To identify genetic events that characterize cancer progression, we conducted a comprehensive genetic evaluation of 161 primary breast tumors. Similar to the ''mountain-and-hill'' view of mutations, gene amplification also shows high-and low-frequency alterations in breast cancers. The frequently amplified genes include the well-known oncogenes ERBB2, FGFR1, MYC, CCND1, and PIK3CA, whereas other known oncogenes that are amplified, although less frequently, include CCND2, EGFR, FGFR2, and NOTCH3. More importantly, by honing in on minimally amplified regions containing three or fewer genes, we identified six new amplified genes: POLD3, IRAK4, IRX2, TBL1XR1, ASPH, and BRD4. We found that both the IRX2 and TBL1XR1 proteins showed higher expression in the malignant cell lines MCF10CA1h and MCF10CA1a than in their precursor, MCF10A, a normal immortalized mammary epithelial cell line. To study oncogenic roles of TBL1XR1, we performed knockdown experiments using a short hairpin RNA approach and found that depletion of TBL1XR1 in MCF10CA1h cells resulted in reduction of cell migration and invasion as well as suppression of tumorigenesis in mouse xenografts. Intriguingly, our mutation analysis showed the presence of activation mutations in the PIK3CA gene in a subset of tumors that also had DNA copy number increases in the PIK3CA locus, suggesting an additive effect of coexisting activating amino acid substitution and dosage increase from amplification. Our gene amplification and somatic mutation analysis of breast primary tumors provides a coherent picture of genetic events, both corroborating and novel, offering insight into the genetic underpinnings of breast cancer progression. [Cancer Res 2009;69(18):7357-65]
BackgroundAdequate blood supply for the reconstructed organ is important for safe esophagogastric anastomosis during esophagectomy. Recently, indocyanine green (ICG) has been used for visualization of the blood supply when anastomosis is performed in vascular surgery. To visualize the blood supply for reconstruction, we employed ICG fluorescence during esophagectomy.MethodsFrom August 2008, 40 patients received cervical or thoracic esophagectomy. They consisted of 33 patients having esophagectomy for thoracic esophageal cancer, 3 being treated for cervical esophageal cancer, and 4 with double cancer of the thoracic and cervical regions. Before and after pulling up the reconstructed organ, 2.5 mg of ICG was injected as a bolus. Then ICG fluorescence was detected by a camera and recorded.ResultsICG fluorescence was easily detected in all patients at 1 min after injection. The vascular network was well visualized in the gastric wall, colonic grafts, and free jejunal grafts. In five patients, we also performed anastomosis between the short gastric vein and the external cervical vein or superficial cervical vein. The intraoperative and postoperative course of all patients was uneventful apart from three anastomotic leakages.ConclusionsICG fluorescence can be employed to evaluate the blood supply to reconstructed organs and can be useful in selecting the patients who do not need additional vessel anastomosis. However, anastomotic leakage was not reduced, so the microcirculation detected by ICG fluorescence did not necessarily provide appropriate blood supply for a viable anastomosis.
Strong expression of NANOG is an indicator of a poor prognosis for breast cancer patients, whereas KLF4 is a favorable prognostic indicator. Our results suggest that NANOG stimulates the growth and metastasis of breast cancer cells, whereas KLF4 inhibits these processes.
Abstract. Colorectal cancer is a major cause of cancer-related mortality worldwide, with a high incidence of recurrence following curative resection, particularly among patients with stage II and III disease. There is therefore a need for novel prognostic biomarkers for advanced colon cancer and it was recently reported that aquaporin-1 (AQP1) may be associated with aggressive characteristics of colon cancer cells in experimental data. The association of clinicopathological findings with AQP1 expression was evaluated by tissue microarray (TMA) analysis, to determine whether AQP1 is a prognostic biomarker for colon cancer. A total of 120 consecutive stage II and III colon cancer patients (51 with stage II and 69 with stage III) who underwent curative resection between 1997 and 2008 were analyzed. The TMA was prepared from archival formalin-fixed, paraffin-embedded tissue blocks. Immunostaining was graded semi-quantitatively by considering the staining intensity and the percentage of positive tumor cells. Results showed the AQP1-positive rate to be 35.8%. The expression of AQP1 was associated with lymph node metastasis, lymphovascular and vascular invasion. The 5-year survival rate of the AQP1-positive and -negative groups was 73.7 and 87.9%, respectively. The survival rate of the positive group was significantly lower compared to that of the negative group (P=0.030). Furthermore, the expression of AQP1 was an independent poor prognostic factor according to the multivariate analysis. Therefore, AQP1 may be a promising candidate as a prognostic biomarker for colon cancer.
T-cell receptor (TCR) gene therapy is a promising next-generation antitumor treatment. We previously developed a single-T-cell analysis protocol that allows the rapid capture of paired TCRα and β cDNAs. Here, we applied the protocol to analyze the TCR repertoire of tumor-infiltrating lymphocytes (TIL) of various cancer patients. We found clonally expanded populations of T cells that expressed the same clonotypic TCR in 50% to 70% of CD137CD8 TILs, indicating that they responded to certain antigens in the tumor environment. To assess the tumor reactivity of the TCRs derived from those clonally expanded TILs in detail, we then analyzed the CD137CD8 TILs from the tumor of B16F10 melanoma cells in six C57BL/6 mice and analyzed their TCR repertoire. We also found clonally expanded T cells in 60% to 90% of CD137CD8 TILs. When the tumor reactivity of dominant clonotypic TCRs in each mouse was analyzed, 9 of 13 TCRs induced the secretion of IFNγ in response to, and showed killing of, B16F10 cells , and 2 of them showed strong antitumor activity Concerning their antigen specificity, 7 of them reacted to p15E peptide of endogenous murine leukemia virus-derived envelope glycoprotein 70, and the rest reacted to tumor-associated antigens expressed on EL4 lymphoma as well as B16 melanoma cells. These results show that our strategy enables us to simply and rapidly obtain the tumor-specific TCR repertoire with high fidelity in an antigen- and MHC haplotype-independent manner from primary TILs. .
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