Tumorigenic conversion of primary human esophageal epithelial cells using oncogene combinations in the absence of exogenous Ras
Tumorigenic conversion of primary human esophageal epithelial cells using oncogene combinations in the absence of exogenous Ras
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DOI：
10.1158/0008-5472.can-06-2104
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发表时间：
2006-11-01
期刊：
影响因子：
11.2
通讯作者：
El-Deiry, Wafik S.
中科院分区：
文献类型：
--
作者：
Kim, Seok-Hyun;Nakagawa, Hiroshi;El-Deiry, Wafik S.
为了研究人食管鳞状细胞转化的途径，我们使用人端粒酶和SV 40永生化的原代食管上皮细胞（EPC 2）通过过表达选定的癌基因组合产生食管肿瘤细胞。H-Ras，c-Myc，或Akt，但不是表皮生长因子受体（EGFR），诱导转化的菌落在软琼脂。相比之下，遗传改变的永生化食管细胞的生物发光成像显示Akt、EGFR或H-Ras，而不是c-Myc，导致inummodeficient小鼠的肿瘤形成。H-Ras驱动的肿瘤表现出高度致瘤性表型，倍增时间为2.6 +/- 0.6天，而Akt和EGFR肿瘤分别每9.5 +/- 1.6和6.1 +/- 1.2天倍增。H-Ras驱动的肿瘤表达缺氧诱导因子靶Glut 1，而Akt或EGFR驱动的肿瘤有血管生成的证据，没有可检测到的Glat 1表达。这些肿瘤的增殖率相似，但在更具侵袭性的H-Ras驱动的肿瘤中，细胞凋亡减少，这些肿瘤也发生了非整倍体和多个中心体。c-Myc的过度表达并不导致肿瘤的转化，但是将Bcl-XL引入到表达c-Myc的细胞中会产生肿瘤。虽然细胞角蛋白的表达是典型的鳞状细胞癌，基因表达谱进行比较四种不同类型的工程tamors与人食管鳞状细胞癌和腺癌。有趣的是，c-Myc + Bcl-XL转化体模拟鳞状细胞癌，而H-Ras-、EGFR-和Akt-驱动的肿瘤在其分子谱中与腺癌相似。这些基因工程模型可能为了解人类食管癌提供新的平台，并可能有助于评估新的治疗方法。
To investigate pathways of human esophageal squamous cell transformation, we generated esophageal tumor cells using human telomerase- and SV40-immortalized primary esophageal epithelial cells (EPC2) by overexpression of selected combinations of oncogenes. H-Ras, c-Myc, or Akt, but not epidermal growth factor receptor (EGFR), induced transformed colonies in soft agar. By contrast, bioluminescence imaging of genetically altered immortalized esophageal cells revealed that Akt, EGFR, or H-Ras, but not c-Myc, resulted in tumor formation in inummodeficient mice. H-Ras-driven tumors showed highly tumorigenic phenotypes with 2.6 +/- 0.6 days for doubling, whereas Akt and EGFR tumors doubled every 9.5 +/- 1.6 and 6.1 +/- 1.2 days, respectively. H-Ras-driven tumors expressed the hypoxia-inducible factor target Glut1, whereas Akt- or EGFR-driven tumors had evidence of angiogenesis and no detectable Glat1 expression. Proliferation rates among these tumors were similar, but there was reduced apoptosis in the more aggressive H-Ras-driven tumors that also developed aneuploidy and multiple centrosomes. c-Myc overexpression did not result in tumorigemic conversion but introduction of Bcl-XL into c-Myc-expressing cells generated tumors. Although cytokeratin expression was typical of squamous carcinoma, gene expression profiling was done to compare the four different types of engineered tamors with human esophageal squamous cell carcinomas and adenocarcinomas. Interestingly, c-Myc plus Bcl-XL transformants mimicked squamous carcinomas, whereas H-Ras-, EGFR-, and Akt-driven tumors were similar to adenocarcinomas in their molecular profiles. These genetically engineered models may provide new platforms for understanding human esophagus cancer and may assist in the evaluation of new therapies.