| ObjectiveRecently, it has been realized that the tumor microenvironment and neoplastic cells act in concert to promote the growth and progression of the tumor mass.Malignant tumor microenvironment contains a large number of tumor associated macrophage(TAMs) and bioactive cytokines, such as colony stimulating factor-1(CSF-1), interleukin-6(IL-6) and a series of chemokines, etc. This study aimed to explore their relationship and their prognostic significance in surgically resected non-small cell lung cancer(NSCLC), and further analyzed their prognostic value and underlying related mechanisms in the invasion and progression of adenocarcinoma.Methods1. Tissue microarray and immunohistochemistry were used to detect the expression of CSF-1, IL-6 and TAMs marker CD68 in 417 patients with NSCLC undergoing complete pulmonary resection. Every part was carried out analysis,respectively combining with the clinicopathologic features and the clinical prognosis.2. We used immunohistochemistry or immunofluorescent double staining method to investigate the expression of CD68, CSF-1, IL-6, E-cadherin, snail and MMP-2 in lung adenocarcinoma specimens, mainly including 127 cases of lepidic predominant adenocarcinoma(LPA) and 37 cases of adenocarcinoma in situ and minimally invasive adenocarcinoma(AIS/MIA).3. CSF-1 expression was examined in matched cancerous tissues and para-cancerous tissues from 10 cases of adenocarcinoma patients by Western-blotting analysis. Tissue microarray and immunohistochemistry were used to detect the expression of CSF1, EGFR, CD68 in 266 cases of adenocarcinoma patients.Results:1. The expression of CSF-1 and IL-6 in NSCLC correlated positively with the in?ltration degree of interstitial TAMs(r=0.184 and r=0.196, respectively; P<.001).The expression of both CSF-1 and IL-6 was statistically signi?cant for survival(P<.001). Nevertheless, no such relationship was observed for CD68 in the tumor stroma(P>.05). When CSF-1 and/or IL-6 and CD68 were taken into considerationtogether, the result became statistically signi?cant. Multivariate analysis showed that co-expression of CD68/CSF-1/IL-6 remained independent prognostic factor(P <.05).2. Increased TAMs density was negatively associated with the prognosis of patients with adenocarcinoma(P<.05), and the infiltration degree of interstitial TAMs was higher in LPA than that in AIS/MIA(P<.05). Stratified analysis showed that in AIS /MIA patients, there was statistically significant difference between the number of TAMs <=25 and TAMs >25, between the other group and the CD68+CSF-1+IL-6+group(P<.05). While in patients with TAMs >25 and in patients with all 3 positive(CD68, CSF-1, IL-6), the survival rates were not significantly different between AIS/MIA and LPA(P>.05). Correlational analyses showed that E-cadherin, Snail, MMP-2expression were significantly correlated with the infiltration degree of TAMs(P<.05).3. Higher CSF-1 expression was detected in 5 cases of adenocarcinoma tissues relative to matched para-cancerous tissues. Univariate analysis indicated that TNM stage, number of involved nodes, number of involved nodal station, CSF-1 expression,co-expression of CSF-1/EGFR and CSF-1/CD68/EGFR were statistically significant for prognosis(P<.05). Multivariate analysis was performed to determine that TNM stage, co-expression of CSF1/EGFR and CSF1/CD68/EGFR remained independent risk factors(P<.05). Correlational analyses showed that expression of CSF-1, EGFR was positively related to the infiltration degree of TAMs(P<.05).Conclusion1. The combination of TAMs, CSF-1 and IL-6 is very likely to be a valuable independent predictor of survival in patients with NSCLC. Perhaps co-expression of CSF-1 and IL-6 induces TAMs to shift toward the tumor-promoting phenotype.2. TAMs might facilitate AIS /MIA progression to LPA, which may be closely related to induce epithelial-mesenchymal transition and degrade extracellular matrix.3. Co-expression of CSF-1 and EGFR may be a valuable independent prognostic predictor, and its mechanism is probably involved in the interaction of cancer cells and TAMs during the onset and proceeding of lung adenocarcinoma. |
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