Keynote Conference - Interevent

Symp#13 Vascular cell biology
Chair Robson Monteiro
Tumor-Derived Microvesicles and their Role in Cancer Progression
Robson Q. Monteiro
Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Shedding of phosphatidylserine (PS)-containing microvesicles (MVs) by cancer cells have been correlated with several pro-tumoral
responses. In addition, the procoagulant properties of MVs suggest their involvement in the establishment of cancer-associated
prothrombotic states. Comparison of MVs produced by a non-tumorigenic melanocyte-derived cell line (melan-A) with its
tumorigenic melanoma counterpart, Tm1, showed an increased rate of MVs production upon malignant transformation. Moreover,
tumor-derived MVs displayed increased levels of the clotting initiator protein, tissue factor (TF). As a result, Tm1 but not melan-aderived
MVs accelerated thrombosis in vivo. Analysis of plasma obtained from melanoma-bearing mice showed the presence of MVs
with a similar procoagulant pattern as compared to Tm1 MVs produced in vitro. Remarkably, flow-cytometric analysis demonstrated
that 60% of ex-vivo MVs are TF-positive and carry the melanoma-associated antigen, demonstrating its tumor origin. These data
reinforce the possible involvement of tumor-derived MVs in the establishment of cancer-associated hypercoagulant states, indicating
an important role for TF in this process. Since MVs may horizontally transfer their cargo between different cells, we further
investigated the exchange of TF-bearing MVs between human breast cancer cell lines with different aggressiveness potential.
Incubation of low aggressive MCF-7 cells with MVs from the aggressive cell line, MDA-MB-231, rendered a significant gain of TF
activity. This phenomenon was not observed upon pretreatment of MVs with an anti-TF neutralizing antibody or annexin V, which
blocks PS sites on MVs surface. These data indicate that TF-bearing MVs can be transferred between different populations of cancer
cells, and thus may contribute to the propagation of a TF-related aggressive phenotype among heterogeneous cell subsets present in
the tumor microenvironment.
This study was supported by the Brazilian agencies CNPq and FAPERJ.
Cell Adhesion and Signaling Pathways in Neurovascular Development
Joseph H. McCarty
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030,
U.S.A.
The mammalian central nervous system contains billions of neurons and glia that are interlaced with an elaborate network of blood
vessels comprised of endothelial cells, pericytes and vascular basement membranes. During development blood vessels grow and
sprout along a pre-formed latticework of glial cells; however, the mechanisms by which glial cells control central nervous system
neovascularization remain enigmatic. We have used Cre-lox strategies in mice to demonstrate that αvβ8 integrin expressed in glial
cells is essential for neovascularization of the developing central nervous system. Cell type-specific inactivation of αv or β8 integrin
gene expression in radial glia using a Nestin-Cre transgene leads to the development of hemorrhagic blood vessels that form
glomeruloid-like tufts in the embryonic brain and the neonatal retina. These pathologies correlate with diminished activation of latent
TGFβs, which are extracellular matrix-bound protein ligands for αvβ8 integrin. Genetic ablation of canonical TGFβ receptors Alk5 or
TGFβR2 in vascular endothelial cells during embryogenesis result in brain vascular pathologies that are identical to those in integrin
conditional knockout mice. Furthermore, tamoxifen-inducible inactivation of TGFβ receptor signaling in retinal endothelial cells also
leads to defective angiogenesis and intraretinal hemorrhage. Collectively, our data demonstrate that αvβ8 integrin and TGFβ
receptors are components of a paracrine signaling axis that links glial cells to endothelial cells during central nervous system vascular
development.
Vascular growth factor signaling in neurogenesis
Jean-Léon Thomas #, Anne Eichmann *
Departments of Neurology # and Cardiovascular Medicine * , Yale School of Medicine, New Haven, CT, USA
# Brain and Spinal Cord Institute, Paris, France
In the adult mammalian brain, the potential to generate new neurons is restricted to a limited number of sites called neurogenic
niches, which are localized in the subventricular zone (SVZ) lining the cerebral ventricles and in the dentate gyrus (DG) of the
hippocampus. Injury of brain tissue resulting from trauma or pathologies activates neurogenesis in these niches, attesting to an
endogenous repair potential that is generally not sufficient to allow a complete rescue. To enhance this endogenous neurogenic
response without negative side effects, it is crucial to characterize the mechanisms which are active in neurogenic niches.
Functionally, members of the vascular endothelial growth factor (VEGF) family stimulate adult neurogenesis and neuronal plasticity,
opening potential approaches for repair of neurodegenerative diseases. However, it has been unclear whether VEGFs stimulate
neurogenesis directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from
angiogenic capillaries. We have reported that the lymphangiogenic growth factor VEGF-C is expressed by neural cells and provides
trophic support to neural progenitor cells during brain development (Le Bras, Nat Neurosci, 2006). Here, we will discuss our latest
findings on its receptor VEGFR-3, which is expressed by adult NSCs, and is critical for adult neurogenesis by acting directly in NSCs and
niche astrocytes, but not endothelial cells (Calvo, Genes Dev., 2011).
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