Prognostic factors in pulmonary metastasized high‐grade osteosarcoma

Buddingh, Emilie P.; Anninga, Jakob; Versteegh, Michel I.M.; Taminiau, A. H. M.; Egeler, R. Maarten; Rijswijk, Carla S P van; Hogendoorn, Pancras C.W.; Lankester, Arjan C.; Gelderblom, Hans

doi:10.1002/pbc.22293

Cited by 82 publications

(87 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…OS of high-grade osteosarcoma patients with resectable metastatic disease is poor at about 20% (30). Mechanisms for the development of metastases in osteosarcoma are elusive.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents

Buddingh

Kuijjer

Duim

et al. 2011

Clinical Cancer Research

Self Cite

378

341

View full text Add to dashboard Cite

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 ¼ 34) and patients who did not (n ¼ 19) develop metastases within 5 years. Immunohistochemistry (IHC) was performed on pretreatment biopsies from 2 additional cohorts (n ¼ 63 and n ¼ 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-DRa 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.

show abstract

“…OS of high-grade osteosarcoma patients with resectable metastatic disease is poor at about 20% (30). Mechanisms for the development of metastases in osteosarcoma are elusive.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents

Buddingh

Kuijjer

Duim

et al. 2011

Clinical Cancer Research

Self Cite

378

341

View full text Add to dashboard Cite

show abstract

“…Chemotherapy has increased the survival of the patients up to 60% (Marcove et al, 1970;Bacci et al, 2001), however there is no substantial improvement in survival since the 70s (Ferrari and Palmerini, 2007;Lewis et al, 2007). Most often the lung metastases are fatal for the patients (Gorlick et al, 2003), although after repeated metastasectomies, a subset of patients can be cured (Buddingh' et al, 2010). The early onset, lack of a predisposing condition or lesion, and little proof for underlying inheritance make osteosarcoma exceptional as compared to other pleomorphic malignancies that result from a multistep genetic process over many years.…”

Section: Introductionmentioning

confidence: 96%

Small deletions but not methylation underlie CDKN2A/p16 loss of expression in conventional osteosarcoma

Mohseny

Tieken

Velden

et al. 2010

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Conventional osteosarcoma is characterized by rapid growth, high local aggressiveness, and metastasizing potential. Patients developing lung metastases experience poor prognosis despite extensive chemotherapy regimens and surgical interventions. Previously we identified a subgroup of osteosarcoma patients with loss of CDKN2A/p16 protein expression in the primary tumor biopsies which was significantly predictive of a very poor prognosis. Here we aimed to identify the underlying mechanism(s) of this protein loss in relation to osteosarcoma behavior. The CDKN2A locus was analyzed in osteosarcoma cases with total loss of CDKN2A/p16 expression and in cases with high protein expression using melting curve analysis-methylation assay (MCA-Meth), fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and mutation analysis. All cases with complete CDKN2A/p16 protein loss showed homozygous deletions at the CDKN2A locus. In none of the cases hyper methylation of the promoter region was seen which was confirmed by sequencing this region. Taken together we show that large or smaller deletions of the CDKN2A locus are evident in patient samples and underlie the CDKN2A/p16 protein expression loss while promoter methylation does not appear to be a mechanism of this expression loss. Genomic loss of CDKN2A instead of promoter methylation might be a plausible explanation for the rapid proliferation and high aggressiveness of osteosarcoma by simultaneous impairment CDKN2A/p14(ARF) function.

show abstract

“…Overall long-term (5-year) survival for patients with nonmetastatic osteosarcomas has increased from 10% to 65% over the past 20 years, due to improved surgical techniques and multidrug chemotherapy, but further improvement is needed (2). Indeed, 25% to 50% of patients will relapse or metastasize and 5-year survival rate for metastatic osteosarcomas is only 10% to 20% (3,4). It is clear that additional therapies are required to increase the survival of patients with osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

Alternate Splicing of the p53 Inhibitor HDMX Offers a Superior Prognostic Biomarker than p53 Mutation in Human Cancer

et al. 2012

Self Cite

View full text Add to dashboard Cite

Conventional high-grade osteosarcoma is the most common primary bone malignancy. Although altered expression of the p53 inhibitor HDMX (Mdmx/Mdm4) is associated with cancer risk, progression, and outcome in other tumor types, little is known about its role in osteosarcoma. High expression of the Hdmx splice variant HDMX-S relative to the full-length transcript (the HDMX-S/HDMX-FL ratio) correlates with reduced HDMX protein expression, faster progression, and poorer survival in several cancers. Here, we show that the HDMX-S/ HDMX-FL ratio positively correlates with less HDMX protein expression, faster metastatic progression, and a trend to worse overall survival in osteosarcomas. We found that the HDMX-S/HDMX-FL ratio associated with common somatic genetic lesions connected with p53 inhibition, such as p53 mutation and HDM2 overexpression in osteosarcoma cell lines. Interestingly, this finding was not limited to osteosarcomas as we observed similar associations in breast cancer and a variety of other cancer cell lines, as well as in tumors from patients with soft tissue sarcoma. The HDMX-S/HDMX-FL ratio better defined patients with sarcoma with worse survival rates than p53 mutational status. We propose a novel role for alternative splicing of HDMX, whereby it serves as a mechanism by which HDMX protein levels are reduced in cancer cells that have already inhibited p53 activity. Alternative splicing of HDMX could, therefore, serve as a more effective biomarker for p53 pathway attenuation in cancers than p53 gene mutation. Cancer Res; 72(16); 4074-84. Ó2012 AACR.

show abstract

Prognostic factors in pulmonary metastasized high‐grade osteosarcoma

Abstract: This cohort of patients with detailed follow-up data enabled us to identify important risk factors determining survival in OS patients with pulmonary metastases. We demonstrate that after repeated metastasectomies, a subset of patients can be cured.

Cited by 82 publications

References 27 publications

Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents

Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents

Small deletions but not methylation underlie CDKN2A/p16 loss of expression in conventional osteosarcoma

Alternate Splicing of the p53 Inhibitor HDMX Offers a Superior Prognostic Biomarker than p53 Mutation in Human Cancer

Contact Info

Product

Resources

About