Development of a mouse model for lymph node metastasis with endometrial cancer

Takahashi, Kayoko; Saga, Yasushi; Mizukami, Hiroaki; Takei, Yuji; Urabe, Masashi; Kume, Akihiro; Suzuki, Mitsuaki; Ozawa, Keiya

doi:10.1111/j.1349-7006.2011.02099.x

Cited by 13 publications

(22 citation statements)

References 16 publications

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“…The VEGF‐C in culture supernatant is thought to be derived from HEC1A cells, and accumulated during cell culture. In fact, we demonstrated various but similar concentrations of VEGF‐C in tumor cell culture supernatant . In contrast, soluble VEGFR3 was demonstrated specifically to the cells transduced by sVEGFR3 gene, as shown in the Results section.…”

Section: Discussionsupporting

confidence: 58%

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Suppression of lymph node and lung metastases of endometrial cancer by muscle‐mediated expression of soluble vascular endothelial growth factor receptor‐3

Takahashi

Mizukami²,

Saga

et al. 2013

Cancer Science

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Lymph node metastasis is the most important prognostic factor of endometrial cancer. However, effective therapy has not been established against lymph node metastasis. In this study, we explored the efficacy of gene therapy targeting lymph node metastasis of endometrial cancer by suppressing the action of vascular endothelial growth factor (VEGF)-C through soluble VEGF receptor-3 (sVEGFR-3) expression. For this purpose, we first conducted a model experiment by introducing sVEGFR-3 cDNA into an endometrial cancer cell line HEC1A and established HEC1A ⁄ sVEGFR-3 cell line with high sVEGFR-3 expression. The conditioned medium of HEC1A ⁄ sVEGFR-3 cells inhibited lymphatic endothelial cell growth in vitro, and sVEGFR-3 expression in HEC1A cells suppressed in vivo lymph node and lung metastases without inhibiting the growth of a subcutaneously inoculated tumor. To validate the therapeutic efficacy, adeno-associated virus vectors encoding sVEGFR-3 were injected into the skeletal muscle of mice with lymph node metastasis. Lymph node and lung metastases of HEC1A cells were completely suppressed by the muscle-mediated expression of sVEG-FR-3 using adeno-associated virus vectors. These results suggest the possibility of gene therapy against lymph node and lung metastases of endometrial cancer by using muscle-mediated expression of

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Section: Discussionsupporting

confidence: 58%

“…HEC1A cells (5 × 10 6 ) were injected into the uterine cavities of pentobarbital sodium‐anesthetized, laparotomized mice, as described previously . At the same time AAV1‐hfIX or AAV1‐sVEGFR‐3 vector (2.5 × 10 12 genome copy) was injected into the hind‐limb skeletal muscles of the mice.…”

Section: Methodsmentioning

confidence: 99%

Suppression of lymph node and lung metastases of endometrial cancer by muscle‐mediated expression of soluble vascular endothelial growth factor receptor‐3

Takahashi

Mizukami²,

Saga

et al. 2013

Cancer Science

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“…For example, establishment of a mouse model of EC with lymph node metastasis via 5 million HEC1A cells required eight weeks [8]. Of note, 100% of the animals in the present study developed EC with RLN metastasis, which was greater than that observed using the HEC1A mouse model of 86.5% [8]. …”

Section: Discussionmentioning

confidence: 70%

“…Further studies will evaluate the VEGF-c protein levels, as well as markers of epithelial-mesenchymal transition (EMT), in tissues as well as serum samples using immunohistochemistry and enzyme-linked immunosorbent assays (ELISAs). In addition, although previous studies have reported a relationship between VEGF-c and lymphangiogenesis with metastasis [6-8], no mechanistic data were presented in this study. Finally, VEGF receptor expression was not determined.…”

Section: Discussionmentioning

confidence: 77%

“…VEGF-c influences endothelial cell growth, migration and survival; its signaling is medicated by the VEGF receptors-2 and -3 (VEGFR-2 and VEGFR-3) on the surface of endothelial cells [6]. VEGF-c also regulates lymphangiogenesis and promotes metastasis to lymph nodes as well as distant organs [6-8]. Because preoperative VEGF-c levels correlated with tumor stage and were an independent risk factor for survival in patients with certain types of EC [9], circulating VEGF-c levels may be useful as a prognostic tool to identify those EC patients most at risk for RLN metastasis.…”

Section: Introductionmentioning

confidence: 99%

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VEGF-c expression in an in vivo model of orthotopic endometrial cancer and retroperitoneal lymph node metastasis

Huang

Luo

et al. 2013

Reprod Biol Endocrinol

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BackgroundRetroperitoneal lymph node (RLN) metastasis is an important indicator of endometrial cancer (EC) prognosis. Because vascular endothelial growth factor c (VEGF-c) is known to influence lymphangiogenesis and thereby lymph node metastasis, this study assessed the relationship of VEGF-c mRNA expression with RLN metastasis in EC.MethodsThe uterine muscularis mucosae of New Zealand white rabbits were inoculated with a VX2 tumor cell suspension after which they were sacrificed at 15, 18, 21, 24, 27 and 30 days. Control groups consisted of those receiving no treatment or an injection of saline. EC and metastatic RLN tissues along with peripheral blood samples were collected, and VEGF-c mRNA expression was evaluated using fluorescence real-time quantitative PCR.ResultsThe establishment of an in vivo model of EC with complete RLN metastasis was pathologically confirmed at day 21 post-injection with VX2 cells. As compared to the control groups, VEGF-c mRNA expression increased significantly over time in the tumor site, RLN, and peripheral white blood cells of EC rabbits. Significantly higher VEGF-c mRNA expression was observed in metastatic RLNs as compared to those without metastasis (P < 0.001). In addition, increased VEGF-c mRNA expression was observed in peripheral white blood cells of rabbits with RLN metastasis (P < 0.002).ConclusionInjection of a VX2 cell suspension is a simple method of establishing an in vivo EC model. VEGF-c may play an important role in the development of EC and its metastasis to RLN and may be useful marker to predict RLN metastasis.

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Rapamycin inhibits the invasive ability of thyroid cancer cells by down‐regulating the expression of VEGF‐C in vitro

Feng

Song

2012

Cell Biochemistry & Function

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The aim of this study was to observe the effects of rapamycin on proliferation, apoptosis and invasion of SW579 in vitro. The proliferation and apoptosis of SW579 cells were detected by methyl thiazolyl tetrazolium and flow cytometry. Transwell assay was used to observe the changes of invasive ability of SW579 cells after being treated with rapamycin. The effects of rapamycin on the expression of mammalian target of rapamycin (mTOR) signalling and vascular endothelial growth factor C (VEGF-C) were observed by Western blot. The inhibition and apoptosis rates increased obviously when the concentration of rapamycin was 20 nm. When the rapamycin concentration was 10 nm, the invasive ability of SW579 cells changed significantly than when it was 5 nm. Our data showed that when the concentrations of rapamycin were over 20 nm, the expression of mTOR and p70S6K decreased significantly, and the expression of PTEN increased notably. There were no remarkable variations observed when we detected the expression of Akt. We found the expression of VEGF-C was high in SW579 cells and decreased slightly when the cells were treated with 5 nm rapamycin. When the concentration of rapamycin was over 5 nm, significant changes were observed. Rapamycin could inhibit the proliferation and induce the apoptosis of human thyroid cancer cells in vitro by mTOR inhibition. No obvious changes observed in the expression of AKT indicated that there might be a feedback loop effect by the mTOR inhibition induced by rapamycin. Rapamycin could inhibit the invasive ability of SW579 cells by down-regulating the expression of VEGF-C.

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Development of a mouse model for lymph node metastasis with endometrial cancer

Cited by 13 publications

References 16 publications

Suppression of lymph node and lung metastases of endometrial cancer by muscle‐mediated expression of soluble vascular endothelial growth factor receptor‐3

Suppression of lymph node and lung metastases of endometrial cancer by muscle‐mediated expression of soluble vascular endothelial growth factor receptor‐3

VEGF-c expression in an in vivo model of orthotopic endometrial cancer and retroperitoneal lymph node metastasis

Rapamycin inhibits the invasive ability of thyroid cancer cells by down‐regulating the expression of VEGF‐C in vitro

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