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.

• Authors: Shuichi Sakamoto, Hiroyuki Inoue, Shunichi Ohba, Yasuko Kohda, Ihomi Usami, Tohru Masuda, Manabu Kawada, Akio Nomoto
• Journal: Cancer science (Cancer Sci) Vol. 106 Issue 4 Pg. 367-74 (Apr 2015) ISSN: 1349-7006 [Electronic] England
• PMID: 25640943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• 5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
• Antineoplastic Agents
• HGF protein, human
• Indoles
• Sulfones
• Green Fluorescent Proteins
• Hepatocyte Growth Factor
• MET protein, human
• Proto-Oncogene Proteins c-met
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Bone Neoplasms (secondary)
• Brain Neoplasms (secondary)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Female
• Green Fluorescent Proteins (genetics)
• Hepatocyte Growth Factor (biosynthesis, metabolism)
• Humans
• Indoles (pharmacology)
• Kidney Neoplasms (secondary)
• Lung Neoplasms (drug therapy, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Metastasis
• Neoplasm Transplantation
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, metabolism)
• Signal Transduction
• Small Cell Lung Carcinoma (drug therapy, secondary)
• Sulfones (pharmacology)