Pharmacology Institute, Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany.
Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Cells. 2022 Aug 24;11(17):2634. doi: 10.3390/cells11172634.
In addition to the poor prognosis, excruciating abdominal pain is a major challenge in pancreatic cancer. Neurotropism appears to be the underlying mechanism leading to neuronal invasion. However, there is a lack of animal models suitable for translationally bridging in vitro findings with clinical trials. We characterized KPC (Kras; Trp53; P48-Cre) and KPPC (Kras; Trp53; P48-Cre) mice with genetically determined pancreatic ductal adenocarcinoma (PDAC) and compared them with an orthotopic pancreatic cancer mouse model, healthy littermates and human tissue. We analyzed behavioral correlates of cancer-associated pain and well-being, and studied neuronal remodeling and cytokine expression. Histologically, we found similarities between KPC and KPPC tissue with human samples. Compared to healthy littermates, we detect nerve fiber hypertrophy, which was not restricted to a certain fiber type. Interestingly, while KPPC mice showed significantly reduced well-being, KPC mice emerged to be better suited for studying long-lasting cancer pain that emerges over a slow course of tumor progression. To address the neuroinflammatory correlate of loss of well-being, we studied cytokine levels in KPPC mice and observed a significant upregulation of CXCL16, TNFRSF5, CCL24, CXCL1, CCL22, CLL20 and CX2CL1. In summary, we demonstrate that the KPC mouse model is best suited to studying cancer pain, whereas the KPPC model can be employed to study cancer-associated reduction in well-being.
除了预后不良外，剧烈的腹痛也是胰腺癌的一个主要挑战。神经趋向性似乎是导致神经元入侵的潜在机制。然而，目前缺乏适合转化的动物模型，无法将体外研究结果与临床试验联系起来。我们对具有遗传决定的胰腺导管腺癌（PDAC）的 KPC（Kras；Trp53；P48-Cre）和 KPPC（Kras；Trp53；P48-Cre）小鼠进行了特征描述，并将其与原位胰腺癌小鼠模型、健康同窝仔鼠和人类组织进行了比较。我们分析了与癌症相关的疼痛和幸福感的行为相关性，并研究了神经元重塑和细胞因子表达。组织学上，我们发现 KPC 和 KPPC 组织与人类样本之间存在相似之处。与健康同窝仔鼠相比，我们检测到神经纤维肥大，而且不限于特定的纤维类型。有趣的是，虽然 KPPC 小鼠的幸福感明显降低，但 KPC 小鼠更适合研究在肿瘤缓慢进展过程中出现的长期癌症疼痛。为了研究幸福感丧失的神经炎症相关性，我们研究了 KPPC 小鼠中的细胞因子水平，并观察到 CXCL16、TNFRSF5、CCL24、CXCL1、CCL22、CLL20 和 CX2CL1 的显著上调。总之，我们证明 KPC 小鼠模型最适合研究癌症疼痛，而 KPPC 模型可用于研究与癌症相关的幸福感降低。
