title: Significance of interstitial tumor-associated macrophages in the progression of lung adenocarcinoma.
abstract: Stepwise progression from adenocarcinomain situ(AIS) and minimally invasive adenocarcinoma (MIA) to lepidic predominant adenocarcinoma (LPA) was proposed by various scholars. Interstitial tumor-associated macrophages (TAMs) and various potential chemokines involved in the progression from AIS/MIA to LPA were hypothesized. In the present study, immunohistochemistry or immunofluorescent double staining was used to detect the expression of the TAMs marker cluster of differentiation (CD) 68, tumor-derived colony-stimulating factor (CSF)-1, interleukin (IL)-6, matrix metalloproteinase (MMP)-2, E-cadherin and Snail in lung adenocarcinoma specimens, including AIS/MIA, LPA and other types. It was observed that infiltrating TAMs were negatively associated with the prognosis of patients, and that the infiltration degree of interstitial TAMs was higher in LPA than that in AIS/MIA. In addition, E-cadherin, Snail and MMP-2 expression were significantly correlated with the infiltration degree of TAMs. Survival analysis revealed that co-expression of CD68, CSF-1 and IL-6 was an independent prognostic factor. Stratified analysis demonstrated that, in AIS/MIA patients, there was a statistically significant difference between the number of TAMs (TAMs ≤25 and TAMs >25) in the CD68+CSF-1+IL-6+ group compared with other groups (including CD68+CSF-1-IL-6-, CD68+CSF-1+IL-6-, CD68+CSF-1-IL-6+ and CD68- groups). By contrast, in patients with TAMs >25 and in patients with positive CD68, CSF-1 and IL-6 expression, the survival rates were not significantly different between AIS/MIA and LPA. These results suggested that co-expression of TAMs marker CD68, CSF-1 and IL-6 may be a valuable independent prognostic predictor in lung adenocarcinoma. TAMs may facilitate AIS/MIA progression to LPA, which may be closely associated with the induction of the epithelial-mesenchymal transition.
authors.affiliation: Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Lung Cancer Center, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China.
authors.forename: Bing-Sheng
authors.initials: BS
authors.lastname: Sun
authors.affiliation: Department of Thoracic Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China.
authors.forename: Bao-Xiang
authors.initials: BX
authors.lastname: Pei
authors.affiliation: Department of Thoracic Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China.
authors.forename: Lu-Chang
authors.initials: LC
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China.
authors.forename: Guang-Jing
authors.initials: GJ
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China.
authors.forename: Ji-Kuan
authors.initials: JK
authors.lastname: Liu
authors.affiliation: Department of Thoracic Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Cui
authors.affiliation: Department of Thoracic Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China.
authors.forename: Fen
authors.initials: F
authors.lastname: Pan
authors.affiliation: Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Lung Cancer Center, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China.
authors.forename: Zhen-Fa
authors.initials: ZF
authors.lastname: Zhang
keywords: colony-stimulating factor-1; epithelial-mesenchymal transition; interleukin-6; lung adenocarcinoma; progression; tumor-associated macrophages