Sex-specific survival but not tissue wasting in the KPP mouse model of pancreatic cancer-induced cachexia.

IF 3.3 3区 医学 Q1 PHYSIOLOGY
Natalia M Weinzierl, Jayarani Putri, Kathryn M Spitler, Erin E Talbert
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Abstract

Cancer cachexia, a multifactorial condition resulting in muscle and adipose tissue wasting, reduces the quality of life of many people with cancer. Cachexia is highly prevalent in people with pancreatic ductal adenocarcinoma (PDAC), and many animal models of pancreatic cancer are used to understand mechanisms underlying cachexia. One such model is the KrasLSL-G12D, Ptf1aCre-ER/+, Ptenflox/flox (KPP) model, which utilizes an inducible Cre recombinase to initiate tumor development by tamoxifen administration. In our previous work, tumors were induced in KPP mice at 4 weeks of age. However, mice are rapidly growing at this age, and a portion of the body weight differences seen between control and KPP mice is likely due to slowed growth of KPP mice. In our current study, pancreatic tumors were induced to develop with tamoxifen in KPP mice after rapid postnatal growth has slowed at 10 weeks of age (KPP10). Given the expanding evidence of sexual dimorphisms in cancer cachexia, we utilized both male and female mice to assess potential sex differences. Similar to our previous findings, KPP10 mice had lower body, muscle, and adipose tissue weights compared to non-tumor mice, and these differences were similar between male and female mice. However, male mice experienced greater relative weight loss. Unexpectedly, we identified that survival was significantly shorter in female KPP10 mice compared to KPP10 males. Greater body weight at tumor induction was associated with longer survival, suggesting that the sex difference in survival may be related to differences in body weight between male and female mice.

胰腺癌诱导恶病质的KPP小鼠模型的性别特异性生存而非组织消耗。
癌症恶病质是一种导致肌肉和脂肪组织消耗的多因素疾病,降低了许多癌症患者的生活质量。恶病质在胰腺导管腺癌(PDAC)患者中非常普遍,许多胰腺癌动物模型被用来了解恶病质的机制。其中一种模型是KrasLSL-G12D, Ptf1aCre-ER/+, Ptenflox/flox (KPP)模型,该模型利用诱导Cre重组酶通过给药他莫昔芬启动肿瘤发展。在我们之前的工作中,在4周龄的KPP小鼠中诱导肿瘤。然而,小鼠在这个年龄生长迅速,对照组和KPP小鼠之间的体重差异的一部分可能是由于KPP小鼠的生长缓慢。在我们目前的研究中,他莫昔芬诱导KPP小鼠在10周龄(KPP10)出生后快速生长放缓后胰腺肿瘤的发展。鉴于癌症恶病质中性别二态性的证据越来越多,我们利用雄性和雌性小鼠来评估潜在的性别差异。与我们之前的发现相似,KPP10小鼠的下体、肌肉和脂肪组织重量与非肿瘤小鼠相比,这些差异在雄性和雌性小鼠之间相似。然而,雄性小鼠的相对体重减轻幅度更大。出乎意料的是,我们发现雌性KPP10小鼠的生存期明显短于雄性KPP10小鼠。肿瘤诱导时体重越大,生存时间越长,提示生存时间的性别差异可能与雌雄小鼠体重差异有关。
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来源期刊
CiteScore
6.00
自引率
9.10%
发文量
296
审稿时长
2-4 weeks
期刊介绍: The Journal of Applied Physiology publishes the highest quality original research and reviews that examine novel adaptive and integrative physiological mechanisms in humans and animals that advance the field. The journal encourages the submission of manuscripts that examine the acute and adaptive responses of various organs, tissues, cells and/or molecular pathways to environmental, physiological and/or pathophysiological stressors. As an applied physiology journal, topics of interest are not limited to a particular organ system. The journal, therefore, considers a wide array of integrative and translational research topics examining the mechanisms involved in disease processes and mitigation strategies, as well as the promotion of health and well-being throughout the lifespan. Priority is given to manuscripts that provide mechanistic insight deemed to exert an impact on the field.
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