Pharmacological Dual Inhibition of Tumor and Tumor-Induced Functional Limitations in a Transgenic Model of Breast Cancer.
Pharmacological Dual Inhibition of Tumor and Tumor-Induced Functional Limitations in a Transgenic Model of Breast Cancer.
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DOI：
10.1158/1535-7163.mct-17-0717
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发表时间：
2017-12
影响因子：
5.7
通讯作者：
Nakshatri H
中科院分区：
文献类型：
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作者：
Wang R;Bhat-Nakshatri P;Padua MB;Prasad MS;Anjanappa M;Jacobson M;Finnearty C;Sefcsik V;McElyea K;Redmond R;Sandusky G;Penthala N;Crooks PA;Liu J;Zimmers T;Nakshatri H
乳腺癌的进展与全身影响有关，包括功能限制和肌肉减少，但没有明显的恶病质的出现。癌细胞产生的细胞因子/趋化因子的自分泌/旁分泌作用介导了癌症的进展和功能限制。细胞因子诱导的转录因子NF-κB可能是这一过程的核心，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抑制剂二甲氨基大素内酯（DMAPT）验证了这种可能性。我们观察到，随着疾病进展，PyMT+小鼠的身体和功能状况不断恶化。与野生型小鼠相比，携带肿瘤的PyMT+小鼠表现出脂肪量减少，旋转能力受损，握力下降以及肌肉中细胞外基质（ECM）沉积增加。与文献中描述的急性恶病质模型相反，乳腺肿瘤的进展与骨骼肌干/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的减少，Pgc-1β控制线粒体的生物发生。DMAPT治疗在乳房肿瘤发生前6-8周龄开始，延迟了乳房肿瘤的发生和肿瘤的生长速度，而不影响转移。DMAPT克服了癌症诱导的功能限制，提高了生存率，同时恢复了Pax7、Pgc-1β和线粒体水平，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以用作功能限制的生物标志物。
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 to 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 6-8 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 six 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.