OUTLINE

Carcinomas of the colon-rectum and breast represent among the most prevalent malignancies in the Western world. A stepwise accumulation of genetic alterations in oncogenes and tumor suppressor genes is considered as the driving force along tumor initiation, progression and metastasis. However, although formally correct, this model does not take into account other essential characteristics of human cancers, i.e. tumor heterogeneity and the role played by a subpopulation of tumor cells, the cancer stem cells (CSCs), in determining local invasion into surrounding tissues and distant metastasis. Tumors are not autonomously acting proliferation machines, but are very heterogeneous, both in their morphological and functional aspects. In fact, an individual tumor shows distinct sub-areas of proliferation, cell cycle arrest, epithelial differentiation, cell adhesion and dissemination. According to this more dynamic model (see Figure), the majority of tumor types, and in particular breast and colon cancer, arise within stem cell niches characterized by a tightly coordinated balance among self-renewal, migration, proliferation, differentiation and apoptosis. The initial and rate-limiting mutation affects this balance and leads to a relative increase in stem cells without drastically compromising their differentiation capacity. This unbalance eventually leads to the formation of a partially differentiated and heterogeneous tumor mass that, upon additional somatic mutations and micro-environmental factors, progresses towards malignancy. Tumor cells are shed from this heterogeneous mass into the micro-environment. However, they will reflect the heterogeneity of the primary tumor and only few will retain the necessary plasticity to undergo trans-differentiation and enable homing and metastasis in distal organs.

This 'Migrating Cancer Stem Cells' (MCSCs) model is central to our proposal and experimental plans. Our MCSCs consortium has been designed and assembled to address these issues by exploiting the unique expertise, experimental models and collections of human cancer samples of the different participants towards the development of tailor-made diagnostic and therapeutic strategies for breast and colorectal cancer patients.