Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
Prostate. 2014 Feb;74(3):260-72. doi: 10.1002/pros.22747. Epub 2013 Oct 26.
The observation that angiogenesis, the process of new blood vessel formation, in healthy prostate and early prostate cancer is androgen-dependent gave rise to significant questions on how hypervascularization and increased angiogenesis is also achieved at the molecular level in advanced androgen-independent prostate cancer. The exact paracrine molecular network that is hardwired into the proteome of the endothelial and cancer subpopulations participating in this process remains partially understood.
Here, we interrogated the signaling pathways and the molecular functional signatures across the proteome of endothelial cells after interacting with various secretomes produced by androgen-dependent and -independent prostate cancer cells.
We found the significant overexpression (P < 0.05) of prominent markers of angiogenesis, such as vonWillebrand factor (vWF) (∼ 2.5-fold) and CD31 (∼ 2-fold) in HUVECs stimulated with conditioned media from the androgen-independent prostate cancer cell line PC3. By mining the proteome of PC3 conditioned media, we discovered a signature of chemokine CXC motif ligands (i.e., CXCL3, CXCL5, CXCL6 and CXCL8) that could potentially coordinate increased angiogenesis in androgen-independent prostate cancer and verified their increased expression (P < 0.05) in both in vitro and xenograft models of androgen-independence.
Our findings form the basis for understanding the regulation of crucial metastatic phenomena during the transition of androgen-dependent prostate cancer into the highly aggressive, androgen-independent state and provide further insight on potential therapeutic targets of cancer-related angiogenesis.
在健康的前列腺和早期前列腺癌中，新生血管形成（血管生成过程）是雄激素依赖性的，这一观察结果引发了重大问题，即雄激素非依赖性晚期前列腺癌中，血管过度形成和血管生成增加如何在分子水平上实现。参与这一过程的内皮细胞和肿瘤亚群的蛋白质组中，确切的旁分泌分子网络仍然部分未知。
在这里，我们研究了与雄激素依赖性和非依赖性前列腺癌细胞产生的各种分泌组相互作用后，内皮细胞中信号通路和蛋白质组分子功能特征。
我们发现，与雄激素依赖性前列腺癌细胞系 PC3 的条件培养基刺激的 HUVECs 中，血管生成的显著标志物（如血管性血友病因子（vWF）（∼2.5 倍）和 CD31（∼2 倍））的过表达（P<0.05）。通过挖掘 PC3 条件培养基的蛋白质组，我们发现了趋化因子 CXC 基序配体（即 CXCL3、CXCL5、CXCL6 和 CXCL8）的特征，这些配体可能协调雄激素非依赖性前列腺癌中的血管生成增加，并在雄激素非依赖性的体外和异种移植模型中验证了它们的表达增加（P<0.05）。
我们的发现为理解雄激素依赖性前列腺癌向高度侵袭性雄激素非依赖性状态过渡过程中的关键转移现象的调节提供了基础，并为癌症相关血管生成的潜在治疗靶点提供了进一步的见解。
