Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Gastric Cancer
Published in: Gastric Cancer 4/2015

01-10-2015 | Original Article

Infiltration of diametrically polarized macrophages predicts overall survival of patients with gastric cancer after surgical resection

Authors: Heng Zhang, Xuefei Wang, Zhenbin Shen, Jiejie Xu, Jing Qin, Yihong Sun

Published in: Gastric Cancer | Issue 4/2015

Login to get access

Abstract

Background

Tumor-associated macrophages (TAMs), the most predominant tumor-infiltrating immune cells, are emerging prognostic factors and therapeutic targets for personalized therapy against malignant neoplasms. We aimed to evaluate the prognostic significance of diametrically polarized TAMs in gastric cancer and generate a predictive nomogram to refine a risk stratification system.

Methods

We evaluated polarized functional status of infiltrated TAMs by immunohistochemical staining of CD68, CD11c, and CD206 in 180 consecutive gastric cancer patients from Zhongshan Hospital, Shanghai, China. Prognostic values were assessed in these patients. We created a predictive nomogram by integrating polarized TAMs with the TNM staging system for overall survival of gastric cancer patients.

Results

CD68+ TAMs display polarized programs comprising CD11c+ proinflammatory macrophages (M1) and CD206+ immunosuppressive macrophages (M2) that configure versatile infiltration files in gastric cancer. CD11c+ TAMs negatively correlated with lymph node metastasis (p = 0.012), whereas CD206+ TAMs correlated with the Lauren classification (p = 0.031). No prognostic difference was observed for overall survival for CD68 density (high vs low, p = 0.1031), whereas high versus low CD11c density (p < 0.0001) and low vs high CD206 density (p = 0.0105) indicate better overall survival. Multivariate Cox regression analysis identified CD11c and CD206 as independent prognostic factors (p < 0.001 and p = 0.030, respectively), which could be integrated with the TNM staging system to generate a predictive nomogram for patient outcomes.

Conclusion

Infiltration of polarized TAMs, a novel identified independent prognostic factor, could be combined with the TNM stage to refine a risk stratification system and better stratify patients with different prognosis. Tipping TAMs to an antitumoral phenotype might be a promising therapeutic target for postoperative treatment.
Literature
1.
Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet. 2009;374:477–90.CrossRefPubMed
2.
Fridman WH, Mlecnik B, Bindea G, Pages F, Galon J. Immunosurveillance in human non-viral cancers. Curr Opin Immunol. 2011;23:272–8.CrossRefPubMed
3.
4.
Wiktor-Jedrzejczak W, Gordon S. Cytokine regulation of the macrophage (M phi) system studied using the colony stimulating factor-1-deficient op/op mouse. Physiol Rev. 1996;76:927–47.PubMed
5.
Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–86.CrossRefPubMed
6.
7.
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.CrossRefPubMed
8.
Ojalvo LS, King W, Cox D, Pollard JW. High-density gene expression analysis of tumor-associated macrophages from mouse mammary tumors. Am J Pathol. 2009;174:1048–64.PubMedCentralCrossRefPubMed
9.
Lissbrant IF, Stattin P, Wikstrom P, Damber JE, Egevad L, Bergh A. Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival. Int J Oncol. 2000;17:445–51.PubMed
10.
Ohno S, Ohno Y, Suzuki N, Kamei T, Koike K, Inagawa H, et al. Correlation of histological localization of tumor-associated macrophages with clinicopathological features in endometrial cancer. Anticancer Res. 2004;24:3335–42.PubMed
11.
Hanada T, Nakagawa M, Emoto A, Nomura T, Nasu N, Nomura Y. Prognostic value of tumor-associated macrophage count in human bladder cancer. Int J Urol. 2000;7:263–9.CrossRefPubMed
12.
Lee CH, Espinosa I, Vrijaldenhoven S, Subramanian S, Montgomery KD, Zhu S, et al. Prognostic significance of macrophage infiltration in leiomyosarcomas. Clin Cancer Res. 2008;14:1423–30.CrossRefPubMed
13.
Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res. 2007;13:1472–9.CrossRefPubMed
14.
Ohno S, Inagawa H, Dhar DK, Fujii T, Ueda S, Tachibana M, et al. The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival in gastric cancer patients. Anticancer Res. 2003;23:5015–22.PubMed
15.
Kurahara H, Shinchi H, Mataki Y, Maemura K, Noma H, Kubo F, et al. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res. 2011;167:e211–9.CrossRefPubMed
16.
Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer. 2006;42:717–27.CrossRefPubMed
17.
18.
19.
Kattan MW, Karpeh MS, Mazumdar M, Brennan MF. Postoperative nomogram for disease-specific survival after an R0 resection for gastric carcinoma. J Clin Oncol. 2003;21:3647–50.CrossRefPubMed
20.
Falini B, Flenghi L, Pileri S, Gambacorta M, Bigerna B, Durkop H, et al. PG-M1: a new monoclonal antibody directed against a fixative-resistant epitope on the macrophage-restricted form of the CD68 molecule. Am J Pathol. 1993;142:1359–72.PubMedCentralPubMed
21.
Morris DL, Singer K, Lumeng CN. Adipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states. Curr Opin Clin Nutr Metab Care. 2011;14:341–6.CrossRefPubMed
22.
Ito A, Suganami T, Yamauchi A, Degawa-Yamauchi M, Tanaka M, Kouyama R, et al. Role of CC chemokine receptor 2 in bone marrow cells in the recruitment of macrophages into obese adipose tissue. J Biol Chem. 2008;283:35715–23.CrossRefPubMed
23.
Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009;15:914–20.CrossRefPubMed
24.
De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell. 2013;23:277–86.CrossRefPubMed
25.
Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008;26:2707–16.CrossRefPubMed
26.
He H, Wang C, Shen Z, Fang Y, Wang X, Chen W, et al. Upregulated expression of C-X-C chemokine receptor 4 is an independent prognostic predictor for patients with gastric cancer. PLoS One. 2013;8:e71864.PubMedCentralCrossRefPubMed
27.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. REporting recommendations for tumour MARKer prognostic studies (REMARK). Eur J Cancer. 2005;41:1690–6.CrossRefPubMed
28.
Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 2010;22:231–7.CrossRefPubMed
29.
Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 2005;7:211–7.CrossRefPubMed
30.
Suzuki H, Forrest AR, van Nimwegen E, Daub CO, Balwierz PJ, Irvine KM, et al. The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line. Nat Genet. 2009;41:553–62.CrossRefPubMed
31.
Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci. 2008;13:453–61.CrossRefPubMed
32.
Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–8.CrossRefPubMed
33.
Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–96.CrossRefPubMed
34.
35.
Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66:605–12.CrossRefPubMed
36.
37.
Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, Van den Bossche J, et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 2010;70:5728–39.CrossRefPubMed
38.
Senovilla L, Vacchelli E, Galon J, Adjemian S, Eggermont A, Fridman WH, et al. Trial watch: prognostic and predictive value of the immune infiltrate in cancer. Oncoimmunology. 2012;1:1323–43.PubMedCentralCrossRefPubMed
39.
Wu H, Xu JB, He YL, Peng JJ, Zhang XH, Chen CQ, et al. Tumor-associated macrophages promote angiogenesis and lymphangiogenesis of gastric cancer. J Surg Oncol. 2012;106:462–8.CrossRefPubMed
40.
Okita Y, Tanaka H, Ohira M, Muguruma K, Kubo N, Watanabe M, et al. Role of tumor-infiltrating CD11b+ antigen-presenting cells in the progression of gastric cancer. J Surg Res. 2014;186:192–200.CrossRefPubMed
41.
Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Okumura H, Matsumoto M, et al. Tumor-associated macrophage (TAM) infiltration in gastric cancer. Anticancer Res. 2003;23:4079–83.PubMed
42.
Xu L, Zhu Y, Chen L, An H, Zhang W, Wang G, et al. Prognostic value of diametrically polarized tumor-associated macrophages in renal cell carcinoma. Ann Surg Oncol. 2014;21:3142–50.CrossRefPubMed
43.
Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.CrossRefPubMed
44.
Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov. 2012;11:215–33.CrossRefPubMed
45.
Saccani A, Schioppa T, Porta C, Biswas SK, Nebuloni M, Vago L, et al. p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res. 2006;66:11432–40.CrossRefPubMed
46.
Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 2005;65:3437–46.PubMed
Metadata
Title
Infiltration of diametrically polarized macrophages predicts overall survival of patients with gastric cancer after surgical resection
Authors
Heng Zhang
Xuefei Wang
Zhenbin Shen
Jiejie Xu
Jing Qin
Yihong Sun
Publication date
01-10-2015
Publisher
Springer Japan
Published in
Gastric Cancer / Issue 4/2015
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-014-0422-7

Other articles of this Issue 4/2015

Gastric Cancer 4/2015 Go to the issue

Original Article

Application of reduced-port laparoscopic total gastrectomy in gastric cancer preserving the pancreas and spleen

Original Article

MiR-125b promotes cell migration and invasion by targeting PPP1CA-Rb signal pathways in gastric cancer, resulting in a poor prognosis

Original Article

Preferential HER2 expression in liver metastases and EGFR expression in peritoneal metastases in patients with advanced gastric cancer

Original Article

Relationship between body mass index and the risk of early gastric cancer and dysplasia regardless of Helicobacter pylori infection

Original Article

Multicenter large-scale study of prognostic impact of HER2 expression in patients with resectable gastric cancer

Original Article

Follow-up endoscopy for benign-appearing gastric ulcers has no additive value in detecting malignancy
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits