CXCR4 antagonists suppress small cell lung cancer progression.
Small cell lung cancer (SCLC) is an aggressive tumor with poor prognosis due to early metastatic spread and development of chemoresistance. Playing a key role in tumor-stroma interactions the CXCL12-CXCR4 axis may be involved in both processes and thus represent a promising therapeutic target in SCLC treatment. In this study we investigated the effect of CXCR4 inhibition on metastasis formation and chemoresistance using an orthotopic xenograft mouse model. This model demonstrates regional spread and spontaneous distant metastases closely reflecting the clinical situation in extensive SCLC. Tumor engraftment, growth, metabolism, and metastatic spread were monitored using different imaging techniques: Magnetic Resonance Imaging (MRI), Bioluminescence Imaging (BLI) and Positron Emission Tomography (PET). Treatment of mice bearing chemoresistant primary tumors with the specific CXCR4 inhibitor AMD3100 reduced the growth of the primary tumor by 61% (P<0.05) and additionally suppressed metastasis formation by 43%. In comparison to CXCR4 inhibition as a monotherapy, standard chemotherapy composed of cisplatin and etoposide reduced the growth of the primary tumor by 71% (P<0.01) but completely failed to suppress metastasis formation. Combination of chemotherapy and the CXCR4 inhibitor integrated the highest of both effects. The growth of the primary tumor was reduced to a similar extent as with chemotherapy alone and metastasis formation was reduced to a similar extent as with CXCR4 inhibitor alone. In conclusion, we demonstrate in this orthotopic mouse model that the addition of a CXCR4 inhibitor to chemotherapy significantly reduces metastasis formation. Thus, it might improve the overall therapy response and consequently the outcome of SCLC patients.
Department of Medicine, Division of Hematology/Oncology, University Medical Center, Hugstetter, D-79106 Freiburg, Germany.
Sanaz
S
Taromi
Department of Pathology, University Medical Center, Breisacher, D-79106 Freiburg.
Gian
G
Kayser
Department of Medicine, Division of Hematology/Oncology, University Medical Center, Hugstetter, D-79106 Freiburg, Germany.
Julie
J
Catusse
Department of Radiology Medical Physics, University Medical Center, Breisacher, D-79106 Freiburg.
Dominik
D
von Elverfeldt
Department of Radiology Medical Physics, University Medical Center, Breisacher, D-79106 Freiburg.
Wilfried
W
Reichardt
Institute of Nuclear Medicine, University Medical Center, Hugstetter D-79106 Freiburg, Germany.|Department of Radiology, Memorial Sloan Kettering Cancer Center, New York 10065, NY, USA.|University of Freiburg, Faculty of Biology, Schaenzlestrasse, D-79106 Freiburg, Germany.
Friederike
F
Braun
Institute of Nuclear Medicine, University Medical Center, Hugstetter D-79106 Freiburg, Germany.|Department of Radiology, Memorial Sloan Kettering Cancer Center, New York 10065, NY, USA.
Wolfgang A
WA
Weber
Department of Medicine, Division of Hematology/Oncology, University Medical Center, Hugstetter, D-79106 Freiburg, Germany.
Robert
R
Zeiser
Department of Medicine, Division of Hematology/Oncology, University Medical Center, Hugstetter, D-79106 Freiburg, Germany.|University Furtwangen, Faculty of Medical and Life Sciences, Campus Schwenningen, VS-78054 Schwenningen, Germany.
Meike
M
Burger
D000818:Animals; D001596:Benzylamines; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002465:Cell Movement; D002945:Cisplatin / Q000627:therapeutic use; D000080027:Cyclams; D004268:DNA-Binding Proteins / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000627:therapeutic use; D006571:Heterocyclic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D004268:DNA-Binding Proteins; D006571:Heterocyclic Compounds; D009687:Nuclear Proteins; D010455:Peptides; C499311:RAG2 protein, human; D019718:Receptors, CXCR4; C488289:TN14003; D005047:Etoposide; D002945:Cisplatin; C088327:plerixafor
AMD3100; CXCL12; metastasis; mouse model; small cell lung cancer