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Migrating cancer stem cells in breast and colon cancer

Final Report Summary - MCSCS (Migrating cancer stem cells in breast and colon cancer)

Cancer stem cells (CSC) have received much attention in the recent scientific literature as they are thought to maintain and propagate human malignancies and as such represent an attractive therapeutic target. Nevertheless, CSC are poorly defined by their tumour-initiating capacity when transplanted into a recipient (immuno-deficient) animal, a feature that on its own does not encompass other essential characteristics of these cells, e.g. their capacity to self-renew and differentiate, and to detach and migrate away from the primary site and invade distal organs. This more functional view of resident (located in the primary mass) and Migrating cancer stem cells (MCSCs) is of clinical relevance and is likely to have important consequences on the clinical management of cancer patients. The CSC concept is also intimately bound to another feature of neoplastic diseases, namely tumour heterogeneity. By asymmetric cell division CSCs may give rise to new stem cells together with more differentiated cells, thus continuously fuelling the tumour mass providing with proliferating but progressively differentiating cells, but also retaining their multipotency (i.e. 'stemness') and preventing their own exhaustion.

Recent experimental evidences point out that cancer stem cells are key factors not only tumour onset, growth, local invasion, and distant metastasis but also in the development of drug resistance, thus posing a major challenge towards the development of novel tailor-made cancer therapies directed against CSCs. Yet, the increasing knowledge of the structure and regulation of the mouse and human genomes together with the awareness that (migrating) cancer stem cell could be the ultimate target for effective therapies offer unprecedented research opportunities.

The MCSCS consortium was originally designed to seize these opportunities and has been focusing on understanding the function, regulation and evolution of (M)CSCs in a multicellular organism. To this end our original plan was to identify and isolate breast and colon (M)CSCs by developing and taking advantage of unique reagents, animal models, and technical approaches, and translate the results on large collections of human cancers, disseminating cancer cells, and metastases. The ultimate goal being the characterisation and functional analysis of the MCSCs and their micro-environment (the MCSC niche) and define a 'MCSC signature', instrumental for the development of future tailor-made therapeutic approaches.

The goals of MCSCS

- To isolate intestinal and breast cancer stem cells from both experimental mouse models and cancer patients;
- To analyse the genetic and protein profiles of the above cancer stem cells and their micro-environment;
- To establish high-throughput compound screens based on (isogenic) cell models;
- To develop new models for breast and colon cancer that closely reproduce the natural history of cancer stem cells and their progression towards malignancy and metastasis;
- To generate pre-clinical animal models for (M)CSCs-targeted drug intervention;
- To develop diagnostic, prognostic, and therapeutic tests for the early detection of (M)CSCs and the prediction of metastases in breast and colon cancer patients.

To address these objectives the MCSCs consortium comprises five participants from four different European Union (EU) Member States that form a multidisciplinary and highly-competitive community of European research institutes dedicated to the isolation and analysis of cancer stem cells in breast and colon cancer.


The results of the work conducted within the MCSCs consortium can be summarised into five main points:

- Intracellular beta-catenin accumulation represents a functional marker of CSCs and MCSCs
This is reflected in the activation of the canonical Wnt signaling pathway in these cells, known to elicit self-renewing and EMT while inhibiting differentiation. This is true for Apc-driven mouse models of intestinal and mammary tumourigenesis, for the majority of colon cancer cases in man, and for a relatively small group of Wnt-driven breast cancers.
- The generation of isogenic human cell models carrying targeted mutations in (endogenous) genes known to play rate-limiting roles in CSCs represent a powerful tool to conduct multiple pharmacogenomic analyses and identify genotype-drug specific relationships. Given that CSCs and MCSCs are thought to underlie onset and growth of primary cancer and their distant metastases, the development and use isogenic cell lines will be of great relevance in the development of CSC-targeted therapies.
- The ZEB1 gene and the miR-200 non-coding RNA play rate-limiting roles in CSCs
Expression of ZEB1 increases tumourigenicity by increasing the expression of stem cell factors like Bmi1. This increase is due to a diminished repression of Bmi1 by the miR-200 family.
- Specific epigenetic profiles at both the mRNA and miRNA levels characterises CSCs
The elucidation further characterisation of these changes will open novel therapeutic avenues to the use of epigenetic drugs (e.g. methylation- and acetylation-affecting agents) in the clinic.
- Single-cell genomic and expression profiling of DTCs (disseminated tumour cells) coupled with the analysis of their cell surface antigens is likely to lead to the elucidation of the functional heterogeneity that characterise these cells and the primary lesions they are derived from.