TY - JOUR
T1 - High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic Kras
AU - Wislez, Marie
AU - Fujimoto, Nobukazu
AU - Izzo, Julie G.
AU - Hanna, Amy E.
AU - Cody, Dianna D.
AU - Langley, Robert R.
AU - Tang, Hongli
AU - Burdick, Marie D.
AU - Sato, Mitsuo
AU - Minna, John D.
AU - Mao, Li
AU - Wistuba, Ignacio
AU - Strieter, Robert M.
AU - Kurie, Jonathan M.
PY - 2006/4/15
Y1 - 2006/4/15
N2 - CXCL8, a ligand for the chemokine receptor CXCR2, was recently reported to be a transcriptional target of Ras signaling, but its role in Ras-induced tumorigenesis has not been fully defined. Here, we investigated the role of KC and MIP-2, the murine homologues of CXCL8, in Kras LA1 mice, which develop lung adenocarcinoma owing to somatic activation of the KRAS oncogene. We first investigated biological evidence of CXCR2 ligands in Kras LA1 mice. Malignant progression of normal alveolar epithelial cells to adenocarcinoma in Kras LA1 mice was associated with enhanced intralesional vascularity and neutrophilic inflammation, which are hallmarks of chemoattraction by CXCR2 ligands. In in vitro migration assays, supernatants of bronchoalveolar lavage samples from Kras LA1 mice chemoattracted murine endothelial cells, alveolar inflammatory cells, and the LKR-13 lung adenocarcinoma cell line derived from Kras LA1 mice, an effect that was abrogated by pretreatment of the cells with a CXCR2-neutralizing antibody. CXCR2 and its ligands were highly expressed in LKR-13 cells and premalignant alveolar lesions in Kras LA1 mice. Treatment of Kras LA1 mice with a CXCR2-neutralizing antibody inhibited the progression of premalignant alveolar lesions and induced apoptosis of vascular endothelial cells within alveolar lesions. Whereas the proliferation of LKR-13 cells in vitro was resistant to treatment with the antibody, LKR-13 cells established as syngeneic tumors were sensitive, supporting a role for the tumor microenvironment in the activity of CXCR2. Thus, high expression of CXCR2 ligands may contribute to the expansion of early alveolar neoplastic lesions induced by oncogenic KRAS.
AB - CXCL8, a ligand for the chemokine receptor CXCR2, was recently reported to be a transcriptional target of Ras signaling, but its role in Ras-induced tumorigenesis has not been fully defined. Here, we investigated the role of KC and MIP-2, the murine homologues of CXCL8, in Kras LA1 mice, which develop lung adenocarcinoma owing to somatic activation of the KRAS oncogene. We first investigated biological evidence of CXCR2 ligands in Kras LA1 mice. Malignant progression of normal alveolar epithelial cells to adenocarcinoma in Kras LA1 mice was associated with enhanced intralesional vascularity and neutrophilic inflammation, which are hallmarks of chemoattraction by CXCR2 ligands. In in vitro migration assays, supernatants of bronchoalveolar lavage samples from Kras LA1 mice chemoattracted murine endothelial cells, alveolar inflammatory cells, and the LKR-13 lung adenocarcinoma cell line derived from Kras LA1 mice, an effect that was abrogated by pretreatment of the cells with a CXCR2-neutralizing antibody. CXCR2 and its ligands were highly expressed in LKR-13 cells and premalignant alveolar lesions in Kras LA1 mice. Treatment of Kras LA1 mice with a CXCR2-neutralizing antibody inhibited the progression of premalignant alveolar lesions and induced apoptosis of vascular endothelial cells within alveolar lesions. Whereas the proliferation of LKR-13 cells in vitro was resistant to treatment with the antibody, LKR-13 cells established as syngeneic tumors were sensitive, supporting a role for the tumor microenvironment in the activity of CXCR2. Thus, high expression of CXCR2 ligands may contribute to the expansion of early alveolar neoplastic lesions induced by oncogenic KRAS.
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U2 - 10.1158/0008-5472.CAN-05-3842
DO - 10.1158/0008-5472.CAN-05-3842
M3 - Article
C2 - 16618742
AN - SCOPUS:33646255924
SN - 0008-5472
VL - 66
SP - 4198
EP - 4207
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -