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Paracrine Placental Growth Factor Signaling in Response to Ionizing Radiation Is p53-Dependent and Contributes to Radioresistance
Molecular Cancer Research ( IF 5.2 ) Pub Date : 2021-06-01 , DOI: 10.1158/1541-7786.mcr-20-0403
Tamara Kazimova 1 , Fabienne Tschanz 1 , Ashish Sharma 2 , Irma Telarovic 1 , Marco Wachtel 3 , Gloria Pedot 3 , Beat Schäfer 3 , Martin Pruschy 1
Affiliation  

Placental growth factor (PlGF) is a pro-angiogenic, N-glycosylated growth factor, which is secreted under pathologic situations. Here, we investigated the regulation of PlGF in response to ionizing radiation (IR) and its role for tumor angiogenesis and radiosensitivity. Secretion and expression of PlGF was induced in multiple tumor cell lines (medulloblastoma, colon and lung adenocarcinoma) in response to irradiation in a dose- and time-dependent manner. Early upregulation of PlGF expression and secretion in response to irradiation was primarily observed in p53 wild-type tumor cells, whereas tumor cells with mutated p53 only showed a minimal or delayed response. Mechanistic investigations with genetic and pharmacologic targeting of p53 corroborated regulation of PlGF by the tumor suppressor p53 in response to irradiation under normoxic and hypoxic conditions, but with so far unresolved mechanisms relevant for its minimal and delayed expression in tumor cells with a p53-mutated genetic background. Probing a paracrine role of IR-induced PlGF secretion in vitro , migration of endothelial cells was specifically increased towards irradiated PlGF wild type but not towards irradiated PlGF-knockout (PIGF-ko) medulloblastoma cells. Tumors derived from these PlGF-ko cells displayed a reduced growth rate, but similar tumor vasculature formation as in their wild-type counterparts. Interestingly though, high-dose irradiation strongly reduced microvessel density with a concomitant high rate of complete tumor regression only in the PlGF-ko tumors. Implications: Our study shows a strong paracrine vasculature-protective role of PlGF as part of a p53-regulated IR-induced resistance mechanism and suggest PlGF as a promising target for a combined treatment modality with RT.

中文翻译:

响应电离辐射的旁分泌胎盘生长因子信号传导依赖于 p53 并有助于抗辐射

胎盘生长因子 (PlGF) 是一种促血管生成的 N-糖基化生长因子,在病理情况下分泌。在这里,我们研究了 PlGF 对电离辐射 (IR) 的反应及其在肿瘤血管生成和放射敏感性中的作用。PlGF 的分泌和表达在多种肿瘤细胞系(髓母细胞瘤、结肠和肺腺癌)中以剂量和时间依赖性方式响应辐射而被诱导。PlGF 表达和分泌响应辐射的早期上调主要在 p53 野生型肿瘤细胞中观察到,而具有突变 p53 的肿瘤细胞仅表现出最小或延迟的反应。对 p53 的遗传和药理学靶向的机制研究证实了肿瘤抑制因子 p53 在常氧和低氧条件下对辐射的反应对 PlGF 的调节,但迄今为止尚未解决与其在具有 p53 突变基因的肿瘤细胞中最小和延迟表达相关的机制背景。在体外探索 IR 诱导的 PlGF 分泌的旁分泌作用,内皮细胞的迁移向受辐射的 PlGF 野生型特异性增加,而不是向受辐射的 PlGF 敲除 (PIGF-ko) 髓母细胞瘤细胞迁移。源自这些 PlGF-ko 细胞的肿瘤显示出生长速度降低,但与野生型对应物相似的肿瘤血管形成。不过有趣的是,仅在 PlGF-ko 肿瘤中,高剂量照射大大降低了微血管密度,同时伴随着很高的肿瘤完全消退率。启示:我们的研究表明 PlGF 作为 p53 调节的 IR 诱导的耐药机制的一部分具有强大的旁分泌血管保护作用,并表明 PlGF 作为与 RT 联合治疗方式的有希望的靶标。
更新日期:2021-06-03
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