There is a need to establish animal models which are suitable for investigation of human gastric cancer metastasis to the liver. To this end, a human gastric carcinoma line, AZ521 was injected into the spleens of nude mice. Cells from the few liver metastatic foci of injected AZ521 were expanded in vitro and subsequently injected into the spleens of nude mice. By repeating these procedures three times, we were able to obtain a cell line, designated as AZ‐M3c, with high metastatic potential in nude mice. Liver metastasis developed in 15 of 21 (71%) animals injected with AZ‐H3c, but in only 14% of those injected with parental AZ521. Further, AZ‐H3c caused faster tumor development than did AZ521. However, the primary AZ‐H3c tumors and liver metastatic AZ‐H3c tumors showed essentially the same histological appearance. We also analyzed the cell surface expression of adhesion molecules. The data showed that the expression of VLA‐1, VLA‐2, VLA‐3, VLA‐4, VLA‐5 was enhanced in AZ‐H3c. In contrast, the expression of VLA‐6, αvβ3, E‐cadherin, ICAM‐1 and LFA‐1 was reduced in this high‐metastatic line. These results suggest that β1 mtegrins play an important role in the liver metastasis of human gastric carcinoma cells. Our high‐metastatic line should be useful for studies aimed at the prevention of liver metastasis.
This report describes a giant peritoneal loose body in the pelvic cavity. A 63-year-old man who was asymptomatic underwent a routine medical examination, which revealed a tumor in the pelvic space. Computed tomography and magnetic resonance imaging showed a smooth-surfaced mass with two marked calcifications in the central position. Preoperatively, we suspected a calcified leiomyoma originating from the wall of the sigmoid colon; however, at laparoscopic surgery we extracted a hard, egg-shaped mass 5 cm in diameter, with detached appendices epiploicae. Histological examination revealed that this peritoneal loose body was made up of thick layers of fibrous tissue with a few cellular components, and necrotic fat tissue in the central position. Small peritoneal loose bodies are occasionally found during laparotomy or autopsy, but such a large one is very unusual.
Survivin is a member of the inhibitor of apoptosis protein (IAP) family containing a single baculovirus IAP repeat domain. It is expressed during fetal development but becomes undetectable in terminally differentiated normal adult tissues. We previously reported that survivin and its splicing variant survivin-2B was expressed abundantly in various types of tumor tissues as well as tumor cell lines and was suitable as a target antigen for active-specific anti-cancer immunization. Subsequently, we identified an HLA-A24-restricted antigenic peptide, survivin-2B80-88 (AYACNTSTL) recognized by CD8+ cytotoxic T lymphocytes (CTLs). We, therefore, started a phase I clinical study assessing the efficacy of survivin-2B peptide vaccination in patients with advanced or recurrent colorectal cancer expressing survivin. Vaccinations with survivin-2B peptide were given subcutaneously six times at 14-day intervals. Of 15 patients who finished receiving the vaccination schedule, three suffered slight toxicities, including anemia (grade 2), general malaise (grade 1), and fever (grade 1). No severe adverse events were observed in any patient. In 6 patients, tumor marker levels (CEA and CA19-9) decreased transiently during the period of vaccination. Slight reduction of the tumor volume was observed in one patient, which was considered a minor responder. No changes were noted in three patients while the remaining eleven patients experienced tumor progression. Analysis of peripheral blood lymphocytes of one patient using HLA-A24/peptide tetramers revealed an increase in peptide-specific CTL frequency from 0.09% to 0.35% of CD8+ T cells after 4 vaccinations. This phase I clinical study indicates that survivin-2B peptide-based vaccination is safe and should be further considered for potential immune and clinical efficacy in HLA-A24-expression patients with colorectal cancer.
BACKGROUND Despite the recent clinical finding that high telomerase activity is an unfavorable prognostic marker for various human malignant tumors, there has been no experimental evidence supporting the link between telomerase and tumor aggressiveness. In the current investigation, the authors examined the relation between telomerase activity and potential for biologic aggressiveness in human pancreatic carcinoma cells. METHODS Telomerase activity was measured in a poorly metastatic cell line HPC‐3 and its highly metastatic variant HPC‐3H4, as well as in many pancreatic carcinoma cell lines. Aggressive behavior of cancer cells was assessed by in vitro migration and invasion assay. RESULTS Compared with parental HPC‐3, HPC‐3H4 displayed higher telomerase activity, which was associated with a scattered phenotype and enhanced migration activity. Furthermore, the authors found that relative telomerase levels correlated well with both motility (P = 0.0041) and invasion (P = 0.0114) in 13 pancreatic carcinoma cell lines. There was, however, no significant association between telomerase activity and cell proliferation. When telomerase activity of KP‐1N cells was inhibited by transfection with antisense oligonucleotides, their motility and invasion rates were significantly decreased. CONCLUSIONS The authors concluded that the magnitude of telomerase activation may reflect the potential for aggressive behavior within cancer cells. These findings support the clinical utility of telomerase activity as a prognostic indicator. Their results also suggest a therapeutic potential for telomerase inhibitors to prevent tumor invasion and possibly metastasis. Cancer 2001;91:496–504. © 2001 American Cancer Society.
Liver metastasis is very often observed in human pancreatic carcinoma, which is the fifth leading cause of cancer death in Japan and the United States.1-3) To improve the 5-year survival rate of pancreatic carcinoma, more extensive surgery and combination chemotherapy [4][5][6] should be attempted to prevent lymph node metastasis and liver metastasis. In addition, there is a need for a new therapy to inhibit tumor-specific angiogenesis. The establishment of relevant animal metastatic models of pancreatic carcinoma is highly important in the search for the development of such new therapeutics for pancreatic carcinoma. We established cell lines, designated HPC-3H1, HPC-3H2, HPC-3H3 and HPC-3H4, with various metastatic potentials in the nude mouse liver by using intrasplenic injections of human pancreatic carcinoma line HPC-3 (manuscript in preparation).The growth of solid tumors is generally dependent on angiogenesis.7) This suggests that the process of micrometastasis, especially the growth of metastatic cells, is also dependent on angiogenesis at the metastatic site and that inhibition of angiogenesis may become an effective therapy for metastasis of solid tumors.O-(Chloroacetyl-carbamoyl) fumagillol (TNP-470), an analog of fumagillin derived from Aspergillus fumigatus, inhibits angiogenesis both in vivo and in vitro, regardless of the presence of angiogenesis factors. It is also less toxic than fumagillin.8) In addition, it has been reported that TNP-470 has an inhibitory effect on the growth and metastasis of human cell lines [9][10][11][12] and rodent tumors. 13) In this study, we investigated the effects of TNP-470 and cisplatin (CDDP), a chemotherapeutic agent, against human pancreatic carcinoma cell line HPC-3H4, which had the highest metastatic potential in the liver. MATERIALS AND METHODS
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