Cancer Research - Europa

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