Tumor growth and metastasis suppression by Glipr1 gene-modified macrophages in a metastatic prostate cancer model.
Tumor growth and metastasis suppression by Glipr1 gene-modified macrophages in a metastatic prostate cancer model.
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我们之前分别发现小鼠和人类Glipr1和Glipr1 /RTVP-1基因是p53的直接靶点，在包括前列腺癌在内的各种癌细胞系中具有促凋亡活性。肿瘤内注射一种能够有效转导和表达Glipr1的腺病毒载体（AdGlipr1）在原位转移性前列腺癌小鼠模型中产生了有希望的治疗效果。adglipr1转导的巨噬细胞（mφ /Glipr1）在体外比对照巨噬细胞产生更多的CD40、CD80和MHC II类分子的表面表达和更多的白细胞介素(IL)-12和IL-6的产生。机制分析表明，mφ /Glipr1中IL-12的增加依赖于p38信号级联的激活。体内注入原位178-2BMA肿瘤的m φ /Glipr1显著抑制了前列腺肿瘤的生长和自发性肺转移，与对照组相比，存活时间更长。此外，这些临床前数据表明，产生系统性自然杀伤细胞活性和肿瘤特异性细胞毒性t淋巴细胞反应。贩运研究证实瘤内注射的m φ /Glipr1可以迁移到引流淋巴结。总的来说，我们的数据表明，这种新的基因修饰细胞方法是一种有效的治疗途径，在临床前研究中诱导抗肿瘤免疫反应。
We previously identified the mouse and human Glipr1 and GLIPR1/RTVP-1 (respectively) genes as direct p53 targets with proapoptotic activities in various cancer cell lines, including prostate cancer. Intratumoral injection of an adenoviral vector capable of efficient transduction and expression of Glipr1 (AdGlipr1) yielded promising therapeutic results in an orthotopic, metastatic mouse model of prostate cancer. AdGlipr1-transduced macrophages (Mϕ/Glipr1) generated greater surface expression of CD40, CD80, and MHC class II molecules and greater production of interleukin (IL)-12 and IL-6 in vitro than control macrophages did. Mechanistic analysis indicated that increased production of IL-12 in Mϕ/Glipr1 depends on activation of the p38 signaling cascade. Mϕ/Glipr1 injected into orthotopic 178-2BMA tumors in vivo resulted in significantly suppressed prostate tumor growth and spontaneous lung metastases and longer survival relative to those observed in control-treated mice. Furthermore, these preclinical data indicate the generation of systemic natural killer-cell activity and tumor-specific cytotoxic T-lymphocyte responses. Trafficking studies confirmed that intratumorally injected Mϕ/Glipr1 could migrate to draining lymph nodes. Overall, our data suggest that this novel gene-modified cell approach is an effective treatment avenue that induces antitumor immune responses in preclinical studies.
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影响因子：
11.2
作者：
Movahedi, Kiavash;Laoui, Damya;Van Ginderachter, Jo A.
通讯作者：
Van Ginderachter, Jo A.
影响因子：
4.4
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Denkers, EY
影响因子：
3.5
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Rich, T;Chen, PC;Israel, MA
通讯作者：
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影响因子：
4.2
作者：
Eastham, JA;Chen, SH;Thompson, TC
通讯作者：
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影响因子：
8.8
作者：
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