Lee Geun Taek, Kwon Seok Joo, Lee Jae-Ho, Jeon Seong Soo, Jang Kee Taek, Choi Han Yong, Lee Hyun Moo, Kim Wun-Jae, Lee Dong Hyeon, Kim Isaac Yi
Section of Urologic Oncology, Dean and Betty Gallo Prostate Cancer Center, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey.
Prostate. 2011 Oct 1;71(14):1525-37. doi: 10.1002/pros.21369. Epub 2011 Mar 3.
Frequently associated with hormone refractory prostate cancer are neuroendocrine cells. Because these cells do not express androgen receptors and are castration-resistant, further understanding the mechanism of neuroendocrine differentiation (NED) of prostate cancer cells may yield novel intervention methods in hormone refractory prostate cancer. In this regard, the present study investigated the effect of macrophages on prostate cancer NED.
THP-1 and LNCaP or RAW264.7 and TRAMP-C2 cell line co-cultures were used to investigate NED-macrophage interactions. Also interleukin-6 (IL-6) knockout mice and macrophage-depleted mice were used to test NED in vivo.
We found that co-culturing with THP-1 human monocytic cell line and RAW 264.7 murine macrophage cell line led to the NED of LNCaP and TRAMP-C2 prostate cancer cells, respectively. Specifically, the conditioned media of activated macrophages stimulated the expression of parathyroid hormone-related peptide (PTHrP), a marker of NED, in both LNCaP and TRAMP-C2 cells. Mechanistically, bone morphogenetic protein-6 (BMP-6) derived from prostate cancer cells increased the expression of IL-6 in macrophages. Subsequently, IL-6 induced the NED of prostate cancer cells. When this feedback loop was disrupted with neutralizing antibodies to either BMP-6 or IL-6, NED was no longer observed. In human prostate cancer tissues, neuroendocrine cells frequently co-localized with macrophages and BMP-6. In mice, the removal of IL-6 or macrophages blocked the BMP-6-induced NED of prostate cancer cells.
Therefore, we propose that BMP-6 secreted by prostate cancer cells induces IL-6 expression in macrophages; IL-6, in turn, stimulates the NED of prostate cancer cells.
神经内分泌细胞常与激素难治性前列腺癌相关。由于这些细胞不表达雄激素受体且具有去势抵抗性，进一步了解前列腺癌细胞神经内分泌分化（NED）的机制可能会产生针对激素难治性前列腺癌的新干预方法。在这方面，本研究调查了巨噬细胞对前列腺癌NED的影响。
使用THP-1和LNCaP或RAW264.7和TRAMP-C2细胞系共培养来研究NED与巨噬细胞的相互作用。还使用白细胞介素-6（IL-6）基因敲除小鼠和巨噬细胞耗竭小鼠在体内测试NED。
我们发现，与THP-1人单核细胞系和RAW 264.7鼠巨噬细胞系共培养分别导致LNCaP和TRAMP-C2前列腺癌细胞发生NED。具体而言，活化巨噬细胞的条件培养基刺激了LNCaP和TRAMP-C2细胞中甲状旁腺激素相关肽（PTHrP，一种NED标志物）的表达。从机制上讲，前列腺癌细胞衍生的骨形态发生蛋白-6（BMP-6）增加了巨噬细胞中IL-6的表达。随后，IL-6诱导前列腺癌细胞发生NED。当用针对BMP-6或IL-6的中和抗体破坏这个反馈环时，不再观察到NED。在人前列腺癌组织中，神经内分泌细胞常与巨噬细胞和BMP-6共定位。在小鼠中，去除IL-6或巨噬细胞可阻断BMP-6诱导的前列腺癌细胞NED。
因此，我们提出前列腺癌细胞分泌的BMP-6诱导巨噬细胞中IL-6表达；反过来，IL-6刺激前列腺癌细胞发生NED。
