Lung cancer is the leading cause of cancer-related death in industrialised countries. The majority of patients with lung cancer have incurable advanced disease with very poor therapeutic options, so new treatment approaches such as targeted therapy are urgently needed. The malignant phenotype of lung cancer may be partially attributable to abnormalities in growth factors and their receptors acting via both autocrine and paracrine pathways. An understanding of the abnormal expression of such growth factors and their receptors is crucial to find new therapeutic targets. Lung cancer can be classified into small cell lung cancer (SCLC), which has a neuroendocrine phenotype, and non-small cell lung cancer (NSCLC), which includes adenocarcinoma, squamous cell carcinoma and large cell carcinoma. Both SCLC and NSCLC have been shown to produce a variety of growth factors (Woll, 1996).
Interleukin-8/CXCL8 (IL-8) is a member of the CXC chemokine family, which was originally classified as a neutrophil chemoattractant with inflammatory activity (Baggiolini et al, 1989). Two IL-8 receptors, CXCR1 and CXCR2, have been identified. They share 77% amino-acid identity and belong to the superfamily of seven transmembrane domain, G protein-coupled receptors, whose signalling is mediated by heterotrimeric G proteins, resulting in the exchange of GDP for GTP on the α subunit of the G protein (Wess, 1997). CXCR1 and CXCR2 have been found on many normal cells such as neutrophils, basophils, lymphocytes, monocytes, keratinocytes and endothelial cells.
Interleukin-8 is a potent angiogenic factor in several cancers including NSCLC (Smith et al, 1994) and is associated with metastasis (Singh et al, 1994; Ueda et al, 1994; Luca et al, 1997). Elevated IL-8 is correlated with angiogenesis, tumour progression and poor survival in NSCLC (Yuan et al, 2000; Masuya et al, 2001; Orditura et al, 2002; Chen et al, 2003). CXCL8 has been shown to be mitogenic for cancers such as melanoma (Schadendorf et al, 1993), colon cancer (Brew et al, 2000; Li et al, 2001), pancreatic cancer (Miyamoto et al, 1998), malignant mesothelioma (Galffy et al, 1999) and Kaposi's sarcoma (Masood et al, 2001). However, the role of IL-8 in lung cancer has been controversial. It was shown that the inhibition of lung cancer growth by targeting IL-8 in a mouse model was solely due to the inhibition of the angiogenic effect of IL-8 (Arenberg et al, 1996). Interleukin-8 was also shown to inhibit directly lung cancer cell proliferation in vitro (Wang et al, 1996). CXCR1 and CXCR2 were found on a variety of tumour cells, but have not been reported in lung cancer. In this study, we investigated the expression of IL-8 and its receptors, CXCR1 and CXCR2, in a panel of NSCLC and SCLC cell lines and characterised the mitogenic role of IL-8 in lung cancer growth.