Abstract
Tumor-associated macrophages (TAMs), most of which display the immunosuppressive M2 phenotype, affect the tumor microenvironment and promote progression and metastasis in lung carcinoma. In this study, we analyzed clinical non-small cell lung cancer (NSCLC) samples and found that high densities of TAMs were associated with a poor prognosis in NSCLC patients. Moreover, the number of TAMs present correlated positively with expression of sex determining region Y (SRY)-related high mobility group box 9 (SOX9) in NSCLC tissues. TAMs secreted TGF-β, which increased SOX9 expression and promoted epithelial-to-mesenchymal transition (EMT) in lung cancer cells, thereby promoting tumor proliferation, migration, and invasion. SOX9 knockdown inhibited EMT, indicating that TGF-β-mediated EMT is SOX9-dependent. TGF-β induced SOX9 expression by upregulating the C-jun/SMAD3 pathway. These results indicate that TGF-β secreted by TAMs promotes SOX9 expression via the C-jun/SMAD3 pathway, thereby promoting tumor metastasis. The TGF-β/SOX9 axis may therefore be an effective target for the treatment of lung cancer.
Highlights
Lung carcinoma is one of the most commonly diagnosed cancers and the leading cause of cancerrelated death, killing more than 1.4 million people worldwide each year [1, 2]
To determine if SOX9 expression is correlated with number of tumor-associated macrophages (TAMs), we analyzed the distribution of TAMs (CD163+ macrophages) and SOX9 in specimens from lung cancer patients using immunofluorescent staining
We found that lung cancer cells promoted the M2 polarization of tumor-associated macrophages (TAMs), which in turn secretes Transforming growth factor-β (TGF-β) and promotes SOX9 expression via the C-jun/SMAD3 pathway, thereby promoting tumor metastasis (Figure 11)
Summary
Lung carcinoma is one of the most commonly diagnosed cancers and the leading cause of cancerrelated death, killing more than 1.4 million people worldwide each year [1, 2]. Up to 90% of all lung cancer mortality is a result of tumor metastasis [3]. Many patients remain at risk for local recurrence, distant metastasis, and subsequent development of additional primary tumors [4, 5]. The mechanisms underlying metastasis in lung cancer require further study to improve the accuracy of prognostic predictions. The development of malignancies and metastasis are closely related to the tumor microenvironment [6]. Transforming growth factor-β (TGF-β), a multifunctional cytokine that participates in various biological processes, suppresses cell growth in benign cells but promotes progression in cancer cells [8, 9]
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