Sorafenib inhibits growth migration and angiogenic potential of ectopic endometrial mesenchymal stem cells derived from patients with endometriosis

Capsule:
Ectopic endometrial mesenchymal stem cells (MSC) show increased proliferation, migration, vascular endothelial growth factor release, and HIF-1a expression in respect to eutopic or control MSC. Sorafenib inhibits both functional properties and angiogenic phenotype.

Authors:
Aldo Moggio, M.Sc., Giulia Pittatore, M.D., Paola Cassoni, M.D., Ph.D., Gian Luigi Marchino, M.D., Alberto Revelli, M.D., Ph.D., Benedetta Bussolati1, M.D., Ph.D.

Volume 98, Issue 6, Pages 1521-1530.e2, December 2012

Abstract:

Objective:
To characterize the proliferation, migration, and angiogenic properties of mesenchymal stem cells (MSC) from ectopic and eutopic endometrial tissue and to investigate the effect of the tyrosine kinase inhibitor sorafenib.

Design:
In vitro studies.

Setting:
University hospital and research center.

Patients:
Patients receiving surgical treatment of endometriosis (n=4) and control patients without endometriosis (n=2) undergoing surgery for benign gynaecological diseases.

Intervention:
MSC lines were isolated from ectopic and eutopic endometrial tissue and Sorafenib was administered to them.

Main Outcome Measure:
Proliferation, migration, invasion of endometrial MSC, and expression of ezrin, vascular endothelial growth factor, and hypoxia-inducible factor-1α (HIF-1α) were measured.

Results:
Ectopic endometrial MSC from patients with endometriosis showed a higher proliferation, migration and angiogenic ability than eutopic MSC from the same patient or control MSC from patients without endometriosis. Sorafenib reduced the proliferation, motility, ezrin phosphorylation, VEGF release and HIF-1α expression of ectopic MSC.

Conclusions:
The increased proliferative, migratory and angiogenic phenotype of ectopic MSC may be reverted by treatment with Sorafenib. Targeting of the MSC population involved in sustaining the ectopic lesions might be useful in eradicating endometriotic implants.

  • Raul Gomez, PhD, IUIVI

    I would like
    to congratulate the authors for the research work done. The paper is really
    interesting, with clear objectives and easy to follow. However, after carefull reading
    I have some issues and comments that I would like to share.

    -Don´t the authors think that perhaps the paper
    had benefeited by including a higher number of patients? I mean how can we be
    sure that results do not merely reflect individual variations rather than differences
    debt to the existence of different mesenchymal stem cell types?

    -Might perhaps the authors speculate a little on molecular
    mechanisms which allow mesenchymal stem
    cells to “remember” their different origins (eutopic vs ectopic) and keep such different
    properties after such a long culture
    period?

    It is published and widely accepted the use of
    the Hoechst 33342 staining for the isolation of SP cells (specifically ESP of
    endometrium: Masuda, et al, 2010). The technique used in this paper is
    novel and really interesting, and with the great advantage that allows the
    isolation of MSC without using a sorter, however it is more time consuming and
    laborious, consisting in a lot of passages. So, I wonder whether the Hoechst
    staining technique o could have been used in this case to save time or whether it
    had not been useful in this case.

    Besides, it
    is known that culturing stem cells under hypoxic conditions (1-2%, O2) inhibit
    the cellular differentiation and the mitochondrial biogenesis. In fact, several
    authors (Mas, et al) culture this kind of cells in low oxygen tensions.
    In the paper it is not specified whether culture is done in hypoxia or
    normoxia, and despite I assume that it was done in normoxia, the fact that afterwards
    the HFI-1α levels were measured, makes me wonder on whether were the
    real tissue culture condition. Might the authors detail this point? I just adventure
    that this is a very interesting issue for all those of us employing difficult
    and expensive to maintain cultures under hypoxic conditions

    Just a minor issue to
    end, VEGF protein and mRNA levels were
    measured during characterization of the different cell lines, however only mRNA
    was measured when evaluating the effects of sorafenib on endometrial MSC-lines?
    Why weren’t VEGF protein levels measured at this point?

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