Tumor-infiltrating macrophages are associated with metastasis suppression in high-grade osteosarcoma: A rationale for treatment with macrophage activating agents

Emilie P. Buddingh, Marieke L. Kuijjer, Ronald A J Duim, Horst Bürger, Konstantin Agelopoulos, Ola Myklebost, Massimo Serra, Fredrik Mertens, Pancras C W Hogendoorn, Arjan C. Lankester, Anne Marie Cleton-Jansen

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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 genomewide 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 of118/132 differentially expressed genes were upregulatedin 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.

Original languageEnglish
Pages (from-to)2110-2119
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number8
DOIs
Publication statusPublished - Apr 15 2011

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Osteosarcoma
Macrophages
Neoplasm Metastasis
Neoplasms
Therapeutics
Genes
Survival
Immunohistochemistry
Biopsy
Gene Expression Profiling
HLA-DR Antigens
Stromal Cells
Carcinogenesis
Research Design
Bone and Bones
Incidence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Tumor-infiltrating macrophages are associated with metastasis suppression in high-grade osteosarcoma : A rationale for treatment with macrophage activating agents. / Buddingh, Emilie P.; Kuijjer, Marieke L.; Duim, Ronald A J; Bürger, Horst; Agelopoulos, Konstantin; Myklebost, Ola; Serra, Massimo; Mertens, Fredrik; Hogendoorn, Pancras C W; Lankester, Arjan C.; Cleton-Jansen, Anne Marie.

In: Clinical Cancer Research, Vol. 17, No. 8, 15.04.2011, p. 2110-2119.

Research output: Contribution to journalArticle

Buddingh, EP, Kuijjer, ML, Duim, RAJ, Bürger, H, Agelopoulos, K, Myklebost, O, Serra, M, Mertens, F, Hogendoorn, PCW, Lankester, AC & Cleton-Jansen, AM 2011, 'Tumor-infiltrating macrophages are associated with metastasis suppression in high-grade osteosarcoma: A rationale for treatment with macrophage activating agents', Clinical Cancer Research, vol. 17, no. 8, pp. 2110-2119. https://doi.org/10.1158/1078-0432.CCR-10-2047
Buddingh, Emilie P. ; Kuijjer, Marieke L. ; Duim, Ronald A J ; Bürger, Horst ; Agelopoulos, Konstantin ; Myklebost, Ola ; Serra, Massimo ; Mertens, Fredrik ; Hogendoorn, Pancras C W ; Lankester, Arjan C. ; Cleton-Jansen, Anne Marie. / Tumor-infiltrating macrophages are associated with metastasis suppression in high-grade osteosarcoma : A rationale for treatment with macrophage activating agents. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 8. pp. 2110-2119.
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T1 - Tumor-infiltrating macrophages are associated with metastasis suppression in high-grade osteosarcoma

T2 - A rationale for treatment with macrophage activating agents

AU - Buddingh, Emilie P.

AU - Kuijjer, Marieke L.

AU - Duim, Ronald A J

AU - Bürger, Horst

AU - Agelopoulos, Konstantin

AU - Myklebost, Ola

AU - Serra, Massimo

AU - Mertens, Fredrik

AU - Hogendoorn, Pancras C W

AU - Lankester, Arjan C.

AU - Cleton-Jansen, Anne Marie

PY - 2011/4/15

Y1 - 2011/4/15

N2 - 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 genomewide 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 of118/132 differentially expressed genes were upregulatedin 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.

AB - 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 genomewide 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 of118/132 differentially expressed genes were upregulatedin 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.

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