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.

multiple role of a transcription factor : connecting metastasis and stem-cell niche/microenvironment ..

Development of hematopoietic stem cells (HSC) and their immediate progeny is maintained by the interaction with cells in the microenvironment. But how the transcription factors involve to regulate the hematopoietic progenitor cell niche was remains unclear. In this phase, Suh etal have demontsrated the cell non-autonomous function of Id1 in the hematopoietic progenitor cell niche by using the knock-out mouse model. Here one practical tip is that Id1-/- stromal cells showed altered production of cytokines in vitro as well as the cytokine levels were deregulated in vivo, which could responsible for the Id1-/- hematopoietic phenotypes. Furthermore, the research group are also adding further more enthusiasms by utilising the ID genes families, which function is required for the mobilization of endothelial precursor cells from the bone marrow during the pathological tumor angiogenesis, and the expression of these genes remains high in tumor vasculature ( Shaked Y etal in Science 2006 and Lyden etal in Nature 1999). Here there is an another interesting point; that one is (continue below.!)

Two years ago…

the same gene has also been shown to mediates tumor reinitiation during breast cancer lung metastasis, which was done by Joan Massague

Nevertheless, the whole concepts were also developing number of curiosity questions as well such as: are there any relationship between ID genes and pre-metastatic niche?
does the altered production of the cytokines has any role with the quiescent stem- cells? Does the ID genes also play any role to establish the ‘cancer stem-cell niche’? if the ID genes does role on tumor reinitiation means does it also play any role for modifying and or creating the tumor (favourable) microenvironment? …!

Role of oncogenic K-ras

A subset of neoplastic cells , in the cancer stem-cells niche/microenvironment, has features that not only sustain glioma growth but may also confer resistance to standard glioma treatments. At the very basic level, however, whether glioma stem cells derive from indigenous neural stem cells (NSC), or from tumor cells that have reacquired stem cell-like properties, is still unknown. In this thrilling phase, report from Moses group demonstrating in vivo that the infiltrating tumor cells may arise from NSC transformed by activation of oncogenic K-ras.

One Year Ago….:

In medulloblastoma, Hambardzumyan and colleagues demonstrated in vivo that PI3K signaling pathway regulates survival of cancer stem cells residing in the perivascular niche following the radiation

up-dating the niche model

According to the osteoblastic niche model, which was originally proposed by Scadden and Linheng Li, the hematopoietic stem cells (HSCs) are maintained by the junction protein called N-cadherin-mediated homophilic adhesion to osteoblasts at the bone marrow endosteum. In contrast to this model, recent report from Sean Morrison group demonstrating that the N-cadherin expression by HSCs is not necessary for niche function. Extending this surprise results they have also demonstrated that N-cadherin deficiency did not affect bone marrow cellularity or lineage composition, the numbers of colony-forming progenitors, the frequency of HSCs, the ability of HSCs to sustain hematopoiesis over time, or their ability to reconstitute irradiated mice in primary or secondary transplants. This is quite interesting reports.

One Year Ago….:

Linheng Li and colleagues reveal differential N-cadherin expression reflects functional distinctions between two HSC subpopulations i.e., reserved versus primed states of hematopoietic stem cells.