The Edpm5 locus prevents the 'angiogenic switch' in an estrogen-induced rat pituitary tumor.
The Edpm5 locus prevents the 'angiogenic switch' in an estrogen-induced rat pituitary tumor.
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Edpm5 基因座可防止雌激素诱导的大鼠垂体瘤中的“血管生成开关”。
DOI：
10.1093/carcin/bgh192
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Wendell,DouglasL
中科院分区：
文献类型：
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作者：
Pandey,Jyotsna;Bannout,Anas;Wendell,DouglasL
Edpm5是导致Fischer 344(F344)株和Brown挪威株(BN)对雌激素诱导的催乳素瘤易感性差异的一组数量性状基因座之一。在长期雌激素治疗下，F344大鼠会出现大的、出血的和侵袭性的垂体瘤，这些肿瘤既表现为肿瘤血管生成，也表现为肿瘤生长。相比之下，BN大鼠不会发生肿瘤，尽管雌激素诱导的哺乳细胞密度增加。为了研究Edpm5在这些肿瘤发展中的作用，我们通过将BN中携带Edpm5的大鼠染色体片段导入F344株背景中，产生了一个新的同源大鼠品系F344-Edpm5BN。F344和F344.BN-Edpm5BN的表型差异可能是由于Edpm5染色体区间内的一个基因(S)所致。通过使用这些菌株，我们发现Edpm5特异性地调节向血管生成表型的转换，而不是肿瘤。F344.BN-Edpm5BN大鼠出现肿瘤，肿瘤明显生长，质量是未经治疗的大鼠的7倍，肿瘤与F344株的肿瘤难以区分。然而，F344.BN-Edpm5BN大鼠肿瘤具有非血管生成表型。在长期雌激素治疗后，F344-BN-Edpm5BN肿瘤的微血管计数与未经治疗的对照组相比没有增加，而F344大鼠肿瘤的微血管计数明显增加(P<；0.0005)。F344BN-Edpm5BN大鼠垂体瘤血管超微结构未见明显的血管生成相关改变。相比之下，亲本菌株F344具有显著的血管生成活性。F344.BN-Edpm5BN株也不能在雌激素治疗后的F344大鼠脑垂体中高水平表达血管内皮生长因子。因此，至少有一个直接或间接对血管生成表型转换有较大影响的基因必须位于染色体区间内，即Edpm5数量性状基因座。
Edpm5is one member of a group of quantitative trait loci that are responsible for the difference in susceptibility to estrogen-induced prolactinoma between the Fischer 344 (F344) and Brown Norway (BN) strains. Upon chronic estrogen treatment F344 rats develop large, hemorrhagic and invasive pituitary tumors, which exhibit both tumor angiogenesis and neoplasia. In contrast, BN rats do not develop a tumor despite an estrogen-induced increase in lactotroph density. To investigate the role ofEdpm5in the development of these tumors, we have generated a novel congenic rat strain F344.BN-Edpm5BNby introgressing the segment of rat chromosome bearingEdpm5from BN into the F344 strain background. Phenotypic differences between F344 and F344.BN-Edpm5BNmust be due to a gene(s) within the chromosomal interval encompassingEdpm5. Through use of these strains, we find thatEdpm5specifically regulates the switch to angiogenic phenotype, independent of neoplasia. The F344.BN-Edpm5BNrats developed tumors, which exhibited significant growth, 7-fold greater mass than the pituitary of untreated rats, and neoplasia indistinguishable from that of the F344 strain. However, the F344.BN-Edpm5BNrat tumor had a non-angiogenic phenotype. After chronic estrogen treatment, there was no increase in microvessel count over untreated controls in F344.BN-Edpm5BNtumors, whereas F344 rat tumors showed a significant increase (P< 0.0005). The ultrastructural morphology of the pituitary blood vessels also did not show significant angiogenesis associated changes in F344.BN-Edpm5BNrat pituitary tumors. In contrast the parental strain F344 had pronounced angiogenic activity. The F344.BN-Edpm5BNstrain also fails to express VEGF at the high levels seen in the F344 rat pituitary after estrogen treatment. Hence at least one gene that has a large impact, directly or indirectly, on the switch to angiogenic phenotype must reside within the chromosomal interval that is theEdpm5quantitative trait locus.