Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors.
Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors.
复制标题
DOI：
10.1371/journal.pone.0030062
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Montgomery RB
中科院分区：
文献类型：
--
作者：
Mostaghel EA;Solomon KR;Pelton K;Freeman MR;Montgomery RB
前列腺癌（PCa）是男性中第二常见的癌症。雄激素剥夺疗法（ADT）导致肿瘤消退和肿瘤负荷的减少。然而，肿瘤最终重新出现，克服了性腺雄激素的缺乏，称为去势抵抗性PCa（CRPC）。CRPC发生的基础理论包括雄激素受体（AR）突变，允许非雄激素的混杂激活，AR扩增和过表达导致对低雄激素水平的超敏反应，和/或肿瘤摄取和肾上腺源性雄激素的转化。最近有人提出，前列腺肿瘤细胞通过从头类固醇合成来合成它们自己的雄激素，这涉及从胆固醇逐步合成雄激素。使用体内LNCaP PCa异种移植物模型，来自我们组的先前数据表明，高胆固醇血症饮食通过诱导血管生成而增强前列腺肿瘤生长。使用这个相同的模型，我们现在证明，循环胆固醇水平与肿瘤大小（R = 0.3957，p = 0.0049）和肿瘤内睾酮水平（R = 0.41，p = 0.0023）在LNCaP肿瘤生长在睾丸完整的小鼠显着相关。 我们证明了肿瘤中胆固醇摄取基因的表达以及胆固醇合成雄激素所必需的类固醇生成酶的谱。此外，我们发现循环胆固醇水平与CYP 17 A的肿瘤表达直接相关，CYP 17 A是从胆固醇从头合成雄激素所需的关键酶（R = 0.4073，p = 0.025）。由于高胆固醇血症不提高循环雄激素水平，小鼠肾上腺合成最小的雄激素，本研究提供了高胆固醇血症增加瘤内从头类固醇生成的证据。 我们的研究结果与胆固醇驱动的瘤内雄激素合成可能加速前列腺肿瘤生长的假设一致，并表明CRPC的治疗可以通过纳入胆固醇降低疗法与靶向雄激素合成和AR的疗法相结合来优化。
Prostate cancer (PCa) is the second most common cancer in men. Androgen deprivation therapy (ADT) leads to tumor involution and reduction of tumor burden. However, tumors eventually reemerge that have overcome the absence of gonadal androgens, termed castration resistant PCa (CRPC). Theories underlying the development of CRPC include androgen receptor (AR) mutation allowing for promiscuous activation by non-androgens, AR amplification and overexpression leading to hypersensitivity to low androgen levels, and/or tumoral uptake and conversion of adrenally derived androgens. More recently it has been proposed that prostate tumor cells synthesize their own androgens through de novo steroidogenesis, which involves the step-wise synthesis of androgens from cholesterol. Using the in vivo LNCaP PCa xenograft model, previous data from our group demonstrated that a hypercholesterolemia diet potentiates prostatic tumor growth via induction of angiogenesis. Using this same model we now demonstrate that circulating cholesterol levels are significantly associated with tumor size (R = 0.3957, p = 0.0049) and intratumoral levels of testosterone (R = 0.41, p = 0.0023) in LNCaP tumors grown in hormonally intact mice. We demonstrate tumoral expression of cholesterol uptake genes as well as the spectrum of steroidogenic enzymes necessary for androgen biosynthesis from cholesterol. Moreover, we show that circulating cholesterol levels are directly correlated with tumoral expression of CYP17A, the critical enzyme required for de novo synthesis of androgens from cholesterol (R = 0.4073, p = 0.025) Since hypercholesterolemia does not raise circulating androgen levels and the adrenal gland of the mouse synthesizes minimal androgens, this study provides evidence that hypercholesterolemia increases intratumoral de novo steroidogenesis. Our results are consistent with the hypothesis that cholesterol-fueled intratumoral androgen synthesis may accelerate the growth of prostate tumors, and suggest that treatment of CRPC may be optimized by inclusion of cholesterol reduction therapies in conjunction with therapies targeting androgen synthesis and the AR.
登录
查看更多内容
影响因子：
2.3
作者：
Batty, G. David;Kivimaeki, Mika;Clarke, Robert;Smith, George Davey;Shipley, Martin J.
通讯作者：
Shipley, Martin J.
影响因子：
39.3
作者：
Knopp, RH;Gitter, H;Veltri, EP
通讯作者：
Veltri, EP
影响因子：
4.8
作者：
Davis, HR;Zhu, LJ;Altmann, SW
通讯作者：
Altmann, SW
DOI：
10.1038/ncpuro1296
发表时间：
2009-02
期刊：
NATURE CLINICAL PRACTICE UROLOGY
影响因子：
--
作者：
Harris, William P.;Mostaghel, Elahe A.;Nelson, Peter S.;Montgomery, Bruce
通讯作者：
Montgomery, Bruce
影响因子：
56.9
作者：
Altmann, SW;Davis, HR;Graziano, MP
通讯作者：
Graziano, MP