Significance of interstitial tumor-associated macrophages in the progression of lung adenocarcinoma

Sun,Bing‑Sheng; Pei,Bao‑Xiang; Zhang,Kang; Zhang,Lu‑Chang; Zhang,Guang‑Jing; Liu,Ji‑Kuan; Cui,Hong‑Wei; Pan,Fen; Zhang,Zhen‑Fa

doi:10.3892/ol.2016.5270

Significance of interstitial tumor-associated macrophages in the progression of lung adenocarcinoma

Authors:
- Bing‑Sheng Sun
- Bao‑Xiang Pei
- Kang Zhang
- Lu‑Chang Zhang
- Guang‑Jing Zhang
- Ji‑Kuan Liu
- Hong‑Wei Cui
- Fen Pan
- Zhen‑Fa Zhang
View Affiliations

Affiliations: 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, Department of Thoracic Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
Published online on: October 17, 2016 https://doi.org/10.3892/ol.2016.5270
Pages: 4467-4476
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Stepwise progression from adenocarcinoma in 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.

View Figures

View References

1	Devesa SS, Bray F, Vizcaino AP and Parkin DM: International lung cancer trends by histologic type: Male: Female differences diminishing and adenocarcinoma rates rising. Int J Cancer. 117:294–299. 2005. View Article : Google Scholar : PubMed/NCBI
2	Soh J, Toyooka S, Ichihara S, Asano H, Kobayashi N, Suehisa H, Otani H, Yamamoto H, Ichimura K, Kiura K, et al: Sequential molecular changes during multistage pathogenesis of small peripheral adenocarcinomas of the lung. J Thorac Oncol. 3:340–347. 2008. View Article : Google Scholar : PubMed/NCBI
3	Mantovani A, Allavena P, Sica A and Balkwill F: Cancer-related inflammation. Nature. 454:436–444. 2008. View Article : Google Scholar : PubMed/NCBI
4	Solinas G, Germano G, Mantovani A and Allavena P: Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 86:1065–1073. 2009. View Article : Google Scholar : PubMed/NCBI
5	Mantovani A, Schioppa T, Porta C, Allavena P and Sica A: Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev. 25:315–322. 2006. View Article : Google Scholar : PubMed/NCBI
6	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
7	Detterbeck FC, Boffa DJ and Tanoue LT: The new lung cancer staging system. Chest. 136:260–271. 2009. View Article : Google Scholar : PubMed/NCBI
8	Richardsen E, Uglehus RD, Due J, Busch C and Busund LT: The prognostic impact of CSF-1, CSF-1 receptor, CD68 and CD3 in prostatic carcinoma. Histopathology. 53:30–38. 2008. View Article : Google Scholar : PubMed/NCBI
9	Gwak JM, Jang MH, Kim DI, Seo AN and Park SY: Prognostic value of tumor-associated macrophages according to histologic locations and hormone receptor status in breast cancer. PLoS One. 10:e01257282015. View Article : Google Scholar : PubMed/NCBI
10	Quail DF and Joyce JA: Microenvironmental regulation of tumor progression and metastasis. Nat Med. 19:1423–1437. 2013. View Article : Google Scholar : PubMed/NCBI
11	Hu M and Polyak K: Microenvironmental regulation of cancer development. Curr Opin Genet Dev. 18:27–34. 2008. View Article : Google Scholar : PubMed/NCBI
12	Zhang W, Zhu XD, Sun HC, Xiong YQ, Zhuang PY, Xu HX, Kong LQ, Wang L, Wu WZ and Tang ZY: Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res. 16:3420–3430. 2010. View Article : Google Scholar : PubMed/NCBI
13	Zabuawala T, Taffany DA, Sharma SM, Merchant A, Adair B, Srinivasan R, Rosol TJ, Fernandez S, Huang K, Leone G and Ostrowski MC: An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. Cancer Res. 70:1323–1333. 2010. View Article : Google Scholar : PubMed/NCBI
14	Subimerb C, Pinlaor S, Khuntikeo N, Leelayuwat C, Morris A, McGrath MS and Wongkham S: Tissue invasive macrophage density is correlated with prognosis in cholangiocarcinoma. Mol Med Rep. 3:597–605. 2010.PubMed/NCBI
15	Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, Wang XZ, Zhao YW and Wei YQ: Prognostic significance of tumor-associated macrophages in solid tumor: A meta-analysis of the literature. PloS One. 7:e509462012. View Article : Google Scholar : PubMed/NCBI
16	Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney A, Jones SJ, Iqbal J, Weisenburger DD, et al: Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med. 362:875–885. 2010. View Article : Google Scholar : PubMed/NCBI
17	Qian BZ and Pollard JW: Macrophage diversity enhances tumor progression and metastasis. Cell. 141:39–51. 2010. View Article : Google Scholar : PubMed/NCBI
18	Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, Rimoldi M, Biswas SK, Allavena P and Mantovani A: Macrophage polarization in tumour progression. Semin Cancer Biol. 18:349–355. 2008. View Article : Google Scholar : PubMed/NCBI
19	Sica A and Bronte V: Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 117:1155–1166. 2007. View Article : Google Scholar : PubMed/NCBI
20	Lippitz BE: Cytokine patterns in patients with cancer: A systematic review. Lancet Oncol. 14:e218–e228. 2013. View Article : Google Scholar : PubMed/NCBI
21	Bonecchi R, Locati M and Mantovani A: Chemokines and cancer: A fatal attraction. Cancer cell. 19:434–435. 2011. View Article : Google Scholar : PubMed/NCBI
22	Sica A, Allavena P and Mantovani A: Cancer related inflammation: The macrophage connection. Cancer Lett. 267:204–215. 2008. View Article : Google Scholar : PubMed/NCBI
23	Duluc D, Delneste Y, Tan F, Moles MP, Grimaud L, Lenoir J, Preisser L, Anegon I, Catala L, Ifrah N, et al: Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. Blood. 110:4319–4330. 2007. View Article : Google Scholar : PubMed/NCBI
24	Dijkgraaf EM, Heusinkveld M, Tummers B, Vogelpoel LT, Goedemans R, Jha V, Nortier JW, Welters MJ, Kroep JR and van der Burg SH: Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor micro-environment. Cancer Res. 73:2480–2492. 2013. View Article : Google Scholar : PubMed/NCBI
25	Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED and Thompson EW: Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol. 213:374–383. 2007. View Article : Google Scholar : PubMed/NCBI
26	Yilmaz M and Christofori G: EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 28:15–33. 2009. View Article : Google Scholar : PubMed/NCBI
27	Yang J and Weinberg RA: Epithelial-mesenchymal transition: At the crossroads of development and tumor metastasis. Dev Cell. 14:818–829. 2008. View Article : Google Scholar : PubMed/NCBI
28	González-Arriaga P, Pascual T, García-Alvarez A, Fernández-Somoano A, López-Cima MF and Tardón A: Genetic polymorphisms in MMP-2, 9 and 3 genes modify lung cancer risk and survival. BMC Cancer. 12:1212012. View Article : Google Scholar : PubMed/NCBI
29	Bonde AK, Tischler V, Kumar S, Soltermann A and Schwendener RA: Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors. BMC Cancer. 12:352012. View Article : Google Scholar : PubMed/NCBI
30	Gao D, Vahdat LT, Wong S, Chang JC and Mittal V: Microenvironmental regulation of epithelial-mesenchymal transitions in cancer. Cancer Res. 72:4883–4889. 2012. View Article : Google Scholar : PubMed/NCBI