TGF-β1 induces an age-dependent inflammation of nerve ganglia and fibroplasia in the prostate gland stroma of a novel transgenic mouse.
TGF-β1 induces an age-dependent inflammation of nerve ganglia and fibroplasia in the prostate gland stroma of a novel transgenic mouse.
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DOI：
10.1371/journal.pone.0013751
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发表时间：
2010-10-29
期刊：
影响因子：
3.7
通讯作者：
Rowley DR
中科院分区：
文献类型：
--
作者：
Barron DA;Strand DW;Ressler SJ;Dang TD;Hayward SW;Yang F;Ayala GE;Ittmann M;Rowley DR
TGF-β1在伤口修复和大多数增殖性疾病（包括良性前列腺增生和前列腺癌）中过表达。这些部位的基质微环境是反应性的，典型表现为表型改变、基质沉积、炎症反应以及神经密度和生物学改变。已知TGF-β1调节多种基质反应;然而，很少有转基因模型来研究其整合生物学。为了解决TGF-β1在前列腺疾病中的作用，我们通过增强的probasin启动子将表位标记且组成型活性的TGF-β1的表达靶向于小鼠前列腺上皮。转基因小鼠出现了年龄依赖性病变，导致严重的，但局灶性衰减的上皮细胞和不连续的基底层。这些变化与塌陷腺泡中纤维组织增生和胶原微结节的频率升高相关，沿着神经节和小血管中的诱导炎症。在神经节中观察到CD 115+髓样细胞而非成熟巨噬细胞的募集增加，也呈年龄依赖性。使用人前列腺上皮组织重组异种移植模型观察到类似的表型变化，其中上皮细胞工程化以过表达TGF-β1诱导纤维化和改变基质沉积，同时基质隔室中存在炎症。总之，这些数据表明，TGF-β1表达升高诱导与上皮壁结构破坏和神经节和血管炎症累及相关的纤维增生基质反应。与塌陷腺泡中胶原微结节形成相关的神经节和血管炎症的新发现很重要，因为这些发现都在人前列腺癌中观察到，并可能在疾病进展中发挥作用。
TGF-β1 is overexpressed in wound repair and in most proliferative disorders including benign prostatic hyperplasia and prostate cancer. The stromal microenvironment at these sites is reactive and typified by altered phenotype, matrix deposition, inflammatory responses, and alterations in nerve density and biology. TGF-β1 is known to modulate several stromal responses; however there are few transgenic models to study its integrated biology. To address the actions of TGF-β1 in prostate disorders, we targeted expression of an epitope tagged and constitutively active TGF-β1 via the enhanced probasin promoter to the murine prostate gland epithelium. Transgenic mice developed age-dependent lesions leading to severe, yet focal attenuation of epithelium, and a discontinuous basal lamina. These changes were associated with elevated fibroplasia and frequency of collagenous micronodules in collapsed acini, along with an induced inflammation in nerve ganglia and small vessels. Elevated recruitment of CD115+ myeloid cells but not mature macrophages was observed in nerve ganglia, also in an age-dependent manner. Similar phenotypic changes were observed using a human prostate epithelium tissue recombination xenograft model, where epithelial cells engineered to overexpress TGF-β1 induced fibrosis and altered matrix deposition concurrent with inflammation in the stromal compartment. Together, these data suggest that elevated TGF-β1 expression induces a fibroplasia stromal response associated with breach of epithelial wall structure and inflammatory involvement of nerve ganglia and vessels. The novel findings of ganglia and vessel inflammation associated with formation of collagenous micronodules in collapsed acini is important as each of these are observed in human prostate carcinoma and may play a role in disease progression.
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DOI：
10.1038/labinvest.2010.5
发表时间：
2010-04
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.92.10.4254
发表时间：
1995-05-09
影响因子：
11.1
作者：
PIERCE, DF;GORSKA, AE;MOSES, HL
通讯作者：
MOSES, HL
影响因子：
50.3
作者：
Acevedo, Victor D.;Gangula, Rama D.;Spencer, David M.
通讯作者：
Spencer, David M.
影响因子：
2.2
作者：
Wolfraim, LA;Alkemade, GM;Letterio, JJ
通讯作者：
Letterio, JJ
影响因子：
6.6
作者：
Shoskes, DA;Albakri, Q;Cook, D
通讯作者：
Cook, D