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Keywords | Colon cancer | breast cancer | migrating cancer stem cells | mouse models | beta catenin | miRNA |<br />
kinome | phosphatome | single-cell analysis | epigenetics |<br />
MCSCs<br />
Migrating cancer stem cells (MCSCs)<br />
in breast and colon cancer<br />
Summary<br />
Carcinomas of the colon-rectum and breast represent<br />
among the most prevalent malignancies in the western<br />
world. A stepwise accumulation of genetic alterations in<br />
oncogenes and tumour suppressor genes is considered as<br />
the driving force behind tumour initiation, progression and<br />
metastasis.<br />
However, although formally correct, this model does not<br />
take into account other essential characteristics of human<br />
cancers, i.e. tumour heterogeneity and the role played by<br />
a subpopulation of tumour cells, the cancer stem cells<br />
(CSCs), in determining local invasion into surrounding tissues<br />
and distant metastasis. Tumours are not autonomously<br />
acting proliferation machines, but are very heterogeneous,<br />
both in their morphological and functional aspects. In fact,<br />
an individual tumour shows distinct sub-areas of proliferation,<br />
cell cycle arrest, epithelial diff erentiation, cell adhesion<br />
and dissemination.<br />
According to this more dynamic model (see Figure), the<br />
majority of tumour types, and in particular breast and colon<br />
cancer, arise within stem cell niches characterised by<br />
a tightly coordinated balance between self-renewal, migration,<br />
proliferation, diff erentiation and apoptosis. The initial<br />
and rate-limiting mutation aff ects this balance and leads<br />
to a relative increase in stem cells without drastically compromising<br />
their diff erentiation capacity. This imbalance<br />
eventually leads to the formation of a partially diff erentiated<br />
and heterogeneous tumour mass that, in response to<br />
additional somatic mutations and micro-environmental factors,<br />
progresses towards malignancy. Tumour cells are shed<br />
from this heterogeneous mass into the micro-environment.<br />
However, they will refl ect the heterogeneity of the primary<br />
tumour, and only few will retain the necessary plasticity to<br />
undergo trans-diff erentiation and enable homing and<br />
metastasis in distal organs.<br />
This ‘Migrating <strong>Cancer</strong> Stem Cells’ (MCSCs) model is central<br />
to our proposal and experimental plans. Our MCSCs<br />
consortium has been designed and assembled to address<br />
these issues by exploiting the unique expertise, experimental<br />
models and collections of human cancer samples of the<br />
diff erent participants, in order to develop tailor-made diagnostic<br />
and therapeutic strategies for breast and colorectal<br />
cancer patients.<br />
EARLY DETECTION, DIAGNOSIS AND PROGNOSIS<br />
Problem<br />
• Which signal transduction pathways underlie the onset<br />
of CSCs?<br />
• Which additional genetic and epigenetic factors modulate<br />
their invasive behaviour?<br />
• How does the tumour micro-environment, and therefore<br />
the cancer patient’s genetic background, aff ect the<br />
capacity of MCSCs to successfully invade and metastatise<br />
distant sites thus determining good vs. poor prognosis?<br />
Aim<br />
• To prospectively isolate and characterise intestinal and<br />
mammary cancer stem cells.<br />
• To elucidate the mechanisms underlying the aberrant<br />
behaviour of cancer stem cells during tumour initiation<br />
and progression to malignancy.<br />
Expected results<br />
• The isolation of intestinal and breast CSCs from both<br />
experimental mouse models and cancer patients.<br />
• The establishment of expression, genomic and epigenetic<br />
signatures for CSCs and their micro-environment.<br />
• The generation of new animal models for breast and<br />
colon cancer that closely reproduce the natural history<br />
of cancer stem cells and their progression towards<br />
malignancy and metastasis.<br />
• The development of diagnostic and prognostic tests<br />
based on the early detection of MCSCs and the prediction<br />
of metachronous metastases in breast and colon<br />
cancer patients by specifi c antibodies.<br />
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