Cancer Research - Europa

Keywords | Multiple myeloma | cancer stem cell | clonal disease progression |
MSCNET
Myeloma Stem Cell Network:
a translational programme identifying
and targeting the myeloma stem cell
Summary
Multiple myeloma (MM) is a disease where malignant plasma
cells accumulate in the bone marrow. Normal plasma
cell development at this site is thought to refl ect a synchronous
terminal diff erentiation of B cells that have followed
sequential stages of maturation. In MM, however, disease
characterisation has revealed a number of phenotypic and
molecular features that suggest the existence of a clonally
related ‘less mature’ cell, and the question arises whether
this may be a stem cell critical to propagating disease.
To address this, the MSCNET has formulated a strategy
which includes genomic and proteomic approaches, in
order to examine the nature of the cell underlying MM disease
origins and progression. This will utilise both in vitro
and in vivo models of the disease, and examine MM at presentation
and during its advance, in order to track factors
governing disease behaviour in this regard.
Problem
MM is at present an incurable disease, for which eff ective
new therapies are being actively sought. It is by no means
clear, however, what the nature of clonal propagation is in
MM. To progress work in this area, the MSCNET has set out
to identify the nature of the cell underlying disease survival
and persistence.
One of the most striking concepts emerging in cancer biology
is a role for cancer stem cells (CSCs) in feeding malignant
cell growth and tumour maintenance. By defi nition, these
CSCs have an indefi nite self-renewal potential, and are able
to populate both their own pool and the growth of the
tumour. Although the fi rst indication that such a cell might
exist came from studies in leukaemia, evidence for CSCs
in solid tumours lends further support for the concept of
a myeloma stem cell. The question for the MSCNET is whether
such a stem cell exists in MM.
BIOLOGY
Aim
Based on the above hypothesis, the aims will be:
• to study whether the putative myeloma stem cell (MSC)
exists as a less diff erentiated clonally related memory
B-cell or as a more mature plasma blast/plasma clonogenic
cell;
• to identify genes of potential impact on stem cell function;
• to propose new therapeutic strategies.
Expected results
The results of the scientifi c programme are expected to
redefi ne stem cell characteristics and especially to characterize
the myeloma stem cell compartment and its progeny,
as well as its relationship to the tumour micro-environment.
This insight will allow us to examine whether there are any
MSC-related features that can be targeted by future specifi c
therapies to ablate malignant disease.
Potential applications
Identifying the nature of the MSC will have a profound
impact on our understanding of pathogenesis, not only for
MM but for all malignant B-cell diseases. Importantly, the
MSCNET is well placed to identify potential drug-based
approaches to attack MSC and disease progression.
55