The Tumor Microenvironment of Pediatric Sarcoma: Mesenchymal Mechanisms Regulating Cell Migration and Metastasis

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Abstract

Purpose of Review

This review presents a selection of regulatory molecules of tumor microenvironmental properties and metastasis. Signaling pathways controlling mesenchymal biology in bone and soft-tissue sarcomas found in children and adolescents are prioritized.

Recent Findings

The tumor microenvironment of pediatric tumors is still relatively unexplored. Highlighted findings are mainly on deregulated genes associated with cell adhesion, migration, and tumor cell dissemination. How these processes are involved in a mesenchymal phenotype and metastasis is further discussed in relation to the epithelial to mesenchymal transition (EMT) in epithelial tumors. Cell plasticity is emerging as a concept with impact on tumor behavior.

Summary

Sarcomas belong to a heterogeneous group of tumors where local recurrence and tumor spread pose major challenges despite intense multimodal treatments. Molecular pathways involved in the metastatic process are currently being characterized, and tumor-regulatory properties of structural components, and infiltrating, non-malignant cell types should be further investigated.

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Most cited references 87

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The distribution of secondary growths in cancer of the breast. 1889.

S. PAGET (1989)

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PDGF, TGF-beta, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages.

Felicia Ng, Shayne Boucher, Susie Koh … (2008)

We compared the transcriptomes of marrow-derived mesenchymal stem cells (MSCs) with differentiated adipocytes, osteocytes, and chondrocytes derived from these MSCs. Using global gene-expression profiling arrays to detect RNA transcripts, we have identified markers that are specific for MSCs and their differentiated progeny. Further, we have also identified pathways that MSCs use to differentiate into adipogenic, chondrogenic, and osteogenic lineages. We identified activin-mediated transforming growth factor (TGF)-beta signaling, platelet-derived growth factor (PDGF) signaling and fibroblast growth factor (FGF) signaling as the key pathways involved in MSC differentiation. The differentiation of MSCs into these lineages is affected when these pathways are perturbed by inhibitors of cell surface receptor function. Since growth and differentiation are tightly linked processes, we also examined the importance of these 3 pathways in MSC growth. These 3 pathways were necessary and sufficient for MSC growth. Inhibiting any of these pathways slowed MSC growth, whereas a combination of TGF-beta, PDGF, and beta-FGF was sufficient to grow MSCs in a serum-free medium up to 5 passages. Thus, this study illustrates it is possible to predict signaling pathways active in cellular differentiation and growth using microarray data and experimentally verify these predictions.

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Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma.

Daniel Williamson, Edoardo Missiaglia, Aurélien de Reyniès … (2010)

To determine whether the clinical and molecular biologic characteristics of the alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) subtypes have relevance independent of the presence or absence of the PAX/FOXO1 fusion gene. The fusion gene status of 210 histopathologically reviewed, clinically annotated rhabdomyosarcoma samples was determined by reverse transcriptase polymerase chain reaction. Kaplan-Meier analysis was used to assess event-free survival and overall survival in fusion gene-negative ARMS (ARMSn; n = 39), fusion gene-positive ARMS (ARMSp; n = 94), and ERMS (n = 77). A total of 101 RMS samples were also profiled for whole-genome expression, and 128 were profiled for genomic copy number imbalances. Profiling data were analyzed by supervised and unsupervised methods to compare features related to histopathology and fusion gene status. Results were also projected by meta-analysis techniques across three separate publically available data sets. Overall and event-free survival, frequency of metastases, and distribution of site at initial presentation were not significantly different between ARMSn and ERMS. Consistent with this, analysis of gene expression signatures could not reproducibly distinguish ARMSn from ERMS whereas fusion gene-positive cases were distinct. ARMSn and ERMS frequently show whole-chromosome copy number changes, notably gain of chromosome 8 with associated high levels of expression of genes from this chromosome. The clinical behavior and molecular characteristics of alveolar cases without a fusion gene are indistinguishable from embryonal cases and significantly different from fusion-positive alveolar cases. This implies that fusion gene status irrespective of histology is a critical factor in risk stratification of RMS.

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Author and article information

Contributors

Monika Ehnman: monika.ehnman@ki.se

Wiem Chaabane: Wiem.Sivler@ki.se

Felix Haglund: Felix.Haglund@ki.se

Panagiotis Tsagkozis: Panagiotis.Tsagkozis@karolinska.se

Journal

Journal ID (nlm-ta): Curr Oncol Rep

Journal ID (iso-abbrev): Curr Oncol Rep

Title: Current Oncology Reports

Publisher: Springer US (New York )

ISSN (Print): 1523-3790

ISSN (Electronic): 1534-6269

Publication date (Electronic): 15 August 2019

Publication date PMC-release: 15 August 2019

Publication date (Print): 2019

Volume: 21

Issue: 10

Electronic Location Identifier: 90

Affiliations

[1 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Oncology-Pathology, , Karolinska Institutet, ; Stockholm, Sweden

[2 ]ISNI 0000 0000 9241 5705, GRID grid.24381.3c, PO Bröst- endokrina tumörer och sarkom, Tema Cancer, BioClinicum J6:20, , Karolinska University Hospital, ; Visionsgatan 4, 171 64 Solna, Sweden

[3 ]ISNI 0000 0000 9241 5705, GRID grid.24381.3c, Section of Orthopaedics, Department of Molecular Medicine and Surgery, Karolinska Institutet and Department of Orthopaedics, , Karolinska University Hospital, ; Stockholm, Sweden

Article

Publisher ID: 839

DOI: 10.1007/s11912-019-0839-6

PMC ID: 6695368

PubMed ID: 31418125

SO-VID: 1554bf9b-8528-4596-8ce8-bb31056c788b

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Funding

Funded by: Karolinska Institute

Open Access :

Open access funding provided by Karolinska Institute.

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: pediatric sarcoma,osteosarcoma,rhabdomyosarcoma,ewing sarcoma,tumor microenvironment,metastasis,emt,met,extracellular matrix,stroma,tgfβ,pdgf,cxcr4

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: pediatric sarcoma, osteosarcoma, rhabdomyosarcoma, ewing sarcoma, tumor microenvironment, metastasis, emt, met, extracellular matrix, stroma, tgfβ, pdgf, cxcr4

The Tumor Microenvironment of Pediatric Sarcoma: Mesenchymal Mechanisms Regulating Cell Migration and Metastasis

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Abstract

Purpose of Review

Recent Findings

Summary

Related collections

Karger: Oncology

Most cited references 87

The distribution of secondary growths in cancer of the breast. 1889.

PDGF, TGF-beta, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages.

Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma.

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