Enhanced L1CAM expression on pancreatic tumor endothelium mediates selective tumor cell transmigration.

L1 cell adhesion molecule (L1CAM) is a transmembrane cell adhesion molecule initially defined as a promigratory molecule in the developing nervous system that appears to be also expressed in some endothelial cells. However, little is known about the functional role of L1CAM on endothelial cells. We observed that L1CAM expression was selectively enhanced on endothelium associated with pancreatic adenocarcinoma in situ and on cultured pancreatic tumor-derived endothelial cells in vitro. L1CAM expression of endothelial cells could be augmented by incubation with immunomodulatory cytokines such as tumor necrosis factor alpha, interferon gamma, or transforming growth factor beta 1. Antibodies to L1CAM and the respective ligand neuropilin-1 blocked tube formation and stromal cell-derived factor 1beta induced transmigration of tumor endothelial cells in vitro. L1CAM expression on tumor-derived-endothelial cells enhanced Panc1 carcinoma cell adhesion to endothelial cell monolayers and transendothelial migration. Our data demonstrate a functional role of L1CAM expression on tumor endothelium that could favor metastasis and angiogenesis during tumor progression.

Detection of disseminated tumor cells in liver biopsies of colorectal cancer patients is not associated with a worse prognosis.

BACKGROUND: Liver metastases occur frequently in colorectal cancer and are probably caused by disseminated tumor cells having been trapped in the liver. The prognostic significance of hematogenous tumor cell dissemination has already been demonstrated for blood and bone marrow of patients with colorectal cancer. The aim of this study was to investigate the frequency and prognostic significance of disseminated tumor cells in liver biopsies of colorectal cancer patients. METHODS: Liver biopsies from 100 patients with UICC stage I-III colorectal cancer were taken prospectively during resection of the primary tumor. Liver biopsies obtained from 16 patients with benign gastrointestinal diseases served as negative controls. Liver samples from seven patients with liver cirrhosis were additionally taken. Liver biopsies were examined using a reverse transcriptase (RT)-PCR assay to amplify cytokeratin (CK) 20 transcripts. The median follow-up of the patients was 55 months. RESULTS: Disseminated tumor cells were detected in liver samples of 10/100 (10%) patients with UICC stage I-III colorectal cancer. Liver specimens from all seven patients with liver cirrhosis were CK 20-positive, whereas 16 patients with other benign gastrointestinal diseases were all CK 20-negative. There was no correlation between tumor cell detection in liver biopsies and survival of the patients. The only significant prognostic factor on uni- and multivariate analysis was the UICC stage. CONCLUSIONS: This study demonstrates that detection of disseminated tumor cells in liver samples from patients with UICC stage I-III colorectal cancer has no prognostic influence. UICC classification was the strongest prognostic factor in this patient series.

Expression of cytokeratin-20 in pancreatic cancer: an indicator of poor outcome after R0 resection.

BACKGROUND: After complete removal of the neoplasm (R0 resection), approximately 80% of pancreatic cancer patients will die of the disease within 5 years. The expression panel of cytokeratins (CK) is linked closely with cell differentiation. The aim of the study was to investigate the expression of CK-20 in pancreatic cancer tissue and to correlate CK-20 expression with survival in R0-resected pancreatic cancer patients. METHODS: Tissue samples of 63 patients with pancreatic cancer were subjected to CK-20 reverse-transcription polymerase chain reaction. Thirty-four of 63 patients underwent R0 resection and were followed-up for survival statistics. From these 34 patients, 26 (76%) neoplasms were CK-20 positive and 8 (24%) samples were CK-20 negative. The mean follow-up period for the entire group was 17 months (range, 4-36 mo), the follow-up period in censored patients was 23 months (range, 10-36 mo). RESULTS: In the R0-resected group, 3 of 8 (38%) patients with CK-20-negative neoplasms, and 16 of 26 (62%) patients with CK-20-positive neoplasms (P = .15) died of recurrent disease. The median survival time of patients with CK-20-positive neoplasms was 13 months (range, 4-36), the median survival in R0-resected patients with CK-20-negative neoplasm was 26 months (range, 13-35; P = .06). The survival difference observed in patients with CK-20-negative neoplasms could not be attributed to intergroup variations in tumor stage or tumor grade. CONCLUSIONS: A majority of primary ductal pancreatic adenocarcinomas express CK-20. This seems to be associated with poorer survival in R0-resected patients. Our data suggest that ductal pancreatic adenocarcinomas negative for CK-20 constitute a subgroup of patients showing a more favorable disease outcome. The expression of CK-20 in resected pancreatic cancer may be of interest as a prognostic parameter.

Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver.

ATP binding cassette (ABC)-transporters like P-glycoprotein (multidrug resistance (MDR)1/ABCB1), the multidrug resistance associated proteins 1 and 2 (MRP1/ABCC1 and MRP2/ABCC2), and the breast cancer resistance protein (BCRP/ABCG2) have a large impact on the pharmacokinetics of numerous drugs and may also modulate the effectiveness of drug therapy. Prediction of a patient's susceptibility to xenobiotics and individualization of drug therapy would become possible, if a simple test were available for an easy screening of transporter expression. This study quantified the mRNA expression of the four ABC-transporters and of the pregnane X receptor (PXR), a key regulator in drug metabolism and efflux, in peripheral blood mononuclear cells (PBMCs), and corresponding liver or small intestine samples of humans by real-time reverse transcription-polymerase chain reaction (RT-PCR). The results obtained prove the absence of a correlation between the expression of four major ABC-transporters in PBMCs and in the intestine or liver. For all transporters (except MRP1/ABCC1 in the intestine), mRNA amount of the ABC-transporters was positively correlated with PXR expression in PBMCs and intestine. In conclusion, the study suggests that basal expression levels of the transporters are directly influenced by PXR expression in liver and PBMCs and demonstrates that PBMCs do not qualify as surrogate tissue for the expression of the four ABC-transporters in small intestine and liver. However, the transporter status in PBMCs remains important for drugs, whose primary site of therapeutic action is the lymphocyte and which are known substrates of the transporters.

Detection and prognostic relevance of cytokeratin 20 in differentiated and anaplastic thyroid carcinomas by RT-PCR.

BACKGROUND: Metastatic disease in epithelial cancer results from tumor cell dissemination. We investigated an expression of cytokeratin 20 (CK20) by reverse transcriptase-polymerase chain reaction (RT-PCR) in differentiated (DTC) and anaplastic thyroid carcinomas (ATC) and correlated the results with TNM categories and the clinical follow-up. METHODS: Tissue and blood samples of 32 patients with papillary (PTC), 17 patients with follicular (FTC), and 7 patients with ATC were obtained during operation and subjected to CK20 RT-PCR. RESULTS: An expression of CK20 transcripts was detected in 47% of the tissue samples of PTC, 71% of the FTC, and 14% of the ATC. Patients with CK20-positive FTC had a significantly better outcome than patients with CK20-negative FTCs (P=.0016). Disseminated tumor cells were found in 9 of 22 (41%) blood samples of patients with CK20-positive carcinomas. The detection of CK20 transcripts in peripheral blood correlated with tumor categories. Four of 8 (50%) patients with DTC and circulating tumor cells developed local or distant recurrence compared with 3 of 13 (23%) patients with CK20-positive carcinomas and CK20-negative blood samples. CONCLUSION: Our results suggest that CK20 might be a suitable differentiation marker in thyroid carcinomas. In patients with CK20-positive tumors, those with CK20-positive blood samples had a poorer prognosis. We suggest that patients with thyroid cancer with positive CK20 blood samples should be evaluated for further adjuvant therapies after surgery.