ABSTRACT
BACKGROUND: Cancer-associated fibroblasts (CAFs) are recognized as a pivotal promoter in cancer initiation and development. However, the role of CAFs in the progression and metastasis of oral squamous cell carcinoma (OSCC) has not been fully elucidated. MATERIALS AND METHODS: Lymphatic vessel density (LVD) and microvessel density (MVD) and the expression of α-smooth muscle actin (α-SMA) and matrix metalloproteinase-9 (MMP-9) were evaluated by immunohistochemistry in 86 cases of OSCC. The correlations between α-SMA expression and MMP-9 expression, LVD, MVD, and other clinicopathological parameters were analyzed. In vitro invasion assay was performed to assess the effect of CAFs on the invasion of OSCC cells. We also investigated the effect of CAFs on the angiogenesis and lymphangiogenesis by inoculating CAFs with OSCC cells into nude mice subcutaneously. RESULTS: Positive expression of α-SMA protein was detected in 69.8% of the tumors. Increased α-SMA expression was correlated strongly with enhanced tumor invasion, higher tumor grade, increased risk of recurrence, lymph node involvement, and higher peritumoral lymphatic vessel density and microvessel density (P < 0.05). CAFs induced more cancer cells to invade relative to normal fibroblasts (NFs) (P < 0.05). Compared with co-injection of OSCC cells and NFs or injection of tumor cells alone, co-injection of OSCC cells and CAFs resulted in earlier tumor formation and bigger tumor volume accompanied with increased angiogenesis and lymphangiogenesis (P < 0.05). CONCLUSION: CAFs may play critical roles in OSCC progression as an inducer of tumor invasion, angiogenesis, and lymphangiogenesis. Therapeutic strategies targeting CAFs against OSCC is promising and need further exploration.
Subject(s)
Actins/metabolism , Cancer-Associated Fibroblasts/physiology , Carcinoma, Squamous Cell/metabolism , Lymphangiogenesis , Matrix Metalloproteinase 9/metabolism , Mouth Neoplasms/metabolism , Neoplasm Invasiveness , Neovascularization, Pathologic , Animals , Carcinoma, Squamous Cell/physiopathology , Cell Line, Tumor , Cells, Cultured , Humans , Immunohistochemistry , Mice, Nude , Mouth Neoplasms/physiopathologyABSTRACT
Integrin-linked kinase (ILK) plays a key role in cell-excellular matrix interactions mediated by integrins and several growth factors, regulating cell proliferation, apoptosis, differentiation, and migration. It has also been implicated in the development and progression in several malignancies involving epithelial to mesenchymal transition (EMT). However, the correlations between ILK and EMT markers and the progression of salivary adenoid cystic carcinoma (SACC) have not been well elucidated. Here, by immunohistochemistry, we studied the expression of ILK, Snail, E-cadherin, and N-cadherin in 94 SACC specimens and analyzed their correlations with clinicopathologic characteristics. Positive expression of ILK protein was detected in 76.6 % of the tumors. Increased expression of ILK and Snail and decreased E-cadherin expression correlated strongly with tumor solid type (P = 0.017, P = 0.008, and P = 0.038, respectively), advanced TNM stage (P = 0.021, P = 0.034, and P = 0.009, respectively), and increased risk of recurrence (P = 0.023, P = 0.011, and P = 0.039, respectively) and distant metastasis (P < 0.001, P < 0.001, and P = 0.001, respectively). Moreover, up-regulation of Snail and N-cadherin and down-regulation of E-cadherin correlated significantly with ILK over-expression (P < 0.001, P = 0.001, and P < 0.001, respectively) and a neural-invasive phenotype (P = 0.017, P = 0.002, and P < 0.001, respectively). Taken together, our results suggest that ILK may have an important role in progression and metastasis of SACC, possibly through EMT involving up-regulation of Snail and consequent aberrant expression of E-cadherin and N-cadherin. ILK should be considered as a potential therapeutic molecular target for patients with SACC.
