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Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents
Published version of a preprint
Abstract
Purpose: High-grade osteosarcoma is a malignant primary bone tumor with a peak incidence in adolescence. Overall survival (OS) of patients with resectable metastatic disease is approximately 20%. The exact mechanisms of development of metastases in osteosarcoma remain unclear. Most studies focus on tumor cells, but it is increasingly evident that stroma plays an important role in tumorigenesis and metastasis. We investigated the development of metastasis by studying tumor cells and their stromal context. Experimental Design: To identify gene signatures playing a role in metastasis, we carried out genome-wide gene expression profiling on prechemotherapy biopsies of patients who did (n = 34) and patients who did not (n = 19) develop metastases within 5 years. Immunohistochemistry (IHC) was performed on pretreatment biopsies from 2 additional cohorts (n = 63 and n = 16) and corresponding postchemotherapy resections and metastases. Results: A total of 118/132 differentially expressed genes were upregulated in patients without metastases. Remarkably, almost half of these upregulated genes had immunological functions, particularly related to macrophages. Macrophage-associated genes were expressed by infiltrating cells and not by osteosarcoma cells. Tumor-associated macrophages (TAM) were quantified with IHC and associated with significantly better overall survival (OS) in the additional patient cohorts. Osteosarcoma samples contained both M1- (CD14/HLA-DRα positive) and M2-type TAMs (CD14/CD163 positive and association with angiogenesis). Conclusions: In contrast to most other tumor types, TAMs are associated with reduced metastasis and improved survival in high-grade osteosarcoma. This study provides a biological rationale for the adjuvant treatment of high-grade osteosarcoma patients with macrophage activating agents, such as muramyl tripeptide. Clin Cancer Res; 17(8); 2110–9. ©2011 AACR.
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“However, in primary OS, heterogenous TAMs displaying an intermediate phenotype between M1 and M2 have been associated with anti-metastatic effects [4,5].”
From Mesenchymal Stem/Stromal Cells: Immunomodulatory and Bone Regeneration Potential after Tumor Excision in Osteosarcoma Patients (2023) · cites this paper as [5]
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Metadata
- Authors
- Buddingh, E. P., Kuijjer, M. L., Duim, R. A. J., Bürger, H., Agelopoulos, K., Myklebost, O., Serra, M., Mertens, F., Hogendoorn, P. C. W., Lankester, A. C., & Cleton-Jansen, A.-M.
- Affiliations
- Oslo University Hospital (NO)
- Authors' Affiliations: 1Department of Pediatrics; 2Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; 3Institute of Pathology; 4Department of Medicine, Hematology and Oncology, University of Münster, Münster, Germany; 5Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; 6Laboratory of Experimental Oncology Research, Istituto Ortopedico Rizzoli, Bologna, Italy; and 7Department of Clinical Genetics, Lund University Hospital, Lund, Sweden
- Corresponding author
- Cleton-Jansen, Anne-Marie
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2011-04-14
- Volume
- 17
- Issue
- 8
- Pages
- 2110-2119
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2106409672
- Cited by
- 508
- References
- 45
- Citations by year
- 2026: 27 · 2025: 45 · 2024: 48 · 2023: 63 · 2022: 47 · 2021: 54 · 2020: 50 · 2019: 24 · 2018: 20 · 2017: 36 · 2016: 24 · 2015: 17 · 2014: 15 · 2013: 13 · 2012: 18
- FWCI
- 7.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- high-grade osteosarcoma, tumor-infiltrating macrophages, metastasis suppression, tumor-associated macrophages, tumor stroma, gene expression profiling, overall survival, muramyl tripeptide, adjuvant therapy, CD14, CD163, angiogenesis
- MeSH terms
- Bone Neoplasms, Humans, Immunohistochemistry, Macrophages, Neoplasm Metastasis, Prognosis, Osteosarcoma, Time Factors, Cohort Studies, Gene Expression Regulation, Neoplastic, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Cell Line, Tumor
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