Japanese Journal of Cancer Research

1999

DOI: 10.1111/j.1349-7006.1999.tb00674.x

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Preventive Effect of Matrix Metalloproteinase Inhibitor, R‐94138, in Combination with Mitomycin C or Cisplatin on Peritoneal Dissemination of Human Gastric Cancer Cell Line TMK‐1 in Nude Mice

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Yoshihide Otani

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et al.

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Cited by 17 publications

(16 citation statements)

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“…2,15,27) We found that the motile activity of AZ-P7a cells in vitro was significantly stronger than that of AZ-521 cells and even than that of AZ-H5c cells (data not shown). A recent study revealed that lymphoid tissue (so-called milky spots) was found on the peritoneum and free cancer cells in the peritoneal cavity could infiltrate the peritoneum through this tissue in the early stages of peritoneal dissemination.…”

Section: Discussionmentioning

confidence: 88%

A Novel Experimental Mouse Model of Peritoneal Dissemination of Human Gastric Cancer Cells: Different Mechanisms in Peritoneal Dissemination and Hematogenous Metastasis

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et al. 2000

Japanese Journal of Cancer Research

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We established a new cell line, AZ-P7a, with high peritoneal-metastatic potential in nude mice. AZP7a cells were derived from the human gastric carcinoma line AZ-521, which has low capacity for peritoneal dissemination. AZ-P7a cells developed peritoneal metastasis in 11/14 (78.6%) mice, whereas the parental AZ-521 cells developed metastasis in 2/6 (33.3%) mice. The metastatic foci in the peritoneum showed essentially the same histological appearance as those induced by parental cells. The tumorigenicity and the motile activity of AZ-P7a cells were stronger than those of the parental AZ-521 cells; in contrast, adhesion to the extracellular matrix and the production of vascular endothelial growth factor by AZ-P7a cells were decreased. In fluorescence-activated cell sorter (FACS) analysis, AZ-P7a cells expressed significantly greater levels of integrins α α α α2, α α α α3, α α α α5, α α α α6 and α α α αvβ β β β5, as compared with AZ-521 cells. However, α α α α1, α α α α4, α α α αvβ β β β3, hCD44H, hCD44v3, hCD44v6 and hCD44v10 were not expressed in either cell line. AZ-P7a cells developed no liver metastasis when administered by the intrasplenic injection method, though the highly liver metastatic cell line AZ-H5c showed the same rate of peritoneal dissemination as that exhibited by AZP7a cells after intraabdominal injection. These findings suggested that the mechanism of peritoneal dissemination differed from that of hematogenous metastasis. Moreover, the latter appears to be controlled by more complex mechanisms than the former. Thus, this cell line might be useful for investigating the mechanism of peritoneal dissemination of human gastric cancer. Key words: Gastric carcinoma lines -Peritoneal dissemination model -Nude micePeritoneal dissemination is most frequently observed in human gastric cancer and is one of the most important causes of cancer deaths. Although some trials to prevent peritoneal dissemination of gastric cancer have been performed, 1) including chemotherapy, hyperthermia and peritonectomy, no effective prolongation of survival has been attained in most patients.2) The establishment of relevant animal models of metastasis is extremely important for the development of new therapeutic modalities for gastric cancer. To elucidate the molecular mechanisms of metastasis, several excellent hematogenous metastatic models have been established by intrasplenic injection [3][4][5] and the orthotopic implantation technique. [6][7][8] We also established and reported a highly liver metastatic cell line, AZ-H5c, derived from a human gastric cancer line, AZ-521. 9,10)

“…2,15,27) We found that the motile activity of AZ-P7a cells in vitro was significantly stronger than that of AZ-521 cells and even than that of AZ-H5c cells (data not shown). A recent study revealed that lymphoid tissue (so-called milky spots) was found on the peritoneum and free cancer cells in the peritoneal cavity could infiltrate the peritoneum through this tissue in the early stages of peritoneal dissemination.…”

Section: Discussionmentioning

confidence: 88%

A Novel Experimental Mouse Model of Peritoneal Dissemination of Human Gastric Cancer Cells: Different Mechanisms in Peritoneal Dissemination and Hematogenous Metastasis

¹

,

²

,

³

et al. 2000

Japanese Journal of Cancer Research

View full text Add to dashboard Cite

We established a new cell line, AZ-P7a, with high peritoneal-metastatic potential in nude mice. AZP7a cells were derived from the human gastric carcinoma line AZ-521, which has low capacity for peritoneal dissemination. AZ-P7a cells developed peritoneal metastasis in 11/14 (78.6%) mice, whereas the parental AZ-521 cells developed metastasis in 2/6 (33.3%) mice. The metastatic foci in the peritoneum showed essentially the same histological appearance as those induced by parental cells. The tumorigenicity and the motile activity of AZ-P7a cells were stronger than those of the parental AZ-521 cells; in contrast, adhesion to the extracellular matrix and the production of vascular endothelial growth factor by AZ-P7a cells were decreased. In fluorescence-activated cell sorter (FACS) analysis, AZ-P7a cells expressed significantly greater levels of integrins α α α α2, α α α α3, α α α α5, α α α α6 and α α α αvβ β β β5, as compared with AZ-521 cells. However, α α α α1, α α α α4, α α α αvβ β β β3, hCD44H, hCD44v3, hCD44v6 and hCD44v10 were not expressed in either cell line. AZ-P7a cells developed no liver metastasis when administered by the intrasplenic injection method, though the highly liver metastatic cell line AZ-H5c showed the same rate of peritoneal dissemination as that exhibited by AZP7a cells after intraabdominal injection. These findings suggested that the mechanism of peritoneal dissemination differed from that of hematogenous metastasis. Moreover, the latter appears to be controlled by more complex mechanisms than the former. Thus, this cell line might be useful for investigating the mechanism of peritoneal dissemination of human gastric cancer. Key words: Gastric carcinoma lines -Peritoneal dissemination model -Nude micePeritoneal dissemination is most frequently observed in human gastric cancer and is one of the most important causes of cancer deaths. Although some trials to prevent peritoneal dissemination of gastric cancer have been performed, 1) including chemotherapy, hyperthermia and peritonectomy, no effective prolongation of survival has been attained in most patients.2) The establishment of relevant animal models of metastasis is extremely important for the development of new therapeutic modalities for gastric cancer. To elucidate the molecular mechanisms of metastasis, several excellent hematogenous metastatic models have been established by intrasplenic injection [3][4][5] and the orthotopic implantation technique. [6][7][8] We also established and reported a highly liver metastatic cell line, AZ-H5c, derived from a human gastric cancer line, AZ-521. 9,10)

“…Since among the sequential steps of tumor metastasis, the adhesion of tumor cells to ECM is known to be critical, 3,17) we determined whether NUGC-3 and NUGC-3P4T could adhere to such ECMs as fibronectin, type IV collagen and laminin. As shown in Table II, the in vitro adhesive activity of NUGC-3P4T cells to laminin was higher than that of NUGC-3 cells ( * P<0.05), whereas, adhesive activity to fibronectin and type IV collagen showed little difference.…”

Section: Adhesion Activity In Vitromentioning

confidence: 99%

“…1) Although some trials to prevent peritoneal dissemination of gastric cancer have been performed, 2) including chemotherapy, hyperthermia and peritonectomy, no real prolongation of survival has been attained in most patients. 3) The establishment of relevant animal models of metastasis is extremely important to understand and design new therapeutic modalities for gastric cancer. To elucidate the biology of metastasis, several excellent metastatic models have been established by intrasplenic injection [4][5][6] and the orthotopic implantation technique.…”

mentioning

confidence: 99%

A Novel Experimental Mouse Model of Peritoneal Dissemination of Human Gastric Cancer Cells: Analysis of the Mechanism of Peritoneal Dissemination Using cDNA Macroarrays

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et al. 2001

Japanese Journal of Cancer Research

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We established a new cell line, NUGC-3P4T, with high peritoneal metastatic disseminating potential in nude mice. NUGC-3P4T cells were derived from the human gastric carcinoma line NUGC-3, which has low capacity for peritoneal dissemination. NUGC-3P4T cells developed peritoneal dissemination in 10/10 (100%) mice, whereas the parental NUGC-3 cells developed dissemination in 1/5 (20.0%) mice. The metastatic foci in the peritoneum showed essentially the same histological appearance as those induced by parental cells. The tumorigenicity, the motile activity and the adhesive activity to the laminin of NUGC-3P4T cells were stronger than those of NUGC-3 cells. Production of IL-8 was significantly higher in NUGC-3P4T than in NUGC-3. cDNA macroarrays analysis showed that a variety of cytokines, interleukins, and other immunomodulators and their receptors were up-or down-regulated at the mRNA level in NUGC-3P4T cells, compared with NUGC-3 cells. Thus, this unique cell line and in vivo model might be useful to study the biology of peritoneal dissemination of human gastric cancer.

“…Epidemiological studies have indicated that flavonoid ingestion is associated with a reduced risk of certain forms of cancer. 5) Nobiletin (5,6,7,8,3′, is a polymethoxyflavonoid extracted from Citrus depressa Hayata (Rutaceae), a popular citrus fruit in Okinawa, Japan. Nobiletin is known to inhibit proliferation of human cancer cells 6) and production of MMPs 7,8) in vitro.…”

mentioning

confidence: 99%

The Citrus Flavonoid, Nobiletin, Inhibits Peritoneal Dissemination of Human Gastric Carcinoma in SCID Mice

et al. 2001

Japanese Journal of Cancer Research

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The flavonoid nobiletin (5,6,7,8,3′ ′ ′ ′,4′ ′ ′ ′-hexamethoxyflavone), found in Citrus depressa Rutaceae, a popular citrus fruit in Okinawa, Japan, reportedly inhibits the production of pro-matrix metalloproteinase (proMMP)-1, 3, and 9 in rabbit synovial fibroblasts in vitro. In the present study, we demonstrated the inhibitory effects of nobiletin on the proliferation of the cancer cell line, TMK-1, and its production of MMPs. In the SCID mouse model, we found that nobiletin inhibited the formation of peritoneal dissemination nodules from TMK-1. The enzymatic activity of MMP-9 expressed in culture medium obtained from a co-culture of TMK-1 and mouse fibroblastic cells was inhibited by nobiletin in a concentration-dependent manner. In the SCID mouse model, total weight of dissemination nodules was significantly lower in the treated group compared with the vehicle control group (0.07 g vs. 0.78 g, P = = = =0.0059). The total number of dissemination nodules was also significantly lower than in the vehicle control group (7.5 vs. 69.3/body, P = = = =0.0001). These results suggest that nobiletin may be a candidate anti-metastatic drug for prevention of peritoneal dissemination of gastric cancer. Key words: Flavonoid -Nobiletin -Gastric cancer -Peritoneal dissemination -Matrix metalloproteinaseIn spite of the general decline in gastric cancer rates, this cancer remains one of the most important causes of death among Japanese people. In particular, peritoneal dissemination at the final stage of gastric cancer remains untreatable. Although several trials have attempted to control peritoneal dissemination of gastric cancer by chemotherapy and hyperthermia, no significant prolongation of survival was found. Peritoneal dissemination involves several steps, including tumor cell attachment, invasion and growth in the peritoneum. We investigated the role of matrix metalloproteinases (MMPs) in the invasion and metastasis of gastric cancer, and found a close relationship between MMPs expression and malignant potential of gastric cancer.1, 2) We postulated that an appropriate inhibitor of MMP could prevent peritoneal dissemination by controlling the initial steps, and demonstrated a preventive effect of the MMP inhibitor R-94138 in a peritoneal dissemination model using the human gastric cancer cell line TMK-1 in nude mice.3)The intake of citrus fruits is considered beneficial for health, and in a recent literature review of citrus flavonoids, a broad spectrum of biological activities including anti-carcinogenic and antitumor activities was discussed. It is commonly accepted that cancer formation can be prevented by the ingestion of certain foods, 4) and flavonoids in citrus fruits and juices are among the most prominent cancer-preventing agents. Epidemiological studies have indicated that flavonoid ingestion is associated with a reduced risk of certain forms of cancer. 5) Nobiletin (5,6,7,8,3′, is a polymethoxyflavonoid extracted from Citrus depressa Hayata (Rutaceae), a popular citrus fruit in Okinawa, Japan. Nobiletin is kn...

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