TY - JOUR
T1 - Host Cxcr2-Dependent Regulation of Pancreatic Cancer Growth, Angiogenesis, and Metastasis
AU - Purohit, Abhilasha
AU - Saxena, Sugandha
AU - Varney, Michelle
AU - Prajapati, Dipakkumar R.
AU - Kozel, Jessica A.
AU - Lazenby, Audrey
AU - Singh, Rakesh K.
N1 - Publisher Copyright:
© 2021 American Society for Investigative Pathology
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2021.01.002
DO - 10.1016/j.ajpath.2021.01.002
M3 - Article
C2 - 33453178
AN - SCOPUS:85102789931
SN - 0002-9440
VL - 191
SP - 759
EP - 771
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -