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Pharmacological dual inhibition of tumor and tumor-induced functional limitations in transgenic model of breast cancer
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2017-10-04 , DOI: 10.1158/1535-7163.mct-17-0717
Ruizhong Wang 1 , Poornima Bhat-Nakshatri 1 , Maria B. Padua 1 , Mayuri S Prasad 1 , Manjushree Anjanappa 1 , Max Jacobson 2 , Courtney Finnearty 2 , Victoria Sefcsik 2 , Kyle McElyea 2 , Rachael Redmond 2 , George Sandusky 2 , Narsimha Penthala 3 , Peter A Crooks 3 , Jianguo Liu 1 , Teresa Zimmers 1 , Harikrishna Nakshatri 1, 4, 5
Affiliation  

Breast cancer progression is associated with systemic effects, including functional limitations and sarcopenia without the appearance of overt cachexia. Autocrine/paracrine actions of cytokines/chemokines produced by cancer cells mediate cancer progression and functional limitations. The cytokine-inducible transcription factor NF-κB could be central to this process, as it displays oncogenic functions and is integral to the Pax7:MyoD:Pgc-1β:miR-486 myogenesis axis. We tested this possibility using the MMTV-PyMT transgenic mammary tumor model and the NF-κB inhibitor dimethylaminoparthenolide (DMAPT). We observed deteriorating physical and functional conditions in PyMT+ mice with disease progression. Compared with wild-type mice, tumor-bearing PyMT+ mice showed decreased fat mass, impaired rotarod performance, and reduced grip strength as well as increased extracellular matrix (ECM) deposition in muscle. Contrary to acute cachexia models described in the literature, mammary tumor progression was associated with reduction in skeletal muscle stem/satellite-specific transcription factor Pax7. Additionally, we observed tumor-induced reduction in Pgc-1β in muscle, which controls mitochondrial biogenesis. DMAPT treatment starting at 6 to 8 weeks age prior to mammary tumor occurrence delayed mammary tumor onset and tumor growth rates without affecting metastasis. DMAPT overcame cancer-induced functional limitations and improved survival, which was accompanied with restoration of Pax7, Pgc-1β, and mitochondria levels and reduced ECM levels in skeletal muscles. In addition, DMAPT restored circulating levels of 6 out of 13 cancer-associated cytokines/chemokines changes to levels seen in healthy animals. These results reveal a pharmacological approach for overcoming cancer-induced functional limitations, and the above-noted cancer/drug-induced changes in muscle gene expression could be utilized as biomarkers of functional limitations. Mol Cancer Ther; 16(12); 2747–58. ©2017 AACR.

中文翻译:

乳腺癌转基因模型中肿瘤的药理学双重抑制和肿瘤诱导的功能限制

乳腺癌进展与全身效应有关,包括功能受限和肌肉减少症,但没有明显的恶病质。癌细胞产生的细胞因子/趋化因子的自分泌/旁分泌作用介导癌症进展和功能限制。细胞因子诱导型转录因子 NF-κB 可能是该过程的核心,因为它具有致癌功能,并且是 Pax7:MyoD:Pgc-1β:miR-486 肌生成轴的组成部分。我们使用 MMTV-PyMT 转基因乳腺肿瘤模型和 NF-κB 抑制剂二甲氨基小白菊内酯 (DMAPT) 测试了这种可能性。我们观察到随着疾病进展的 PyMT+ 小鼠身体和功能状况恶化。与野生型小鼠相比,荷瘤 PyMT+ 小鼠的脂肪量减少,旋转杆性能受损,握力降低,肌肉中细胞外基质 (ECM) 沉积增加。与文献中描述的急性恶病质模型相反,乳腺肿瘤进展与骨骼肌干/卫星特异性转录因子 Pax7 的减少有关。此外,我们观察到肿瘤诱导的肌肉中 Pgc-1β 减少,这控制着线粒体生物发生。在乳腺肿瘤发生前 6 至 8 周龄开始的 DMAPT 治疗延迟了乳腺肿瘤的发病和肿瘤生长速度,而不影响转移。DMAPT 克服了癌症引起的功能限制并提高了生存率,同时恢复了 Pax7、Pgc-1β 和线粒体水平,并降低了骨骼肌中的 ECM 水平。此外,DMAPT 将 13 种癌症相关细胞因子/趋化因子变化中的 6 种循环水平恢复到健康动物的水平。这些结果揭示了克服癌症诱导的功能限制的药理学方法,并且上述癌症/药物诱导的肌肉基因表达变化可用作功能限制的生物标志物。摩尔癌症治疗; 16(12); 2747-58。©2017 AACR。
更新日期:2017-10-04
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