Thymidine Phosphorylase (dThdPase) is the rate-tissues expressed high levels of DPD (median >70 U/mg limiting enzyme that metabolizes 5'-deoxy-5-fluorouridine protein), while high concentrations of the dThdPase were (5'-dFUrd, doxifluridine), an intermediate metabolite of expressed in esophageal, cervical, breast, and pancreatic capecitabine, to the active drug 5-fluorouracil (5-FUra), while cancers and hepatoma (median >150 U/mg protein). The dihydropyrimidine dehydrogenase (DPD) catabolizes 5-FUra dThdPase/DPD ratio, which was reported to correlate with to an inactive molecule. The susceptibility of tumors to the susceptibility of human cancer xenografts to capecitabine, fluoropyrimidines is reported to correlate with tumor levels was high in esophageal, renal, breast, colorectal, and gastric of these enzymes. To obtain some insight into the tumor cancers (median ratio of > 1.5). In any of these three parameters, types susceptible to fluoropyrimidine therapy, we measured the inter-patient DPD variability for each cancer type was expression levels of these two enzymes in various types of much larger than the DPD variability among cancer types; human cancer tissues (241 tissue samples) by the ELISA highest/lowest ratios for dThdPase, DPD, and dThdPase/DPD methods. DPD exists in all the cancer types studied, such were 10-321, 7-513, and 2-293, respectively. These results as bladder, breast, cervical, colorectal, esophageal, gastric, indicate that measurements of the three parameters, DPD, hepatic, pancreatic, prostate, and renal cancers. Among them, dThdPase and dThdPase/DPD, would be useful criteria for the cervical, hepatic, pancreatic, esophageal, and breast cancer selecting cancer patients suitable for fluoropyrimidine therapy rather than for selecting cancer types.
The current study was conducted to identify robust methylation markers and their combinations that may prove useful for the diagnosis of early hepatocellular carcinoma (HCC). To achieve this, we performed in silico CpG mapping, direct sequencing and pyrosequencing after bisulfite treatment, and quantitative methylation-specific PCR (MSP) in HCC and non-HCC liver tissues. In the filtering group (25 HCCs), our direct sequencing analysis showed that, among the 12 methylation genes listed by in silico CpG mapping, 7 genes (RASSF1A, CCND2, SPINT2, RUNX3, GSTP1, APC and CFTR) were aberrantly methylated in stages I and II HCCs. In the validation group (20 pairs of HCCs and the corresponding non-tumor liver tissues), pyrosequencing analysis confirmed that the 7 genes were aberrantly and strongly methylated in early HCCs, but not in any of the corresponding nontumor liver tissues (p < 0.00001). The results obtained using our novel quantitative MSP assay correlated well with those observed using the pyrosequencing analysis. Notably, in MSP assay, RASSF1A showed the most robust performance for the discrimination of HCC and non-HCC liver tissues. Furthermore, a combination of RASSF1A, CCND2 and SPINT2 showed 89-95% sensitivity, 91-100% specificity and 89-97% accuracy in discriminating between HCC and non-HCC tissues, and correctly diagnosed all early HCCs. These results indicate that the combination of these 3 genes may aid in the accurate diagnosis of early HCC. ' 2009 UICC
To clarify the genetic aberrations involved in the development and progression of hepatitis C virus-associated hepatocellular carcinoma (HCV-HCC), we investigated DNA copy number aberrations (DCNAs) in 19 surgically resected HCCs by conventional CGH and array CGH. Conventional CGH revealed that increases of DNA copy number were frequent at 1q (79% of the cases), 8q (37%), 6p (32%), and 10p (32%) and that decreases were frequent at 17p (79%), 16q (58%), 4q (53%), 13q (42%), 10q (37%), 1p (32%), and 8p (32%). In general, genes that showed DCNAs by array CGH were usually located in chromosomal regions with DCNAs detected by conventional CGH analysis. Increases in copy numbers of the LAMC2, TGFB2, and AKT3 genes (located on 1q) and decreases in copy numbers of FGR/SRC2 and CYLD (located on 1p and 16q, respectively) were observed in more than 30% of tumors, including small, well-differentiated carcinomas. These findings suggest that these genes are associated with the development of HCV-HCC. Increases of MOS, MYC, EXT1, and PTK2 (located on 8q) were detected exclusively in moderately and poorly differentiated tumors, suggesting that these alterations contribute to tumor progression. In conclusion, chromosomal and array CGH technologies allow identification of genes involved in the development and progression of HCV-HCC.
Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad array of cell membrane molecules on a liver-metastasizing subline of B16 melanoma versus the parental B16-F0 revealed unique up-regulation of integrin α2. The direct role of integrin α2 in hepatic metastasis was shown by comparison of high versus low-expressing populations, antibody blockade, and ectopic expression. Integrin α2–mediated binding to collagen type IV (highly exposed in the liver sinusoids) and collagen type IV–dependent activation of focal adhesion kinase are both known to be important in the metastatic process. Analysis of primary colorectal cancers as well as coexisting liver and lung metastases from individual patients suggests that integrin α2 expression contributes to liver metastasis in human colorectal cancer. These findings define integrin α2 as a molecule conferring selective potential for formation of hepatic metastasis, as well as a possible target to prevent their formation.
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