactorial etiology, such as premature coronary artery disease, non‐insulin‐dependent diabetes mellitus, and atherosclerosis 14, 16, 19–25. The role of S128R polymorphism of E‐selectin has been studied in colon cancers, but no information is currently available on pancreatic cancer 26, 27.…”

Role of ICAM-1 and E-selectin gene polymorphisms in pathogenesis of PAOD in Egyptian patients

“…The S 128 R polymorphism of the E-selectin gene is of interest for two reasons: first, it is overrepresented in certain patient groups affected by disease that is characterized by an increased adhesiveness of leukocytes to the endothelium; such as atherosclerosis and myocardial infarction and secondly, it is a functional polymorphism since it modifies ligand affinity 5,6. This mutation confers an alteration in selectin ligand-binding specificity which leads to a gain of function under flow conditions, possibly amplifying the number of leukocytes that roll and subsequently adhere to the endothelium 7.…”

E-selectin gene (S128R) polymorphism in hemorrhagic stroke: Comparison with ischemic stroke

“…On analysing the genotypic differences of ischemic stroke and hemorrhagic stroke in the study population, we found significant difference between AC genotype (p = 0.01) and C allele (p = 0.001) between the two stroke types. The S128R functional polymorphism is known to be overrepresented in certain patient groups and leads to amplification in the number of leukocytes adhering to the endothelium [17,18,31]. Such activated endothelial cells support more rolling of neutrophils and mononuclear cells when compared with cells transduced with wild type E-selectin [35].…”

“…This makes the cytokine inducible cell surface glycoprotein E-selectin, an attractive gene to study variation in inflammatory responses and its severity associated with stroke. The E-selectin (S128R) polymorphism is of major interest because it is a functional polymorphism, which modifies ligand affinity and also causes increased adhesiveness of leukocytes to the endothelium in atherosclerosis and myocardial infarction [17,18].…”