Hypoxia theranostics of a human prostate cancer xenograft and the resulting effects on the tumor microenvironment.
Hypoxia theranostics of a human prostate cancer xenograft and the resulting effects on the tumor microenvironment.
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DOI：
10.1016/j.neo.2020.10.001
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Bhujwalla ZM
中科院分区：
文献类型：
--
作者：
Krishnamachary B;Mironchik Y;Jacob D;Goggins E;Kakkad S;Ofori F;Dore-Savard L;Bharti SK;Wildes F;Penet MF;Black ME;Bhujwalla ZM
开发了一种缺氧治疗诊断成像策略，以消除缺氧细胞。低氧细胞消除导致较少的癌症相关成纤维细胞（CAF）。胶原1纤维模式随着低氧细胞消除而改变。具有HRE驱动的前药酶表达的cDNA纳米颗粒可以靶向缺氧。缺氧在人前列腺癌中经常观察到，并且与化学抗性、放射抗性、转移和去势抗性相关。我们在这些研究中的目的是通过在人前列腺癌异种移植物中结合体内缺氧成像和缺氧癌细胞靶向来进行缺氧治疗诊断。这是通过在低氧反应元件（HRE）的控制下，对PC 3人前列腺癌细胞进行工程改造以表达荧光素酶以及前药酶酵母胞嘧啶脱氨酶来实现的。癌细胞通过缺氧诱导因子（HIF）与靶基因启动子区的HRE结合介导的多个基因的激活而显示出对缺氧的适应性反应，从而导致其转录增加。HIFs促进肿瘤发生的关键步骤，包括血管生成、代谢、增殖、转移和分化。HRE驱动的荧光素酶表达使我们能够检测体内缺氧，以确定无毒前药5-氟胞嘧啶的给药时间，该前药由在HRE调节下表达的酵母胞嘧啶脱氨酶转化为化疗剂5-氟尿嘧啶，以靶向缺氧细胞。通过19 F磁共振光谱法在体内检测5-氟胞嘧啶向5-氟尿嘧啶的转化。进行形态学和免疫组织化学染色和分子分析，以表征癌症相关成纤维细胞、细胞活力、胶原1纤维模式和HIF-1α的肿瘤微环境变化。这些研究扩展了我们对消除缺氧癌细胞对肿瘤微环境的影响以及减少基质细胞群（如癌症相关成纤维细胞）的理解。
Developed a hypoxia theranostic imaging strategy to eliminate hypoxic cells. Hypoxic cell elimination resulted in fewer cancer associated fibroblasts (CAFs) Collagen 1 fiber patterns were altered with hypoxic cell elimination. cDNA nanoparticles with HRE driven prodrug enzyme expression can target hypoxia. Hypoxia is frequently observed in human prostate cancer, and is associated with chemoresistance, radioresistance, metastasis, and castrate-resistance. Our purpose in these studies was to perform hypoxia theranostics by combining in vivo hypoxia imaging and hypoxic cancer cell targeting in a human prostate cancer xenograft. This was achieved by engineering PC3 human prostate cancer cells to express luciferase as well as a prodrug enzyme, yeast cytosine deaminase, under control of hypoxic response elements (HREs). Cancer cells display an adaptive response to hypoxia through the activation of several genes mediated by the binding of hypoxia inducible factors (HIFs) to HRE in the promoter region of target gene that results in their increased transcription. HIFs promote key steps in tumorigenesis, including angiogenesis, metabolism, proliferation, metastasis, and differentiation. HRE-driven luciferase expression allowed us to detect hypoxia in vivo to time the administration of the nontoxic prodrug 5-fluorocytosine that was converted by yeast cytosine deaminase, expressed under HRE regulation, to the chemotherapy agent 5-fluorouracil to target hypoxic cells. Conversion of 5-fluorocytosine to 5-fluorouracil was detected in vivo by 19F magnetic resonance spectroscopy. Morphological and immunohistochemical staining and molecular analyses were performed to characterize tumor microenvironment changes in cancer-associated fibroblasts, cell viability, collagen 1 fiber patterns, and HIF-1α. These studies expand our understanding of the effects of eliminating hypoxic cancer cells on the tumor microenvironment and in reducing stromal cell populations such as cancer-associated fibroblasts.
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影响因子：
17.1
作者：
Li C;Penet MF;Wildes F;Takagi T;Chen Z;Winnard PT;Artemov D;Bhujwalla ZM
通讯作者：
Bhujwalla ZM
影响因子：
5.2
作者：
Marhold, Maximilian;Tomasich, Erwin;Horak, Peter
通讯作者：
Horak, Peter
影响因子：
45.3
作者：
Borad, Mitesh J.;Reddy, Shantan G.;Ryan, David P.
通讯作者：
Ryan, David P.
影响因子：
4.8
作者：
Kakkad, Samata M.;Solaiyappan, Meiyappan;Glunde, Kristine
通讯作者：
Glunde, Kristine
影响因子：
3.5
作者：
Kakkad, Samata M.;Solaiyappan, Meiyappan;Glunde, Kristine
通讯作者：
Glunde, Kristine