Multiple sites of tumorigenesis in transgenic mice overproducing hCG
Multiple sites of tumorigenesis in transgenic mice overproducing hCG
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DOI：
10.1016/j.mce.2004.10.013
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发表时间：
2005-04-29
影响因子：
4.1
通讯作者：
Poutanen, M
中科院分区：
文献类型：
--
作者：
Huhtaniemi, I;Rulli, S;Poutanen, M
我们已经产生了在泛素C启动子下表达糖蛋白激素共同a亚基（Cα）或人绒毛膜促性腺激素(hCG) β亚基的转基因（TG）小鼠。Ca过表达本身没有表型影响，但hCGβ表达的女性，由于TG hCGβ与内源性Ca的二聚化，表现出生物活性LH/hCG水平的适度升高，发展为多种性腺和性腺外肿瘤。Cα与hcg - β小鼠（hcg - αβ）杂交有>；由于无处不在的转基因表达，hCG水平升高了1000倍，并呈现出更具侵袭性的肿瘤形成。卵巢最初表现出所有体细胞类型的强烈黄体素化，导致黄体瘤的形成，随后导致生殖细胞肿瘤（畸胎瘤）。TG组女性垂体肿大，至gt；100毫克，产生大量催乳素（PRL）的巨泌乳素瘤。这种内分泌反应可能导致小鼠患上乳腺癌。与雌性相比，雄性小鼠中类似的高水平hCG在成年期只有轻微的影响，有轻微的间质细胞增生和精系上皮萎缩。然而，在出生后小鼠中观察到明显的间质细胞腺瘤，显然起源于胎儿间质细胞。总之，这些研究表明，在雌性小鼠中，生理上的hCG水平有明显的致瘤作用，但在雄性小鼠中，对类似的变化有明显的抗性。性腺外肿瘤是由hCG刺激的异常卵巢内分泌功能引起的，而不是由hCG直接作用引起的，因为尽管hCG持续升高，但性腺切除术阻止了所有的性腺外表型。TG小鼠的表型明显表现出对hCG/LH和/或性腺类固醇的过度反应。它们在多大程度上模拟了人类对相同激素的病理生理升高的各自反应，这仍有待探索。©2005爱思唯尔爱尔兰公司版权所有。
We have produced transgenic (TG) mice expressing under the ubiquitin C promoter either the glycoprotein hormone common a-subunit (Cα) or human chortonic gonadotropin (hCG) β-subunit. Ca overexpression alone had no phenotypic effect, but the hCGβ expressing females, presenting with moderately elevated levels of bioactive LH/hCG, due to dimerization of the TG hCGβ with endogenous Ca, developed multiple gonadal and extragonadal neoplasias. Crosses of the Cα and hCGβ mice (hCGαβ) had > 1000-fold elevated hCG levels, due to ubiquitous transgene expression, and presented with more aggressive tumour formation. The ovaries displayed initially strong luteinisation of all somatic cell types, leading to formation of luteomas, and subsequently to germ cell tumours (teratomas). The pituitary glands of TG females were massively enlarged, up to > 100 mg, developing macroprolactinomas with very high prolactin (PRL) production. This endocrine response probably induced breast cancers in the mice. In contrast to the females, similar high levels of hCG in male mice had only marginal effects in adulthood, with slight Leydig cell hyperplasia and atrophy in the seminiferous epithelium. However, clear Leydig cell adenomas were observed in postnatal mice, apparently originating from fetal Leydig cells. In conclusion, these studies demonstrate marked tumorigenic effects of supraphysiotogical hCG levels in female mice, but clear resistance to similar changes in males. The extragonadal tumours were induced by hCG stimulated aberrant ovarian endocrine function, rather than by direct hCG action, because gonadectomy prevented all extragonadal phenotypes despite persistent hCG elevation. The phenotypes of the TG mice apparently represent exaggerated responses to hCG/LH and/or gonadal steroids. It remains to be explored to what extent they simulate respective responses in humans to pathophysiological elevation of the same hormones. © 2005 Elsevier Ireland Ltd. All rights reserved.