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Abstract
The interaction between cancer cells and the cancer stroma plays a crucial role in tumor progression and metastasis in diverse malignancies, including oral cancer. However, the mechanism underlying this interaction remains incompletely elucidated. Here, to investigate the interaction between oral cancer cells and fibroblasts, which are major cellular components of the tumor stroma, we conducted an in vitro study by using human oral squamous cell carcinoma (OSCC) cell lines and normal human dermal fibroblasts (NHDFs). The results of transwell assays revealed that the migration and invasion of 2 OSCC cell lines, HO1-N-1 and HSC3, were markedly stimulated upon coculturing with NHDFs. To investigate the factors that promote tumor invasion, we isolated NHDFs from cocultures prepared with HO1-N-1 cells and performed microarray analysis. Among the various genes that were upregulated, we identified the gene encoding leukemia inhibitory factor (LIF), and we focused on LIF in further analyses. We confirmed that all OSCC-derived conditioned media potently upregulated LIF expression in NHDFs, and the results of our transwell analysis demonstrated that NHDF-induced OSCC migration and invasion were inhibited by LIF-neutralizing antibodies. Furthermore, immunohistochemical analysis of patient samples revealed that in 44 out of 112 OSCC cases, LIF was expressed in the tumor stroma, particularly in cancer-associated fibroblasts (CAFs), and, notably, clinicopathological analyses confirmed that LIF expression in CAFs was significantly correlated with increased depth of tumor invasion. Collectively, our results suggest that OSCC stimulates fibroblasts to produce LIF, which, in turn, participates in cancer-cell invasion. Our finding offers a potential therapeutic strategy targeting the cancer stroma for the treatment of OSCC patients.
Highlights
Oral cancer is the most common type of head and neck cancer, and is the sixth most common cancer in the world
The results of transwell assays revealed that the cells of 2 oral squamous cell carcinoma (OSCC) cell lines, HSC3 and HO1-N-1, showed significantly higher migration and invasion activities when cultured with normal human dermal fibroblasts (NHDFs) than when cultured alone (Fig 1A and 1B)
These results suggested that fibroblasts exhibit the potential to promote OSCC cell migration and invasion by producing certain soluble factors in response to the cancer cells
Summary
Oral cancer is the most common type of head and neck cancer, and is the sixth most common cancer in the world. In the tumor progression in various types of malignancies, including oral cancer, a crucial role is played by the cancer stroma, which is composed of fibroblasts, immune cells, capillaries, basement membrane, and the extracellular matrix surrounding the cancer cells. Among these components, the activated fibroblasts present in the cancer stroma, the so-called cancer-associated fibroblasts (CAFs), are dominant components, and numerous studies conducted over the years have revealed that CAFs play a prominent functional role in cancer progression and metastasis by acting through diverse signaling pathways [4, 5]. CAFs can originate from resident fibroblasts in the immediate vicinity of the tumor, circulating mesenchymal stem cells derived from the bone marrow, cancer cells that have undergone epithelial-to-mesenchymal transition (EMT), or endothelial cells in the tumor [4, 5]
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