Patients with pancreatic cancer often suffer from cachexia and experience gastrointestinal symptoms that may be related to intestinal smooth muscle cell (SMC) dysfunction. We hypothesized that pancreatic tumor organoids from cachectic patients release factors that perturb the SMC’s contractile characteristics. Human visceral SMCs were exposed to conditioned medium (CM) from the pancreatic tumor organoid cultures of cachectic (n= 2) and non-cachectic (n= 2) patients. Contractile proteins and markers of inflammation, muscle atrophy, and proliferation were evaluated by qPCR and Western blot. SMC proliferation and migration were monitored by live cell imaging. The Ki-67-positive cell fraction was determined in the intestinal smooth musculature of pancreatic cancer patients. CM from the pancreatic tumor organoids of cachectic patients did not affectIL-1β,IL-6,IL-8,MCP-1, orAtrogin-1expression. However, CM reduced the α-SMA, γ-SMA, and SM22-α levels, which was accompanied by a reduced SMC doubling time and increased expression ofS100A4, a Ca2+-binding protein associated with the synthetic SMC phenotype. In line with this, Ki-67-positive nuclei were increased in the intestinal smooth musculature of patients with a low versus high L3-SMI. In conclusion, patient-derived pancreatic tumor organoids release factors that compromise the contractile SMC phenotype and increase SMC proliferation. This may contribute to the frequently observed gastrointestinal motility problems in these patients.
胰腺癌患者常伴有恶病质，并出现可能与肠道平滑肌细胞功能障碍相关的胃肠道症状。我们假设，来自恶病质患者的胰腺肿瘤类器官会释放干扰平滑肌细胞收缩特性的因子。将人内脏平滑肌细胞分别暴露于恶病质患者（n=2）与非恶病质患者（n=2）胰腺肿瘤类器官培养的条件培养基中。通过qPCR和Western blot检测收缩蛋白及炎症、肌肉萎缩和增殖标志物的表达。采用活细胞成像技术监测平滑肌细胞增殖与迁移情况，并通过检测胰腺癌患者肠道平滑肌组织中Ki-67阳性细胞比例进行评估。恶病质患者胰腺肿瘤类器官的条件培养基未影响IL-1β、IL-6、IL-8、MCP-1或Atrogin-1的表达，但降低了α-SMA、γ-SMA和SM22-α水平，同时伴随平滑肌细胞倍增时间缩短及S100A4（一种与合成型平滑肌细胞表型相关的钙结合蛋白）表达增加。与此一致的是，低L3-SMI患者肠道平滑肌组织中Ki-67阳性细胞核比例较高L3-SMI患者显著增加。结论：患者来源的胰腺肿瘤类器官释放的因子会损害收缩型平滑肌细胞表型并促进其增殖，这可能是导致该类患者常见胃肠道动力障碍的重要原因。
肿瘤(癌症)患者之家