Paediatric sarcoma metastasis: an area that warrants in-depth exploration

Ivan Stamenkovic, Professor of Experimental Pathology at University of Lausanne explores the paediatric sarcoma metastasis and why this warrants an in-depth look

Metastasis is responsible for 90% of cancer–related death. Several solid paediatric malignancies, particularly sarcomas, display high metastatic proclivity, which renders their prognosis poor, as metastases are for the most part unresponsive to conventional chemotherapy, even if the primary tumour is sensitive. Most of our understanding of the multistep process that constitutes metastasis comes from studies on carcinomas, which, at least in part, mimic the sarcoma phenotype to metastasize.

Disseminating carcinoma cells

Most disseminating carcinoma cells undergo epithelial-to-mesenchymal transition (EMT), a reversible process by which they transiently adopt a variable mesenchymal phenotype. EMT appears to be critical for carcinoma cell motility, as epithelial cells are largely non-motile, as well as invasion and possibly other steps leading up to secondary colony formation. Once they have reached their final destination, disseminated carcinoma cells revert to their epithelial phenotype to grow and form metastatic tumours. Being of mesenchymal origin, sarcoma cells are naturally motile and may already possess all the properties necessary for dissemination.

They, therefore, do not need to undergo any phenotypic change and provide ideal cells to study metastasis and determine how metastatic lesions may differ from the corresponding primary tumours. Extensive genomic studies on carcinomas have shown convincingly that there are no metastasis-specific genetic mutations, indicating that cells with metastatic potential are already part of the primary tumour and that epigenetic modifications are most likely responsible for providing them with the properties necessary to complete all the steps required for metastatic tumour growth.

Paediatric sarcomas

The same is likely to hold true for paediatric sarcomas, including Ewing sarcoma, alveolar rhabdomyosarcoma (ARMS), synovial sarcoma and desmoplastic small round cell tumour (DSRCT), all of which tend to metastasize early and with high frequency. However, given their mesenchymal origin and phenotype, it will be important to determine whether metastatic properties are confined to a subset of cells in any given sarcoma or whether they are a common feature of most cells.

An essential property of cancer cells is their plasticity. Thus, carcinoma cells may transition bi-directionally between an epithelial phenotype and EMT or between a stem cell phenotype with tumour initiating properties and a more differentiated phenotype that is not tumorigenic. A pro-metastatic phenotype may therefore not be stable, but rather may be acquired transiently depending on the micro-environmental stimuli to which a tumour cell or subpopulation thereof is exposed at different stages of tumour progression.

Like carcinomas, sarcoma cells display plasticity and may transition in a dynamic manner from metastasis-competent to non-metastatic variants and vice-versa. This phenotypic instability renders therapy particularly challenging for several reasons. Firstly, it is necessary to define the epigenetic profile that is responsible for conferring metastatic properties and to develop therapeutic strategies that can target the relevant epigenetic modifiers or their effects in a way that can cause the cells to lose key properties required for metastasis.

Secondly, it is necessary to understand the mechanisms by which cells without metastatic properties can acquire or re-acquire them. Understanding tumour cell plasticity is at least one requisite in the quest to counter the ability of malignant tumours to metastasize.

Metastasis research

A major focus of metastasis research in recent years has been the isolation and characterisation of circulating tumour cells (CTCs). Once again, circulating carcinoma cells have attracted the greatest attention and it has been demonstrated that CTCs display variable EMT and CTC clusters are more effective in generating metastases than isolated CTCs. Very little work has been done on paediatric sarcoma CTCs, but it will be of interest to determine to what degree sarcoma CTCs differ from bulk tumour cells, whether they require adaptation to sheer stress and whether they are enriched in cancer stem cells.

The relevance of tumour plasticity has been underscored by studies on the CTC phenotype in response to therapy. CTCs from different types of carcinoma have been observed to display increased EMT in response to chemotherapy, suggesting that EMT may confer at least partial resistance to therapy. Much less work has been done on paediatric tumour CTCs and it will obviously be of major importance to determine how such CTCs adjust their phenotype in response to therapy.

Moreover, CTCs may further modify their phenotype once they penetrate a secondary tissue, such that the phenotype observed in the circulation may undergo substantial changes as the cells adapt to the newly colonised tissue in which they must survive and divide. This continued dynamic phenotypic adjustment constitutes a major challenge to precisely identifying the epigenetic changes that are responsible for endowing tumour cells with metastatic properties.

One of our primary goals is to elucidate the epigenetic mechanisms that underlie paediatric sarcoma plasticity and to develop therapeutic approaches that could counteract their effects and possibly redirect the epigenetic changes themselves to generate cells that lack the ability to disseminate and initiate tumour growth.

 

Ivan Stamenkovic

Professor of pathology, director experimental pathology service

Centre Hospitalier Universitaire Vaudois (CHUV) University of Lausanne

Tel:  +41 21 314 7136

Email: Ivan.Stamenkovic@chuv.ch

www.chuv.ch/pathologie

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