The evolutionary impact of androgen levels on prostate cancer in a multi-scale mathematical model.
The evolutionary impact of androgen levels on prostate cancer in a multi-scale mathematical model.
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DOI：
10.1186/1745-6150-5-24
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发表时间：
2010-04-20
期刊：
影响因子：
5.5
通讯作者：
Kuang Y
中科院分区：
文献类型：
--
作者：
Eikenberry SE;Nagy JD;Kuang Y
雄激素与前列腺细胞中的雄激素受体（AR）结合，是健康前列腺上皮细胞的重要存活因子。大多数未经治疗的前列腺癌保留对AR的某种依赖性，并且对雄激素消融治疗至少有短暂的反应。然而，内源性雄激素水平和癌症病因之间的关系尚不清楚。高水平的雄激素传统上被认为是驱动异常增殖导致癌症，但也有人认为，低水平的雄激素可能会诱导异常细胞的选择压力。我们建立了一个雄激素调节前列腺生长的数学模型，以研究雄激素水平异常对早期前列腺癌发展中癌前表型选择的影响。我们发现细胞更新率随着雄激素水平的降低而增加，这可能会增加突变和恶性演变的速度。我们使用一个连续的状态转换模型的异质前列腺细胞群的演变模型。使用该模型，我们研究了在不同雄激素水平下对AR表达的选择，发现低雄激素环境（由低血清睾酮或5α-还原酶活性降低引起）比正常环境更强烈地选择升高的AR表达。高雄激素实际上轻微降低了AR上调的选择性压力。此外，我们的研究结果表明，雄激素环境异常可能会延迟恶性表型的进展，但会导致更危险的癌症。该模型为了解雄激素在前列腺癌病因学中的作用提供了一个有用的初步框架，它表明低雄激素水平可以增加对激素治疗抵抗的表型的选择，这些表型也可能更具侵略性。此外，5α-还原酶抑制剂（如非那肽）的临床治疗可能会增加耐药癌症的发生率。这篇文章由Ariosto S. Marek Kimmel（英语：Marek Kimmel）
Androgens bind to the androgen receptor (AR) in prostate cells and are essential survival factors for healthy prostate epithelium. Most untreated prostate cancers retain some dependence upon the AR and respond, at least transiently, to androgen ablation therapy. However, the relationship between endogenous androgen levels and cancer etiology is unclear. High levels of androgens have traditionally been viewed as driving abnormal proliferation leading to cancer, but it has also been suggested that low levels of androgen could induce selective pressure for abnormal cells. We formulate a mathematical model of androgen regulated prostate growth to study the effects of abnormal androgen levels on selection for pre-malignant phenotypes in early prostate cancer development. We find that cell turnover rate increases with decreasing androgen levels, which may increase the rate of mutation and malignant evolution. We model the evolution of a heterogeneous prostate cell population using a continuous state-transition model. Using this model we study selection for AR expression under different androgen levels and find that low androgen environments, caused either by low serum testosterone or by reduced 5α-reductase activity, select more strongly for elevated AR expression than do normal environments. High androgen actually slightly reduces selective pressure for AR upregulation. Moreover, our results suggest that an aberrant androgen environment may delay progression to a malignant phenotype, but result in a more dangerous cancer should one arise. The model represents a useful initial framework for understanding the role of androgens in prostate cancer etiology, and it suggests that low androgen levels can increase selection for phenotypes resistant to hormonal therapy that may also be more aggressive. Moreover, clinical treatment with 5α-reductase inhibitors such as finasteride may increase the incidence of therapy resistant cancers. This article was reviewed by Ariosto S. Silva (nominated by Marek Kimmel) and Marek Kimmel.
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影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
3
作者：
Ideta, Aiko Miyamura;Tanaka, Gouhei;Aihara, Kazuyuki
通讯作者：
Aihara, Kazuyuki
DOI：
10.1530/acta.0.0980634
发表时间：
1981-01-01
期刊：
ACTA ENDOCRINOLOGICA
影响因子：
--
作者：
ADLERCREUTZ, H;RANNIKKO, S;KARONEN, SL
通讯作者：
KARONEN, SL
影响因子：
8.4
作者：
Briyanti, Alberto;Chun, Felix K. -H.;Karakiewicz, Pierre I.
通讯作者：
Karakiewicz, Pierre I.
影响因子：
0.5
作者：
DOBZHANSKY, T
通讯作者：
DOBZHANSKY, T