Establishment of a postsurgical micro-metastasis model of breast cancer and development of new postsurgical adjuvant therapies

乳腺癌术后微转移模型的建立及新型术后辅助治疗的开发

• 批准号: 08671401
• 负责人: KUREBAYASHI Junichi
• 金额: $ 1.47万
• 依托单位: KAWASAKI MEDICAL SCHOOL
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671401/
• 关键词: Breast cancer; Metastasis; Angiogenesis; Growth factor; Cell line; Cytokine; Hormone; Postsurgical adjuvant therapy; 悪液質; 微少転移; ヌードマウス; 腫瘍切除; UFT; 骨転移; 微小転移

We have established a new postsurgical micrometastasis model of breast cancer using the MKL-4 cell line, which is a transfectant of MCF-7 human breast cancer cell line with fibroblast growth factor (FGF)-4 and bacterial IacZ.Removal of transplanted umors from nude mice at the time of occurrence of micrometastasis significantly enhanced the progression of micrometastasis in either lymph nodes or distant organs. Postsurgical administration of uracil and tegafur (UFT) significantly inhibited the progression. This is the first demonstration of the effectiveness of postsurgical administration of a 5-fluorouracil derivative for preventing the progression of micrometastasis of breast cancer.We have also established three new human breast cancer cell lines (KPL-1, KPL-3C and KPL-4) from patients with recurrent breast cancer. Several interesting findings have been found using these cell lines. Overexpression of FGF-l or vascular endothelial growth factor (VEGF)-B may induce hormone-independence of the KPL-1 cells. We have been involved in the study of hormonal ceguJation of the expression of FGF family members and VEGF family members in breast cancer cells. Several hormones differentially regulate the expression of parathyroid hormone-related protein (PTHrP) and interleukin-6, both of which are known to induce osteolytic bone metastasis. Either estrogen or a progestin, medroxyprogesterone acetate (MPA) decreased PTHrP expression but antiestrogens increased it in KPL-3C cells. MPA significantly decreased IL-6 expression of KIPL-4 cells both in vitro and in vivo. These translational research may contribute to understanding of breast cancer cell biology as well as to the development of new strategies against recurrent breast cancer.

我们利用MKL-4细胞系建立了一种新的乳腺癌术后微转移模型。MKL-4细胞系是转成纤维细胞生长因子4和细菌IacZ的MCF-7人乳腺癌细胞系，在微转移发生时切除裸鼠移植瘤显著促进了淋巴结或远处器官的微转移的进展。术后给予尿嘧啶和替加氟(UFT)显著抑制病情进展。这是首次证明术后应用5-氟尿嘧啶衍生物预防乳腺癌微转移的有效性。我们还从复发乳腺癌患者中建立了三个新的人乳腺癌细胞系(KPL-1，KPL-3C和KPL-4)。使用这些细胞系发现了几个有趣的发现。过表达成纤维细胞生长因子-L或血管内皮生长因子-B可诱导Kpl-1细胞激素非依赖性。我们一直致力于研究激素对乳腺癌细胞中成纤维细胞生长因子家族成员和血管内皮生长因子家族成员表达的影响。几种激素对甲状旁腺激素相关蛋白(PTHrP)和白介素6的表达有不同的调节作用，这两种激素都能诱导溶骨性骨转移。无论是雌激素还是孕激素，甲羟孕酮(MPA)均可降低KPL-3C细胞PTHrP的表达，而抗雌激素可增加其表达。在体内外，甲孕酮均能显著降低KIPL-4细胞IL-6的表达。这些翻译研究可能有助于理解乳腺癌细胞生物学，并有助于开发新的治疗复发乳腺癌的策略。

项目成果

紅林 淳一他: "Erb B familyを高発現する乳癌細胞株KPL-4の樹立とヒト型抗Erb B-2 monoclonal抗体による増殖抑制の検討." 乳癌の臨床. 12(4). 644-645 (1997)

Junichi Kubayashi 等人：“高表达 Erb B 家族的乳腺癌细胞系 KPL-4 的建立以及人抗 Erb B-2 单克隆抗体的生长抑制研究”12(4)。 645（1997）

紅林 淳一: "最新・乳癌の診断と治療" 永井出版, 54 (1997)

久林纯一：《乳腺癌的最新诊断和治疗》永井出版，54（1997）

Kurebayashi, J., et al.: "Establishment of a new human breast cancer cell line, KPL-4, expressing Erb B family receptors and the antiproliferative effect of a humanized anti-Erb B-2 antibody." Japanese Journal of Breast Cancer. 12(4). 644-645 (1997)

Kurebayashi, J. 等人：“表达 Erb B 家族受体的新人类乳腺癌细胞系 KPL-4 的建立以及人源化抗 Erb B-2 抗体的抗增殖作用。”

Kurebayashi, J., et al.: "Medroxyprogesterone acetate directly decreases interleukin-6 secretion from KPL-4 human breast cancer cells in vitro and in vivo." Proceedings of American Association for Cancer Research. 39. 113 (1998)

Kurebayashi, J. 等人：“醋酸甲羟孕酮在体外和体内均可直接降低 KPL-4 人乳腺癌细胞的白细胞介素 6 分泌。”

Kurebayashi, J. , et al.: "Inhibition of progression of micrometastasis by oral administration of UFT in a new postsurgical metastasis model using MKL-4 human breast cancer cells." Proceeding of American Society of Clinical Oncology. 15. 497 (1996)

Kurebayashi, J. 等人：“在使用 MKL-4 人乳腺癌细胞的新术后转移模型中，通过口服 UFT 抑制微转移的进展。”