Granulocyte-macrophage-colony stimulating factor stimulates tumor invasiveness in squamous cell lung carcinoma

Abstract

Bronchial epithelial cells produce a significant amount of granulocyte-macrophage-colony stimulating factor (GM-CSF), which is believed to mediate both the host defense and inflammation. Recently, GM-CSF has been demonstrated to be produced by several tumor cells and also to be associated with tumor growth and metastasis. In the current study, the authors investigated the biologic role of GM-CSF produced by squamous cell lung carcinoma. The production of GM-CSF from 17 human lung carcinoma cell lines was determined by an enzyme-linked immunoabsorbent assay. In vitro invasiveness was investigated by using a Biocoat Matrigel (Collaborative Biomedical Products, Bedford, MA) precoated invasion chamber. The activity of the matrix metalloproteinases (MMPs) were examined by gelatin zymography. The expression of GM-CSF in 113 cases of resected nonsmall cell lung carcinoma was analyzed immunohistochemically, and the association between the expression of GM-CSF and clinicopathologic features was investigated. The production of GM-CSF by squamous cell carcinoma cell lines was closely related to the in vitro invasiveness and MMP activity of the cancer cells. Recombinant GM-CSF stimulated the invasiveness of less invasive LK-2 and LC-1 cells in a dose-dependent manner, and this stimulation was abrogated by the neutralizing anti-GM-CSF antibody. Furthermore, anti-GM-CSF antibody decreased the invasiveness of highly invasive EBC-1 and NCI-H157 cells. GM-CSF also increased the MMP activity of LK-2 and LC-1 cells. Of 113 resected nonsmall cell lung carcinomas, 30 of 71 squamous cell carcinomas (42.3%), and 24 of 42 adenocarcinomas (57.1%) stained positively for GM-CSF. The expression of GM-CSF in squamous cell carcinomas was associated with the local invasion by the primary tumor. These results suggest that the production of GM-CSF is involved in both the in vitro invasiveness and the local progression of squamous cell carcinoma of the lung.