New metastatic model of human small‐cell lung cancer by orthotopic transplantation in mice

Abstract

Small-cell lung cancer (SCLC) is an aggressive cancer with high metastatic ability and novel strategies against the metastasis are urgently needed to improve SCLC treatment. However, the mechanism of metastasis of SCLC remains largely to be elucidated. For further studies of SCLC metastasis, we developed a new orthotopic transplantation model in mice. We established a GFP-labeled subline from the human SCLC cell line DMS273 and transplanted them orthotopically into the lung of nude mice with Matrigel. The GFP-labeled cells showed significant metastatic activity and formed metastatic foci in distant tissues such as bone, kidney, and brain, as observed in SCLC patients. From a bone metastasis focus of the mouse, we isolated another subline, termed G3H, with enhanced metastatic potential and higher hepatocyte growth factor (HGF) expression than the parental line. Further studies indicated that the HGF/MET signaling pathway was involved in in vitro motility and invasion activities of the G3H cells and treatments with MET inhibitors decreased formation of distant metastases in our orthotopic model using G3H cells. These data indicated that our model mimics the clinical aspect of SCLC such as metastatic tropism and autocrine of HGF/MET signaling. Compared with other orthotopic SCLC models, our model has a superior ability to form distant metastases. Therefore, our model will provide a valuable tool for the study of SCLC metastasis.

Impact of MET inhibition on small‐cell lung cancer cells showing aberrant activation of the hepatocyte growth factor/MET pathway

“…Sakamoto et al . showed that treatment with MET inhibitors constrained the formation of distant metastases in SCLC cells showing high HGF production in an orthotopic model . Maulik et al .…”

“…The human SCLC cell lines SBC‐3 and SBC‐5, were kindly provided by Dr. K. Kiura (Okayama University, Okayama, Japan). DMS237 and DMS273‐G3H were obtained as reported previously . Briefly, DMS273‐G3H was established using tumor cells from a bone metastasis after we had implanted DMS273 orthotopically into the left lung of nude mice.…”

Generation and evaluation of a chimeric antibody against coxsackievirus and adenovirus receptor for cancer therapy

“…Human SCLC cell lines NCI‐H69, DMS53, and DMS114 were maintained in RPMI‐1640 medium containing 10% FBS. Human prostate cancer cell line DU‐145, human SCLC cell line DMS273, GFP‐labeled subline DMS273‐GFP, highly metastatic subline G3H, and C5B (S. Sakamoto, H. Inoue & M. Kawada, unpubl. data, manuscript in preparation) were maintained in DMEM (Nissui) containing 10% FBS.…”

“…injection of the antibodies was started. To prepare the orthotopic transplanted xenograft model of the highly metastatic subline of DMS273 human SCLC cells, 2.5 × 10 5 C5B cells were injected into the left lungs of nude mice as described previously . An Olympus OV110 Small Animal Imaging System (Olympus Corp.) was used for imaging orthotopic and metastatic tumor formation in the orthotopic transplanted xenograft model.…”

Lentivirus-mediated knockdown of NLK inhibits small-cell lung cancer growth and metastasis

“…SCLC accounts for ~15% of all new cases of lung cancer, with >150,000 cases every year worldwide 2. Clinically, SCLC is distinguished from NSCLC by aggressive growth and widespread metastasis 3. Most patients with SCLC already show clinically detectable metastases at diagnosis and have extremely poor prognosis even when treated with combined modalities 4.…”