Establishment and characterization of three novel human gastric cancer cell lines with differentiated intestinal phenotype derived from liver metastasis
Establishment and characterization of three novel human gastric cancer cell lines with differentiated intestinal phenotype derived from liver metastasis
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DOI：
10.1007/s10585-005-6526-z
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发表时间：
2005-01-01
影响因子：
4
通讯作者：
Tatematsu, M
中科院分区：
文献类型：
--
作者：
Nakanishi, H;Yasui, K;Tatematsu, M
胃癌肝转移是致命的疾病，进展迅速，患者预后较差。然而，迄今为止，其生长和转移的分子基础仍然基本上未知，这主要是因为从肝转移建立的可用胃癌细胞系很少。在本研究中，我们开发了两种新型培养细胞系（指定为 GLM-1 和 GLM-2）和一种来自胃癌患者肝转移的裸鼠移植细胞系（指定为 GLM-3）。这些 GLM 细胞系具有独特的生物学特征，例如分化、生长和转移。当注射到裸鼠体内时，它们会形成具有CD10阳性和MUC2阴性肠道吸收表型的中度分化肿瘤。与其他胃癌细胞系一样，它们的生长在体外受到 EGF 和 TGF-α 的刺激。然而，GLM 细胞与传统胃癌细胞系的不同之处在于，即使在没有凋亡诱导刺激的情况下，GLM 细胞也具有高凋亡率，如 Caspase3/7 测定和 TUNEL 方法所示。磷脂酰肌醇 3 激酶 (PI3K) 抑制剂 (LY294002) 可进一步增强这种细胞凋亡，但 MEK1/2 抑制剂 (U0126) 不会增强这种细胞凋亡，表明它们的存活强烈依赖于 PI3K/Akt 通路，而不是 EGFR 主要下游信号通路 MAPK 通路。 GLM-1细胞脾内注射后可转移至肝脏，GLM-3细胞皮下移植后具有自发性肺转移潜力。这些结果表明GLM系列是第一个反映肠型分化腺癌的细胞系，肠型分化腺癌是伴有肝转移的胃癌的主要亚型。因此，它们将成为了解转移生长机制和开发新的胃癌肝转移分子靶向治疗的绝佳模型。
Gastric cancers with liver metastasis are fatal diseases with rapid progression and poor patient outcome. To date, however, the molecular basis of their growth and metastasis remains essentially unknown, largely because of the presence of few available gastric cancer cell lines established from liver metastasis. In the present study, we developed two novel cultured cell lines (designated GLM-1 and GLM-2) and one transplantable line in nude mice (designated GLM-3) derived from liver metastasis of gastric cancer patients. These GLM cell lines share unique biological features such as differentiation, growth and metastasis. They form moderately differentiated tumors with CD10 positive and MUC2 negative intestinal absorptive phenotype when injected into nude mice. Their growth is stimulated by EGF and TGF-alpha in vitro like other gastric cancer cell lines. However, GLM cells differ from conventional gastric cancer cell lines in their high apoptotic rate, even in the absence of apoptosis inducing stimuli as revealed by Caspase3/7 assay and the TUNEL method. This apoptosis is further enhanced by phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), but not by MEK1/2 inhibitor (U0126), indicating the strong dependency of their survival on PI3K/Akt pathway rather than MAPK pathway, the major downstream signaling pathways of EGFR. GLM-1 cells can metastasize to the liver after intrasplenic injection, and GLM-3 cells have spontaneous lung metastatic potential after subcutaneous transplantation, respectively. These results indicate that the GLM series are the first cell lines reflecting the intestinal-type differentiated adenocarcinoma, a major subtype of gastric cancer with liver metastasis. Therefore, they would be excellent models for understanding the mechanism of metastatic growth and the development of a new molecular targeting therapy for gastric cancer with liver metastasis.