Accumulation of stabilin‑1 positive macrophages in the early stage of gastric cancer is associated with short cumulative survival

Yin,Shui‑Ping; Gao,Yi; Xie,Xu‑Shi; Xu,Dan‑Dan; Riabov,Vladimir; Du,Wei‑Dong

doi:10.3892/ol.2020.11310

Accumulation of stabilin‑1 positive macrophages in the early stage of gastric cancer is associated with short cumulative survival

Authors:
- Shui‑Ping Yin
- Yi Gao
- Xu‑Shi Xie
- Dan‑Dan Xu
- Vladimir Riabov
- Wei‑Dong Du
View Affiliations

Affiliations: Department of Pathology, Anhui Medical University, Hefei, Anhui 230032, P.R. China, Department of Oncology, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230012, P.R. China, Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, D‑68167 Mannheim, Germany
Published online on: January 16, 2020 https://doi.org/10.3892/ol.2020.11310
Pages: 2404-2412
Copyright: © Yin 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

The scavenger receptor stabilin‑1 has been reported to be expressed by tumor‑associated macrophages (TAMs) and to facilitate tumor growth and metastasis in mouse models of breast carcinoma and melanoma. However, to the best of our knowledge, its expression and association with prognosis in human gastric cancer has not been evaluated. The present study investigated the expression of stabilin‑1 and its association with clinicopathological parameters in patients with gastric cancer. The expression of stabilin‑1 was evaluated by immunohistochemical staining of gastric cancer tissue samples of 371 Chinese patients with primary gastric adenocarcinoma. Confocal laser scanning microscopy was used to determine the cellular source of stabilin‑1 in the gastric cancer tissues using anti‑CD68, anti‑CD163, anti‑stabilin‑1 and anti‑secreted protein acidic and rich in cysteine antibodies. A higher number of stabilin‑1‑positive cells were observed in the cancer tissues of primary gastric adenocarcinoma compared with adjacent non‑cancerous tissues of primary gastric adenocarcinoma (P<0.001); the majority of stabilin‑1‑positve cells were CD68+/CD163+ macrophages. Poorly‑differentiated gastric cancer tissue had fewer stabilin‑1‑positive cells compared with medium‑ and well‑differentiated gastric cancer (P=0.030). A higher number of stabilin‑1‑positive cells were found in the early Tumor‑Node‑Metastasis (TNM) stage (TNM I stage) of primary gastric adenocarcinoma (P=0.038) compared with TNM stage IV. For patients with TNM stage I disease, a higher number of stabilin‑1‑positive TAMs was associated with shorter cumulative survival (P<0.05). Overall, stabilin‑1 was found to be expressed by CD68+ TAMs in human gastric cancer. The high expression of stabilin‑1 in TNM stage I disease was associated with poor patient survival, indicating the clinical significance of stabilin‑1 in gastric cancer.

View Figures

View References

1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Quail DF and Joyce JA: Microenvironmental regulation of tumor progression and metastasis. Nat Med. 19:1423–1437. 2013. View Article : Google Scholar : PubMed/NCBI
3	Jochems C and Schlom J: Tumor-infiltrating immune cells and prognosis: The potential link between conventional cancer therapy and immunity. Exp Biol Med (Maywood). 236:567–579. 2011. View Article : Google Scholar : PubMed/NCBI
4	Liu K, Yang K, Wu B, Chen H, Chen X, Chen X, Jiang L, Ye F, He D and Lu Z: Tumor-infiltrating immune cells are associated with prognosis of gastric cancer. Medicine (Baltimore). 94:e16312015. View Article : Google Scholar : PubMed/NCBI
5	Noy R and Pollard JW: Tumor-associated macrophages: From mechanisms to therapy. Immunity. 41:49–61. 2014. View Article : Google Scholar : PubMed/NCBI
6	Kim J and Bae JS: Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediators Inflamm. 2016:60581472016. View Article : Google Scholar : PubMed/NCBI
7	Yin S, Huang J, Li Z, Zhang J, Luo J, Lu C and Xu H and Xu H: The prognostic and clinicopathological significance of tumor-associated macrophages in patients with gastric cancer: A meta-analysis. PLoS One. 12:e01700422017. View Article : Google Scholar : PubMed/NCBI
8	Biswas SK, Allavena P and Mantovani A: Tumor-associated macrophages: Functional diversity, clinical significance, and open questions. Semin Immunopathol. 35:585–600. 2013. View Article : Google Scholar : PubMed/NCBI
9	Mantovani A, Marchesi F, Malesci A, Laghi L and Allavena P: Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 14:399–416. 2017. View Article : Google Scholar : PubMed/NCBI
10	Medrek C, Pontén F, Jirström K and Leandersson K: The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer. 12:3062012. View Article : Google Scholar : PubMed/NCBI
11	Mei J, Xiao Z, Guo C, Pu Q, Ma L, Liu C, Lin F, Liao H, You Z and Liu L: Prognostic impact of tumor-associated macrophage infiltration in non-small cell lung cancer: A systemic review and meta-analysis. Oncotarget. 7:34217–34228. 2016. View Article : Google Scholar : PubMed/NCBI
12	Ryder M, Ghossein RA, Ricarte-Filho JC, Knauf JA and Fagin JA: Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer. Endocr Relat Cancer. 15:1069–1074. 2008. View Article : Google Scholar : PubMed/NCBI
13	Sugimura K, Miyata H, Tanaka K, Takahashi T, Kurokawa Y, Yamasaki M, Nakajima K, Takiguchi S, Mori M and Doki Y: High infiltration of tumor-associated macrophages is associated with a poor response to chemotherapy and poor prognosis of patients undergoing neoadjuvant chemotherapy for esophageal cancer. J Surg Oncol. 111:752–759. 2015. View Article : Google Scholar : PubMed/NCBI
14	Yuan X, Zhang J, Li D, Mao Y, Mo F, Du W and Ma X: Prognostic significance of tumor-associated macrophages in ovarian cancer: A meta-analysis. Gynecol Oncol. 147:181–187. 2017. View Article : Google Scholar : PubMed/NCBI
15	Sun Y and Xu S: Tumor-associated CD204-positive macrophage is a prognostic marker in clinical stage I lung adenocarcinoma. Biomed Res Int. 2018:84591932018.PubMed/NCBI
16	Ren CX, Leng RX, Fan YG, Pan HF, Li BZ, Wu CH, Wu Q, Wang NN, Xiong QR, Geng XP and Ye DQ: Intratumoral and peritumoral expression of CD68 and CD206 in hepatocellular carcinoma and their prognostic value. Oncol Rep. 38:886–898. 2017. View Article : Google Scholar : PubMed/NCBI
17	Park JY, Sung JY, Lee J, Park YK, Kim YW, Kim GY, Won KY and Lim SJ: Polarized CD163⁺ tumor-associated macrophages are associated with increased angiogenesis and CXCL12 expression in gastric cancer. Clin Res Hepatol Gastroenterol. 40:357–365. 2016. View Article : Google Scholar : PubMed/NCBI
18	Ichimura T, Abe H, Morikawa T, Yamashita H, Ishikawa S, Ushiku T, Seto Y and Fukayama M: Low density of CD204- positive M2-type tumor-associated macrophages in Epstein-Barr virus-associated gastric cancer: A clinicopathologic study with digital image analysis. Hum Pathol. 56:74–80. 2016. View Article : Google Scholar : PubMed/NCBI
19	Riabov V, Yin S, Song B, Avdic A, Schledzewski K, Ovsiy I, Gratchev A, Llopis Verdiell M, Sticht C, Schmuttermaier C, et al: Stabilin-1 is expressed in human breast cancer and supports tumor growth in mammary adenocarcinoma mouse model. Oncotarget. 7:31097–31110. 2016. View Article : Google Scholar : PubMed/NCBI
20	David C, Nance JP, Hubbard J, Hsu M, Binder D and Wilson EH: Stabilin-1 expression in tumor associated macrophages. Brain Res. 1481:71–78. 2012. View Article : Google Scholar : PubMed/NCBI
21	Karikoski M, Marttila-Ichihara F, Elima K, Rantakari P, Hollmén M, Kelkka T, Gerke H, Huovinen V, Irjala H, Holmdahl R, et al: Clever-1/stabilin-1 controls cancer growth and metastasis. Clin Cancer Res. 20:6452–6464. 2014. View Article : Google Scholar : PubMed/NCBI
22	Schledzewski K, Falkowski M, Moldenhauer G, Metharom P, Kzhyshkowska J, Ganss R, Demory A, Falkowska-Hansen B, Kurzen H, Ugurel S, et al: Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1⁺, F4/80⁺, CD11b⁺ macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: Implications for the assessment of lymphangiogenesis. J Pathol. 209:67–77. 2006. View Article : Google Scholar : PubMed/NCBI
23	Algars A, Irjala H, Vaittinen S, Huhtinen H, Sundström J, Salmi M, Ristamäki R and Jalkanen S: Type and location of tumor-infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients. Int J Cancer. 311:864–873. 2012. View Article : Google Scholar
24	Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL and Trotti A: AJCC Cancer Staging Manual, 7th edition. Springer-Verlag; New York: pp. 117–26. 2009
25	Kzhyshkowska J: Multifunctional receptor stabilin-1 in homeostasis and disease. ScientificWorldJournal. 10:2039–2053. 2010. View Article : Google Scholar : PubMed/NCBI
26	Harada K, Dong X, Estrella JS, Correa AM, Xu Y, Hofstetter WL, Sudo K, Onodera H, Suzuki K, Suzuki A, et al: Tumor-associated macrophage infiltration is highly associated with PD-L1 expression in gastric adenocarcinoma. Gastric Cancer. 21:31–40. 2018. View Article : Google Scholar : PubMed/NCBI
27	Pantano F, Berti P, Guida FM, Perrone G, Vincenzi B, Amato MM, Righi D, Dell'aquila E, Graziano F, Catalano V, et al: The role of macrophages polarization in predicting prognosis of radically resected gastric cancer patients. J Cell Mol Med. 17:1415–1421. 2013. View Article : Google Scholar : PubMed/NCBI
28	Kzhyshkowska J, Workman G, Cardó-Vila M, Arap W, Pasqualini R, Gratchev A, Krusell L, Goerdt S and Sage EH: Novel function of alternatively activated macrophages: Stabilin-1-mediated clearance of SPARC. J Immunol. 176:5825–5832. 2006. View Article : Google Scholar : PubMed/NCBI
29	Schönhaar K, Schledzewski K, Michel J, Dollt C, Gkaniatsou C, Géraud C, Kzhyshkowska J, Goerdt S and Schmieder A: Expression of stabilin-1 in M2 macrophages in human granulomatous disease and melanocytic lesions. Int J Clin Exp Pathol. 7:1625–1634. 2014.PubMed/NCBI
30	Zhao ZS, Wang YY, Chu YQ, Ye ZY and Tao HQ: SPARC is associated with gastric cancer progression and poor survival of patients. Clin Cancer Res. 16:260–268. 2010. View Article : Google Scholar : PubMed/NCBI
31	Li Z, Li AD, Xu L, Bai DW, Hou KZ, Zheng HC, Qu XJ and Liu YP: SPARC expression in gastric cancer predicts poor prognosis: Results from a clinical cohort, pooled analysis and GSEA assay. Oncotarget. 7:70211–70222. 2016.PubMed/NCBI
32	Franke K, Carl-McGrath S, Röhl FW, Lendeckel U, Ebert MP, Tänzer M, Pross M and Röcken C: Differential expression of SPARC in intestinal-type gastric cancer correlates with tumor progression and nodal spread. Transl Oncol. 2:310–320. 2009. View Article : Google Scholar : PubMed/NCBI
33	Wang L, Yang M, Shan L, Qi L, Chai C, Zhou Q, Yao K, Wu H and Sun W: The role of SPARC protein expression in the progress of gastric cancer. Pathol Oncol Res. 18:697–702. 2012. View Article : Google Scholar : PubMed/NCBI