Lu Feiqi, Osei-Hwedieh David, Mandell Jonathan B, Morales-Restrepo Alejandro, Hankins Margaret L, Crasto Jared A, Ma Ruichen, Dinh Vu, Watters Rebecca J, Weiss Kurt R
Musculoskeletal Oncology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine Pittsburgh, PA, USA.
School of Medicine, Tsinghua University Beijing, China.
Am J Cancer Res. 2019 Aug 1;9(8):1746-1756. eCollection 2019.
Cancer-associated cachexia is a wasting syndrome that affects up to 50% of cancer patients. It is defined as unintentional weight loss ≥5% over 6 months and characterized by muscle atrophy, fatigue, and anorexia that are refractory to nutritional support. Sarcoma describes a diverse group of malignancies arising from the connective tissues. Sarcoma patients are uniquely susceptible to cancer-associated cachexia given its origins in the musculoskeletal system. Our previous research suggests that sarcoma cells may contribute to sarcoma-associated cachexia (SAC) via establishment of TNF-α-mediated inflammation and dysregulation of muscle homeostasis by abnormal Notch signaling. Here, we examine the role of the Notch pathway and pro-inflammatory cytokines in cells derived from cachectic and non-cachectic human sarcoma patients. We observed increased expression of Notch pathway genes in the cachexia group while no differences in pro-inflammatory cytokines were observed. Co-culture of muscle-derived stem cells (MDSCs) and sarcoma cells demonstrated the inhibition of MDSC maturation with both cachectic and non-cachectic patient cells, corresponding to elevated and Notch pathway expression in MDSCs. Our findings suggest that there is no difference in inflammatory profile between cachexia and non-cachexia sarcoma samples. However, Cachectic sarcoma samples express increased Notch that mediates muscle wasting possibly through inhibition of myogenesis.
癌症相关性恶病质是一种消耗综合征，影响多达50%的癌症患者。它被定义为在6个月内非自愿体重减轻≥5%，其特征为肌肉萎缩、疲劳和厌食，且对营养支持无效。肉瘤是指起源于结缔组织的一组多样的恶性肿瘤。肉瘤患者因其起源于肌肉骨骼系统，故而特别易患癌症相关性恶病质。我们之前的研究表明，肉瘤细胞可能通过建立肿瘤坏死因子-α介导的炎症以及通过异常Notch信号传导导致肌肉稳态失调，从而引发肉瘤相关性恶病质（SAC）。在此，我们研究Notch通路和促炎细胞因子在恶病质和非恶病质人类肉瘤患者来源的细胞中的作用。我们观察到恶病质组中Notch通路基因的表达增加，而促炎细胞因子未观察到差异。肌肉来源的干细胞（MDSC）与肉瘤细胞共培养显示，恶病质和非恶病质患者细胞均抑制了MDSC的成熟，这与MDSC中Notch通路表达升高相对应。我们的研究结果表明，恶病质和非恶病质肉瘤样本之间的炎症特征没有差异。然而，恶病质肉瘤样本中Notch表达增加，可能通过抑制肌生成介导肌肉消耗。
