Development and biological analysis of peritoneal metastasis mouse models for human scirrhous stomach cancer

Yanagihara, Kazuyoshi; Takigahira, Misato; Tanaka, Hiromi; Komatsu, Teruo; Fukumoto, Hisao; Koizumi, Fumiaki; Nishio, Kazuto; Ochiya, Takahiro; Ino, Yoshinori; Hirohashi, Setsuo

doi:10.1111/j.1349-7006.2005.00054.x

Cited by 102 publications

(136 citation statements)

References 37 publications

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“…Indeed, Paclitaxel and CPT-11 have been demonstrated to exhibit a growth-inhibitory effect and survival benefit in this model, 17 but gefitinib did not in preliminary result (data not shown). The positive results with ZD6474 in our present study suggest that this agent may be clinically useful in gastric cancer.…”

Section: Discussionmentioning

confidence: 87%

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ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model

Arao

Yanagihara²,

Takigahira³

et al. 2006

Int. J. Cancer

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Angiogenesis inhibitors have been used to treat some cancers, but the therapeutic potential of these agents for gastric cancer has remained unclear. To investigate their therapeutic potential, we examined the effect of ZD6474, an agent that selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2; KDR) tyrosine kinase and epidermal growth factor receptor (EGFR) tyrosine kinase, in a highly metastatic orthotopic model using an undifferentiated gastric cancer cell line, 58As1. ZD6474 (100 mg/ kg/day, p.o., 2 weeks) significantly inhibited tumor growth (p < 0.05 vs. control) and reduced tumor dissemination into the peritoneal cavity (p < 0.05 vs. control). In addition, to identify putative tumor biomarkers that would reflect the effects of ZD6474 treatment in clinical settings, we examined the gene expression profiles of implanted gastric tumors treated with ZD6474 in vivo. Twentyeight candidate genes were identified, including IGFBP-3, ADM, ANGPTL4, PLOD2, DSIPI, NDRG1, ENO2, HIG2 and BNIP3L, which are known to be hypoxia-inducible genes. These genes and gene products may be useful biomarkers for monitoring the effects of ZD6474 treatment. ZD6474 also improved the survival of mice with implanted another undifferentiated gastric cancer cell line, 44As3. In conclusion, our results suggest that ZD6474 may have clinical activity against gastric cancer, particularly undifferentiated gastric cancer with peritoneal dissemination. We also identified putative biomarkers for monitoring the pharmacodynamic effects of ZD6474 by gene expression profiling. ' 2005 Wiley-Liss, Inc.Key words: ZD6474; gastric cancer; intraperitoneal dissemination; VEGF; oligonucleotide microarray Various anti-cancer agents have been examined for efficacy against gastric cancer over the past two decades, but the median survival time of patients remains around 7 months, 1,2 and the prognosis of gastric cancer patients remains poor. Peritoneal dissemination is common in patients with unresectable gastrointestinal cancer, and many suffer from peritoneal carcinomatosis in the terminal stage. Because undifferentiated gastric cancer is particularly invasive and often accompanied by peritoneal dissemination, 3 a new treatment strategy is needed.Vascular endothelial growth factor (VEGF) is a key mediator of tumor growth and is known to have multiple functions in angiogenesis, vascular permeability, and the regulation of endothelial cell proliferation and migration. 4-6 VEGF receptors (VEGFR) are activated by ligand stimulation with VEGF and commonly expressed in vascular endothelial cells. VEGFR-2 (KDR/Flk-1) is thought to be important for angiogenesis. 7 Because the VEGF-VEGFR system plays a key role in angiogenesis and tumor growth in vivo, the therapeutic potential of many agents targeting this system is being investigated. 8 A recent study has shown that a combination of monoclonal antibody against VEGF and chemotherapy produces a clinically meaningful survival benefit for patients with metastatic colorectal cancer, 5 and these result...

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Section: Discussionmentioning

confidence: 87%

“…16,17 58As1 and 44As3 and human non-small cell lung cancer cell line PC-9 were maintained in RPMI-1640 medium (Sigma, St. Louis, MO) supplemented with 10% heat-inactivated FBS (Gibco BRL, Grand Island, NY). The PC-9 cells were a gift of Tokyo Medical University.…”

Section: Cell Culturesmentioning

confidence: 99%

ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model

Arao

Yanagihara²,

Takigahira³

et al. 2006

Int. J. Cancer

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“…In this way, a metastatic cell line (58As9) with a strong capacity for inducing ascites and strong peritoneal dissemination properties was successfully isolated [14]. All of the cells were cultured in RPMI 1640 supplemented with 10% FBS [13,14].…”

Section: Cancer Cellsmentioning

confidence: 99%

“…58As9 cells (1.5×10 6 cells) were orthotopically inoculated into the stomach wall of 6-week-old BALB/c nude mice (Japan SLC) as described previously [14].…”

Section: Anti-metastasis Therapymentioning

confidence: 99%

“…Recently, we identified various miRNAs [12] associated with peritoneal dissemination using our orthotopic inoculation models [13,14]. In subsequent studies, we used our two established parent cell lines (HSC-44PE and HSC-58) from individual scirrhous gastric cancer patients [13], and further isolated two clones (44As3 and 58As9) with a highly metastatic character [14] from the corresponding parental cells.…”

Section: Introductionmentioning

confidence: 99%

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The microRNA miR-516a-3p regulates the Wnt pathway by targeting extracellular sulfatase 1 in human scirrhous gastric cancers: Anti-metastatic therapy via miRNA-based medicine

Takei

Suzuki

Mihara

et al. 2017

MRAJ

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The microRNA miR-516a-3p regulates the Wnt pathway by targeting extracellular sulfatase 1 in human scirrhous gastric cancers: Anti-metastatic therapy via miRNA-based medicine Copyright 2017 KEI Journals. All Rights Reserved Page │2 AbstractThe mechanism and function of cancer metastasis-associated microRNAs (miRNAs) have not been completely examined. Using a miRNA array, we previously determined that a significantly decreased level of miR-516a-3p was closely associated with the peritoneal dissemination of scirrhous gastric cancers. We previously established HSC-58 cells from a scirrhous gastric cancer patient, and we further isolated metastatic cells (58As9) from ascites in nude mice upon repeated orthotopic transplantation of HSC-58. In our previous report (Takei Y, et al. Cancer Res, 2011), we showed that the miR-516a-3p expression was significantly low and the peritoneal dissemination was significantly high in 58As9 compared with HSC-58. To augment the decreased expression of miR-516a-3p in 58As9 cells, we successfully prepared a cell line (58As9-miR-516a-3p) that stably overexpressed the miRNA. In the present study, we showed that orthotopic transplantation of 58As9-miR-516a-3p into nude mice resulted in significantly decreased primary tumor growth, ascites, and peritoneal dissemination. Moreover, the transplanted nude mice showed long survival time, probably due to the small amount of ascitic fluids pooled. The miRNA directly targeted sulfatase 1, which works to remove a sulfate group from heparan sulfate proteoglycans on the cell surface, and promotes the release of membrane-bound Wnt ligands into medium. Significantly increased concentrations of Wnt3a, Wnt5a, and nuclear-accumulated -catenin were observed in 58As9 cells, and in 58As9-miR-516a-3p, all of the levels were attenuated. Anti-metastatic therapy via injection of the miR-516a-3p expression vector/atelocollagen mixture into 58As9 orthotopic tumors in nude mice resulted in significantly prolonged survival along with the inhibition of ascites and peritoneal dissemination. Our findings thus indicate that the miR-516a-3p-sulfatase 1-Wnt -catenin route can be targeted to block the peritoneal dissemination of scirrhous gastric cancers.

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Cancer‐associated fibroblasts educate normal fibroblasts to facilitate cancer cell spreading and T‐cell suppression

et al. 2021

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In some tumors, a small number of cancer cells are scattered in a large fibrotic stroma. Here, we demonstrate a novel mechanism for expansion of pro-tumor fibroblasts via cancer-associated fibroblast (CAF)-mediated education of normal fibroblasts (NFs). When NFs were incubated with conditioned medium from CAFs, the resulting CAF-educated fibroblasts (CEFs) generated reactive oxygen species (ROS), which induced NF-B-mediated expression of inflammatory cytokines and the extracellular matrix protein asporin (ASPN), while expression of a common CAF marker gene, -SMA, was not increased. ASPN further increased CEF expression of downstream molecules, including indoleamine 2,3-dioxygenase 1 (IDO-1), kynureninase (KYNU) and pregnancy-associated plasma protein-A (PAPP-A). These CEFs induce cytocidal effects against CD8 + T cells and IGF-I activation in cancer cells. CEFs were generated without cancer cells by the direct mixture of NFs and CAFs in mouse xenografts and, once CEFs were generated, they sequentially educated NFs, leading to continuous generation of CEFs.In diffuse-type gastric cancers, ASPN high /IDO-1 high /KYNU high /-SMA -CEFs were located at the distal invading front. These CEFs expanded in the fibrotic stroma and caused dissemination of cancer cells. ASPN may therefore be a key molecule in facilitating tumor spreading and T cell suppression.

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Development and biological analysis of peritoneal metastasis mouse models for human scirrhous stomach cancer

Cited by 102 publications

References 37 publications

ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model

ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model

The microRNA miR-516a-3p regulates the Wnt pathway by targeting extracellular sulfatase 1 in human scirrhous gastric cancers: Anti-metastatic therapy via miRNA-based medicine

Cancer‐associated fibroblasts educate normal fibroblasts to facilitate cancer cell spreading and T‐cell suppression

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