Abstract
Abstract Activation of the receptor tyrosine kinase Axl by its ligand gas6 is implicated in several diseases included inflammation and cancer. Our previous report demonstrated that Axl signal promotes oral squamous cell carcinoma (OSCC) carcinogenesis and progression. Recent studies also suggest that tumor-associated macrophage (TAM) promote tumor growth and metastasis. This study aims to study the potential involvement of Axl signal in the protumoral effect of TAM. We carried out coculture experiment by incubation of oral cancer cells (YD38) and macrophages (THP1). The expression of gas6 and Axl were examined in both cells. Characterized gene expression for M1 and M2 macrophage and EMT gene for cancer were also examined. The effect of Axl signal on cancer cells were further investigated by knockdown Axl expression and neutralized gas6 antibody in coculture system. The association Axl activation (pAxl) and TAM distribution were analyzed by Immunohistochemistry in cancer tissues. Our data indicated that upon coculture with cancer cells, TAM polarized to M2 phenotype with high IL10/low IL12 expression and elevated in gas6 secretion. After coculture with TAM, activation of Axl signal in cancer cells was noted. Furthermore, cancer increased mesenchymal markers expression and invasion/migration ability. While neutralzied gas6 or knockdown Axl, the coculture effects was diminished. In addition our result also demonstrated gas6/Axl signal elevated MMP-2 and -9 through NF-kb pathway to promote tumor invasion/migration, in which coculture of TAM increased NF-kb nuclear translocation and its bonding to MMPs promoter in cancer cells. Finally, in vivo cancer tissues showed significant association between TAM distribution and Axl (phosphorylated) expression. In conclusion, our results showed that TAMs play a protumor role in OSCC. TAM activated Axl signal and promoted tumor progression through NF-kb pathway. Therefore, Gas6/Axl and NF-kb signals in OSCC could be a putative target for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 53. doi:1538-7445.AM2012-53
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