Department of Urology, Lundberg Laboratory for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
BMC Cancer. 2010 Jun 14;10:288. doi: 10.1186/1471-2407-10-288.
Decreased expression of the angiogenesis inhibitor ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif, 1) has previously been reported during prostate cancer progression. The aim of this study was to investigate the function of ADAMTS1 in prostate tumors.
ADAMTS1 was downregulated by shRNA technology in the human prostate cancer cell line LNCaP (androgen-dependent), originally expressing ADAMTS1, and was upregulated by transfection in its subline LNCaP-19 (androgen-independent), expressing low levels of ADAMTS1. Cells were implanted subcutaneously in nude mice and tumor growth, microvessel density (MVD), blood vessel morphology, pericyte coverage and thrombospondin 1 (TSP1) were studied in the tumor xenografts.
Modified expression of ADAMTS1 resulted in altered blood vessel morphology in the tumors. Low expression levels of ADAMTS1 were associated with small diameter blood vessels both in LNCaP and LNCaP-19 tumors, while high levels of ADAMTS1 were associated with larger vessels. In addition, TSP1 levels in the tumor xenografts were inversely related to ADAMTS1 expression. MVD and pericyte coverage were not affected. Moreover, upregulation of ADAMTS1 inhibited tumor growth of LNCaP-19, as evidenced by delayed tumor establishment. In contrast, downregulation of ADAMTS1 in LNCaP resulted in reduced tumor growth rate.
The present study demonstrates that ADAMTS1 is an important regulatory factor of angiogenesis and tumor growth in prostate tumors, where modified ADAMTS1 expression resulted in markedly changed blood vessel morphology, possibly related to altered TSP1 levels.
先前的研究报道，在前列腺癌进展过程中，血管生成抑制剂 ADAMTS1（含血栓反应蛋白 1 型基序的金属蛋白酶 13）的表达降低。本研究旨在探讨 ADAMTS1 在前列腺肿瘤中的作用。
通过短发夹 RNA 技术下调人前列腺癌细胞系 LNCaP（雄激素依赖性）中 ADAMTS1 的表达，并用转染技术上调其亚系 LNCaP-19（雄激素非依赖性）中 ADAMTS1 的表达，后者表达低水平的 ADAMTS1。将细胞皮下植入裸鼠体内，研究肿瘤异种移植物中的肿瘤生长、微血管密度（MVD）、血管形态、周细胞覆盖和血栓反应蛋白 1（TSP1）。
ADAMTS1 表达的改变导致肿瘤中血管形态发生改变。在 LNCaP 和 LNCaP-19 肿瘤中，ADAMTS1 低表达与小直径血管相关，而 ADAMTS1 高表达与大血管相关。此外，肿瘤异种移植物中的 TSP1 水平与 ADAMTS1 表达呈负相关。MVD 和周细胞覆盖不受影响。此外，ADAMTS1 的上调抑制了 LNCaP-19 肿瘤的生长，这表现在肿瘤建立的延迟。相反，下调 LNCaP 中的 ADAMTS1 导致肿瘤生长速度降低。
本研究表明，ADAMTS1 是前列腺肿瘤中血管生成和肿瘤生长的重要调节因子，修饰的 ADAMTS1 表达导致明显改变的血管形态，可能与改变的 TSP1 水平有关。
