A transgenic mouse model for early prostate metastasis to lymph nodes.
A transgenic mouse model for early prostate metastasis to lymph nodes.
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DOI：
10.1158/0008-5472.can-13-1157
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发表时间：
2014-02-01
期刊：
影响因子：
11.2
通讯作者：
Gelman IH
中科院分区：
文献类型：
--
作者：
Ko HK;Akakura S;Peresie J;Goodrich DW;Foster BA;Gelman IH
雄激素剥夺治疗失败后出现的复发性转移性前列腺癌代表了这种疾病的致命表型。然而，人们对调节这一转移过程的基因和途径知之甚少，而且还不清楚转移是早期还是晚期事件。转移抑制基因 SSeCKS/Gravin/AKAP12 或 Rb（在人类前列腺癌中下调或缺失的基因）的个体遗传缺失会导致前列腺增生。在这里，我们发现 Akap12 和 Rb 的联合缺失会导致前列腺上皮内瘤变 (PIN)，但在 18 个月后未能进展为恶性肿瘤。引人注目的是，83% 患有 PIN 病变的小鼠表现出转移至引流淋巴结，其特征是相对分化的肿瘤细胞表达基底标记物（p63、细胞角蛋白 14）和管腔上皮细胞标记物（细胞角蛋白 8 和雄激素受体），尽管没有一个表达基底标记物细胞角蛋白 5。 与 WT 或 Akap12−/− 前列腺叶相比，p63/AR 阳性、细胞角蛋白 5 阴性基底细胞表明这些移行细胞可能是 LN 转移的来源。总而言之，这些数据表明，在 Rb 丢失的情况下，Akap12 抑制基底腔前列腺肿瘤细胞的致癌增殖和早期转移性扩散。
The emergence of recurrent, metastatic prostate cancer following the failure of androgen-deprivation therapy represents the lethal phenotype of this disease. However, little is known regarding the genes and pathways that regulate this metastatic process, and moreover, it is unclear whether metastasis is an early or late event. The individual genetic loss of the metastasis suppressor, SSeCKS/Gravin/AKAP12, or Rb, genes that are downregulated or deleted in human prostate cancer, results in prostatic hyperplasia. Here, we show that the combined loss of Akap12 and Rb results in prostatic intraepithelial neoplasia (PIN) that fails to progress to malignancy after 18 months. Strikingly, 83% of mice with PIN lesions exhibited metastases to draining lymph nodes, marked by relatively differentiated tumor cells expressing markers of basal (p63, cytokeratin 14) and luminal (cytokeratin 8 and androgen receptor) epithelial cells, although none expressed the basal marker, cytokeratin 5. The finding that PIN lesions contain increased numbers of p63/AR-positive, cytokeratin 5-negative basal cells compared to WT or Akap12−/− prostate lobes suggests that these transitional cells may be the source of the LN metastases. Taken together, these data suggest that in the context of Rb loss, Akap12 suppresses the oncogenic proliferation and early metastatic spread of basal-luminal prostate tumor cells.