Results of the self-study : a simple, but testable hypothesis…

Secreted factor Lefty: a novel marker to identify modified hESC niches/
microenvironments

Human Embryonic Stem-Cells (hESCs) provide an opportunity for modelling
human-specific strategies in order to study the earliest molecular events leading to
normal haematopoietic specification versus leukaemia transformation. Although the
profound influence of the stroma on tumorogenesis is now widely accepted, a full
understanding of the crosstalk between stem cells and the niche, and the role of the
stem-cell niche on the development of leukaemia stem-cells (LSCs) and cancer stemcells
(CSCs), are in their earliest stage of research. On the other hand, though much
of active research is focusing mainly on the identification of novel markers for cancer
stem-cells in order to offer new therapeutic strategies to inhibit tumor progression,
the differentiating molecular events that transform normal hESCs into leukaemia
formations is still obscure. In this scenario, there is an urgency to find a simple and
novel secreted molecule and/or morphogen that could help us to identify the earliest
molecular events that transform normal hESCs into leukaemia cells.

In normal adult tissues, paracrine signals that derive from the stem cell niche, or
microenvironment, play an important role in regulating the critical balance between
activity and quiescence of stem cells. Similarly, evidence has emerged to support the
hypothesis that signals derived from the microenvironment regulate cancer cells in
an analogous manner. The stem-cell-associated factors include members of the
Notch, Wingless, and the transformation growth factor beta (TGF-B) super family
such as the teratoma-derived growth factor-1 (TDGF-1/Cripto, which is an EGF-CFC
co-receptor for Nodal signalling) and Lefty (inhibitor of Nodal signalling). Recently,
it has been demonstrated that the exposure of the tumor cells to a hESCs
microenvironment (containing Lefty, which is exclusive to the hESCs) leads to
dramatic down-regulation of the Nodal expression in aggressive tumor cells,
concomitant with a reduction in clonogenicity and tumorigenesis (with apoptosis).

The anti-tumorigeneic potential of Lefty is secreted into the hESCs
microenvironment and exemplifies the tumor suppressive effects of the hESCs
microenvironment. This effect is exclusive to hESCs and not other stem cell types
derived from amniotic fluid, cord blood, or adult bone marrow.

The different and unique qualities of the Lefty protein suggest that it could serve as a
novel marker towards differentiation between normal and transformed or modified
hESCs.

Furthermore, while confirming the hypothesis, we hope this interdisciplinary
research may also shed new light onto other key aspects, such as any Lefty protein
pathway crosstalk in the modified hESCs, and also improved understanding of their
complete feedback signalling networks and their suppressive regulative functions in
the adult cancerous cells.

References:
[1] P Catalina, etal., Genetic stability of human embryonic stem cells: A first-step
toward the development of potential hESC-based systems for modeling childhood
leukemia, Leuk Res 33 (2009), pp.980-90.
[2] JB Sneddon, The contribution of niche-derived factors to the regulation of cancer
cells, Methods Mol Biol 568 (2009), pp. 217-32.
[3] D Besser, Expression of nodal, lefty-a, and lefty-B in undifferentiated human
embryonic stem cells requires activation of Smad2/3, J Biol Chem 279 (2004), pp.
45076-84.
[4] LM Postovit etal., Human embryonic stem cell microenvironment suppresses the
tumorigenic phenotype of aggressive cancer cells, Proc Natl Acad Sci U S A 105
(2008), pp. 4329-34.