Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model.
Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model.
复制标题
DOI：
10.1186/1423-0127-18-6
复制
发表时间：
2011-01-18
影响因子：
11
通讯作者：
Lin DP
中科院分区：
文献类型：
--
作者：
Chang HH;Chen BY;Wu CY;Tsao ZJ;Chen YY;Chang CP;Yang CR;Lin DP
Hedgehog 信号传导与人类受试者和小鼠模型的前列腺肿瘤发生有关，但其对将正常基底细胞/干细胞转化为恶性癌症干细胞的影响仍知之甚少。我们培育出在成年前列腺中持续过度表达 Hedgehog 蛋白的 pCX-shh-IG 小鼠，从而阐明前列腺癌发生和进展过程中的机制。使用各种标记物来表征和证实在Hedgehog过度表达的影响下正常前列腺基底/干细胞向恶性癌症干细胞的转化。 pCX-shh-IG 小鼠出现前列腺上皮内瘤变 (PIN)，并在 90 天内导致侵袭性和转移性前列腺癌。前列腺癌是通过激活 P63+ 基底细胞/干细胞以及同时激活 Hedgehog 信号成员而引发的，这表明 P63+/Patch1+ 和 P63+/Smo+ 细胞可能作为癌症起始细胞并进展为恶性前列腺癌干细胞 (PCSC)。在增生性病变和肿瘤中，PCSC的后代分化为具有基底-中间和中间-管腔特征的细胞，而罕见的ChgA+神经内分泌分化。此外，在淋巴结、肾脏和肺内的转移位点，P63+ PCSC 形成前列腺样腺体结构，这是早期前列腺发育过程中原始结构的特征。此外，在肿瘤进展过程中检测到的雄激素受体（AR）表达存在异质性。 P63+/AR-、CK14+/AR-和CD44+/AR-后代的存在表明AR-恶性癌症特征的直接获得。这些数据支持癌症干细胞场景，其中 Hedgehog 信号传导在正常前列腺基底细胞/干细胞转化为 PCSC 以及 PCSC 发展为转移性肿瘤细胞的过程中发挥着重要作用。
Hedgehog signalling has been implicated in prostate tumorigenesis in human subjects and mouse models, but its effects on transforming normal basal/stem cells toward malignant cancer stem cells remain poorly understood. We produced pCX-shh-IG mice that overexpress Hedgehog protein persistently in adult prostates, allowing for elucidation of the mechanism during prostate cancer initiation and progression. Various markers were used to characterize and confirm the transformation of normal prostate basal/stem cells into malignant cancer stem cells under the influence of Hedgehog overexpression. The pCX-shh-IG mice developed prostatic intraepithelial neoplasia (PIN) that led to invasive and metastatic prostate cancers within 90 days. The prostate cancer was initiated through activation of P63+ basal/stem cells along with simultaneous activation of Hedgehog signalling members, suggesting that P63+/Patch1+ and P63+/Smo+ cells may serve as cancer-initiating cells and progress into malignant prostate cancer stem cells (PCSCs). In the hyperplastic lesions and tumors, the progeny of PCSCs differentiated into cells of basal-intermediate and intermediate-luminal characteristics, whereas rare ChgA+ neuroendocrine differentiation was seen. Furthermore, in the metastatic loci within lymph nodes, kidneys, and lungs, the P63+ PCSCs formed prostate-like glandular structures, characteristic of the primitive structures during early prostate development. Besides, androgen receptor (AR) expression was detected heterogeneously during tumor progression. The existence of P63+/AR-, CK14+/AR- and CD44+/AR- progeny indicates direct procurement of AR- malignant cancer trait. These data support a cancer stem cell scenario in which Hedgehog signalling plays important roles in transforming normal prostate basal/stem cells into PCSCs and in the progression of PCSCs into metastatic tumor cells.
登录
查看更多内容
影响因子：
11
作者：
Chen, Bo-Yie;Lin, David Pei-Cheng;Chang, Han-Hsin
通讯作者：
Chang, Han-Hsin
影响因子：
4.3
作者：
Chen, Mengqian;Tanner, Matthew;Levine, Alice C.;Levina, Elina;Ohouo, Patrice;Buttyan, Ralph
通讯作者：
Buttyan, Ralph
影响因子：
8.4
作者：
Collins, Anne T.;Maitland, Norman J.
通讯作者：
Maitland, Norman J.
DOI：
10.1073/pnas.94.20.10705
发表时间：
1997-09-30
影响因子：
11.1
作者：
Liu, AY;True, LD;vandenEngh, G
通讯作者：
vandenEngh, G
影响因子：
11.2
作者：
Gu, Guangyu;Yuan, Jialing;Kasper, Susan
通讯作者：
Kasper, Susan