HER2 overexpression has been linked to clinical outcomes in several solid tumors, such as breast cancer. However, the correlation between HER2 overexpression and survival in pancreatic carcinoma remains unclear. The impact of HER2 overexpression on survival in pancreatic ductal cancer was examined. Immunohistochemical staining of 129 pancreatic cancers without hematogenous metastases or peritoneal dissemination treated by macroscopically curative resection were analyzed in association with survival data. To determine HER2 overexpression in this pancreatic cancer series, the polyclonal antibody included in HercepTest, which is used worldwide for clinical examination of HER2 overexpression in breast cancer, was used. Immunoreactivity was classified according to the scale presented in the HercepTest Scoring Guidelines. Twenty-two cases (17.1%) had a score of 0, 28 cases (21.7%) had of a score of 1+, 41 cases (31.8%) had a score of 2+, and 38 cases (29.4%) had a score of 3+. Therefore, HER2 overexpression (score 2+ or 3+) was observed in 79 cases (61.2%). Patients with HER2 overexpression tumors had significantly shorter survival times than those with HER2 normal expression (score 0 or 1+) tumors (median survival time, 14.7 vs 20.7 months, respectively; P = 0.0078 on the logrank test). On multivariate survival analysis, HER2 overexpression remained an independent prognostic factor (hazard ratio, 1.806; P = 0.0258). A significant percentage of pancreatic cancers were demonstrated to have HER2 overexpression, and overexpression of this tyrosine kinase receptor proved to be an independent factor for a worse prognosis. These results should encourage further investigation of treatments using new molecular targeting agents against HER2 protein to improve the survival of pancreatic cancer patients. (Cancer Sci 2009; 100: 1243-1247) T he HER2 gene, known as ErbB-2/neu, is located on the long arm of chromosome 17 (17q12-21.32) and encodes the 185-kDa transmembrane tyrosine kinase receptor.(1) HER2 is recognized as a member of the epidermal growth factor receptor family of transmembrane receptors encoded by erbB1 (HER1 or EGFR), erbB3 (HER3), and erbB4 (HER4).(2) EGFR is the coreceptor for the formation of dimers with HER2. After a ligand binds to a single-chain EGFR, the receptor forms a dimer with HER2 that signals within the cell by activating receptor autophosphorylation through tyrosine kinase activity.(2) These dimers play a role in tumor cell proliferation, survival, adhesion, and migration. Many studies have demonstrated that HER2 overexpression is correlated with aggressiveness in breast, (4)(5)(6)(7)(8) lung, (9) and gastric carcinomas.(10,11) However, investigations correlating HER2 overexpression with survival in pancreatic carcinoma have been very limited. (12)(13)(14) The objective of this study was to examine the impact of HER2 overexpression on the survival of patients with pancreatic ductal carcinoma. Materials and MethodsPatients. Pancreatic cancer tissue samples were obtained from 129 patients who underwent...
Lapatinib is a small molecule inhibitor of both HER2 and the epidermal growth factor receptor (EGFR). We investigated the effect of treatment with lapatinib alone or in combination with a fluoropyrimidine derivative S-1 against pancreatic cancer. The HER2/EGFR expression in each of the four pancreatic cancer cell lines MiaPaca-2, PANC-1, Capan-1 and Capan-2 was measured by flow cytometry. The anti-tumor effects of lapatinib (30 mg/kg) and/or S-1 (10 mg/kg) were evaluated using female BALB/c nude mice xenografts generated using these four cell lines. Synergy between lapatinib and S-1 was examined by median effect analysis in vitro. Resected pancreatic cancer tissues from 137 patients were immunohistochemically stained with anti-human HER2 and EGFR antibodies. The administration of lapatinib as a single agent substantially suppressed tumor growth in vivo of all pancreatic cancer cell lines examined. A strong correlation was observed between HER2 expression and the anti-tumor effect of lapatinib in vivo. Lapatinib synergized with S-1 to inhibit the tumor growth of MiaPaca-2 and PANC-1 xenografts. When used as a single agent in vitro, lapatinib barely inhibit the cell growth of any cell line. However, lapatinib synergized with the anti-tumor activity of the S-1 components 5-fluorouracil and 5-chloro-2,4-dihydrogenase against all cell lines. Immunohistochemical staining demonstrated that 70% of the pancreatic cancers overexpressed HER2 and/or EGFR. Both lapatinib monotherapy and combined treatment with S-1 may be promising treatments for patients with pancreatic cancers; the majority these cancers express lapatinib target molecules. (Cancer Sci 2010; 101: 468-473) Pancreatic cancer is the fifth leading cause of cancer death in men and the sixth in women in Japan, and the disease population is similar to that in the USA and Europe. In Japan, the resectability rate of pancreatic cancer is approximately 40% and therefore, the majority of pancreatic cancers are unresectable. Despite recent advances in therapeutic strategies for pancreatic cancer, the 5-year survival rate of International Union against Cancer (UICC) stage IV pancreatic cancer is only 4.0%. (1) Chemotherapy of locally advanced or metastatic pancreatic cancer by intravenous administration of gemcitabine (GEM) modestly improves patient survival compared to treatment with continuous venous infusion of 5-fluorouracil (5-FU), as the median survival time (MST) is 5.65 versus 4.41 months, respectively. (2) To date, two regimens that include GEM have been proved to result in a higher survival rate than GEM alone in phase III studies. One of these regimens is GEM together with erlotinib, an agent whose molecular target is the epidermal growth factor receptor (EGFR) (MST 6.24 vs 5.91 months for GEM alone). (3) The second regimen is GEM together with capecitabine, an oral fluoropyrimidine that is enzymatically converted to 5-FU within the tumor (MST 8.4 vs 7.2 months for GEM alone). (4) In Japan, the oral fluorouracil derivative S-1 has been clinically used for pa...
Vertebrate lens tissues contain several species of acidic and neutral glycosphingolipids in relatively high amounts. However, the epithelia with capsule from dog and rhesus monkey lenses had a simpler composition and lower content of glycosphingolipids than whole lenses. Gangliosides and neutral glycosphingolipids in monolayer cultures of lens epithelial cells were also different from those in whole lenses. Although alpha-galactosyl (Gal alpha 1-3Gal-R) or Lewis(x) (Gal beta 1-4[Fuc alpha 1-3]GlcNAc-R) epitopes were found in glycosphingolipids from whole lenses, they were not detected in those from monolayer cultures of dog and rhesus monkey lens cells. In addition, significant changes in ganglio-series gangliosides were induced in monolayer cultures of both cells, where GM3 and GD3 were predominant. Immunofluorescence study revealed a characteristic distribution of cell surface gangliosides in confluent monolayers. These findings suggest that glycosphingolipid synthesis in lens epithelia is intrinsically different from that in cortical and nuclear fibres, and that the expression of Lewis(x) and alpha-galactosyl epitopes in glycosphingolipids appears to be associated with the differentiation of epithelial cells to fibres.
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