Department of Pathology and Microbiology, Nebraska Medical Center, Omaha, Nebraska.
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
Am J Pathol. 2021 Apr;191(4):759-771. doi: 10.1016/j.ajpath.2021.01.002. Epub 2021 Jan 14.
Pancreatic ductal adenocarcinoma (PDAC) manifests aggressive tumor growth and early metastasis. Crucial steps in tumor growth and metastasis are survival, angiogenesis, invasion, and immunosuppression. Our prior research showed that chemokine CXC- receptor-2 (CXCR2) is expressed on endothelial cells, innate immune cells, and fibroblasts, and regulates angiogenesis and immune responses. Here, we examined whether tumor angiogenesis, growth, and metastasis of CXCR2 ligands expressing PDAC cells are regulated in vivo by a host CXCR2-dependent mechanism. C57BL6 Cxcr2 mice were generated following crosses between Cxcr2 female and Cxcr2 male. Cxcr2 ligands expressing Kirsten rat sarcoma (KRAS-PDAC) cells were orthotopically implanted in the pancreas of wild-type or Cxcr2 C57BL6 mice. No significant difference in PDAC tumor growth was observed. Host Cxcr2 loss led to an inhibition in microvessel density in PDAC tumors. Interestingly, an enhanced spontaneous and experimental liver metastasis was observed in Cxcr2 mice compared with wild-type mice. Increased metastasis in Cxcr2 mice was associated with an increase in extramedullary hematopoiesis and expansion of neutrophils and immature myeloid precursor cells in the spleen of tumor-bearing mice. These data suggest a dynamic role of host CXCR2 axis in regulating tumor immune suppression, tumor growth, and metastasis.
胰腺导管腺癌 (PDAC) 表现出侵袭性肿瘤生长和早期转移。肿瘤生长和转移的关键步骤包括存活、血管生成、侵袭和免疫抑制。我们之前的研究表明，趋化因子 CXC-受体-2 (CXCR2) 在内皮细胞、固有免疫细胞和成纤维细胞上表达，并调节血管生成和免疫反应。在这里，我们研究了表达 CXCR2 配体的 PDAC 细胞的肿瘤血管生成、生长和转移是否受宿主 CXCR2 依赖性机制的调节。通过雌性和雄性 Cxcr2 之间的杂交产生 C57BL6 Cxcr2 小鼠。将表达 Kirsten 大鼠肉瘤 (KRAS-PDAC) 细胞的 CXCR2 配体原位植入野生型或 Cxcr2 C57BL6 小鼠的胰腺中。未观察到 PDAC 肿瘤生长的显著差异。宿主 Cxcr2 缺失导致 PDAC 肿瘤中的微血管密度抑制。有趣的是，与野生型小鼠相比，Cxcr2 小鼠中自发和实验性肝转移明显增加。Cxcr2 小鼠中的转移增加与骨髓外造血增加以及肿瘤携带小鼠脾脏中中性粒细胞和未成熟髓样前体细胞的扩张有关。这些数据表明宿主 CXCR2 轴在调节肿瘤免疫抑制、肿瘤生长和转移方面具有动态作用。
