Abstract
Lung cancer is one of the leading causes of cancer related death worldwide with more than a million deaths per year. The poor prognosis is due to its high aggressiveness and its early metastasis. Although the exact mechanisms are still unknown, the process of epithelial to mesenchymal transition (EMT) seems to be involved in these neoplastic processes. We already demonstrated that serum levels of CCL18, a primate specific chemokine, are highly elevated in patients with lung cancer and correlate with their survival time of patients with adenocarcinoma of the lung. Therefore, we hypothesized that CCL18 may be directly involved in pathological processes of lung cancer, e.g. EMT. We investigated the effect of CCL18 on A549, an adenocarcinoma cell line of the lung, on EMT and other cell functions like proliferation, chemotaxis, invasion, chemoresistance and proliferation. Exposure of A549 lung cancer cells to CCL18 in various concentrations decreases the epithelial marker E-cadherin, whereas FSP-1, a marker of the mesenchymal phenotype increases. Accordingly, CCL18 induced the transcriptional EMT regulator SNAIL1 in a dose dependent fashion. In contrast, an increasing CCL18 concentration was associated with a decline of cell proliferation rate. In addition, CCL18 induced chemotaxis of these cells and increased their chemoresistance. Therefore, CCL18 may be an interesting therapeutic target for NSCLC.
Highlights
Tumor metastasis is a complex event involving multiple steps including separation of cancer cells from the compact primary tumor, migration into vessels, invasion in tissue and formation of a secondary tumor nodule
(R&D Systems, Wiesbaden, FRG), recombinant human CC-Chemokine Ligand 18 (CCL18) from Immunotools, Friesoyte, Germany, polyclonal rabbit antibodies against human FSP-1 and human SNAIL1 and a mouse monoclonal antibody against human tubulin were purchased from abcam and a polyclonal rabbit antibody against human E-cadherin was from upstate
85% of these patients suffer from non-small cell lung cancer (NSCLC), which is subdivided into squamous carcinoma, adenocarcinoma, large cell carcinomas and other rare subtypes [24]
Summary
Tumor metastasis is a complex event involving multiple steps including separation of cancer cells from the compact primary tumor, migration into vessels, invasion in tissue and formation of a secondary tumor nodule. The process of EMT is associated with a loss of E-cadherin, which is positively correlated with tumor stage and poor survival in many epithelial tumor [4,5,6]. TAMs are alternatively activated macrophages secreting a specific pattern of several tumor promoting cytokines and growth factors One of these cytokines is the human specific CC-Chemokine Ligand 18 (CCL18) which is highly present in lung tissue and involved in several pathological processes of malignant diseases or fibrosis [15,16,17,18,19,20]. We already demonstrated that CCL18 is highly elevated in sera of patients with non small cell lung cancer and correlates with tumor stage and overall survival in the subgroup of adenocarcinoma [21,22]. Mean CCL18 serum level of the patients with non-small-cell lung cancer was 150(857) ng/ml vs. 32(61) ng/
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