Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC-7758, San Antonio, TX 78229, USA.
BMC Cancer. 2011 Jan 28;11:43. doi: 10.1186/1471-2407-11-43.
Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells.
The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors
We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further borne out by our finding that neutralizing IFN activity resulted in enhanced RSV infection in non-tumorigenic RWPE-1 prostate cells.
We demonstrated that RSV is potentially a useful therapeutic tool in the treatment of androgen-sensitive and androgen-independent prostate cancer. Moreover, impaired IFN-mediated antiviral response is the likely cause of higher viral burden and resulting oncolysis of androgen-sensitive prostate cancer cells.
溶瘤病毒疗法利用病毒选择性感染和杀死癌细胞，而对正常细胞没有任何不良影响。我们之前报道过，人类呼吸道合胞病毒（RSV）是一种针对雄激素非依赖性 PC-3 人前列腺癌细胞的新型溶瘤病毒。本研究将结果扩展到雄激素依赖性前列腺癌，并探讨了触发 RSV 诱导前列腺癌细胞溶瘤的潜在机制。
在体外培养和异种移植或同种移植肿瘤模型中，研究 RSV 对雄激素敏感的 LNCaP 人前列腺癌细胞和雄激素非依赖性 RM1 鼠前列腺癌细胞的溶瘤作用。体外，通过 MTT 测定、病毒斑测定和 Annexin V 染色分别监测细胞活力、感染性和细胞凋亡。体内研究涉及将病毒施用于在免疫缺陷裸鼠中生长的前列腺肿瘤和在同种免疫 competent C57BL/6J 小鼠中。通过测量肿瘤体积、在活体动物中对生物发光肿瘤进行成像以及对肿瘤进行组织病理学分析和 TUNEL 测定来监测抗肿瘤溶瘤活性。
我们表明 RSV 对 LNCaP 前列腺癌细胞具有强大的溶瘤作用。与非肿瘤性 RWPE-1 人前列腺细胞相比，RSV 在 LNCaP 细胞中的感染性明显更高。增强的病毒负担导致 LNCaP 细胞凋亡和裸鼠中 LNCaP 异种移植肿瘤的生长抑制。功能宿主免疫反应并没有干扰 RSV 诱导的溶瘤作用，因为来自鼠 RM1 细胞的 LNCaP 同种移植肿瘤在 RSV 给药后生长受到抑制。LNCaP 细胞未能激活抗病毒基因表达所需的 I 型干扰素（IFNα/β）诱导转录因子 STAT-1，尽管这些细胞可以对 RSV 感染产生 IFN。中和 IFN 活性导致非肿瘤性 RWPE-1 前列腺细胞中 RSV 感染增强的发现进一步证明了 IFN 在限制感染中的重要作用。
我们证明 RSV 是治疗雄激素敏感和雄激素非依赖性前列腺癌的一种潜在有用的治疗工具。此外，IFN 介导的抗病毒反应受损是雄激素敏感前列腺癌细胞病毒负担增加和由此导致的溶瘤的可能原因。
