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Lymphangiogenic growth factors, receptors and therapies.

PostPosted: Fri Sep 22, 2006 5:30 am
by patoco
Lymphangiogenic growth factors, receptors and therapies.

Lohela M, Saaristo A, Veikkola T, Alitalo K.

Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer
Research, Haartman Institute and Helsinki University Central Hospital,
Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.

The lymphatic vasculature is essential for the maintenance of normal
fluid balance and for the immune responses, but it is also involved in
a variety of diseases. Hypoplasia or dysfunction of the lymphatic
vessels can lead to lymphedema, whereas hyperplasia or abnormal growth of these vessels are associated with lymphangiomas and
lymphangiosarcomas. Lymphatic vessels are also involved in lymph node
and systemic metastasis of cancer cells. Recent novel findings on the
molecular mechanisms involved in lymphatic vessel development and
regulation allow the modulation of the lymphangiogenic process and
specific targeting of the lymphatic endothelium.

Recent results show that the homeodomain transcription factor Prox-1 is
an important lymphatic endothelial cell (LEC) fate-determining factor
which can induce LEC-specific gene transcription even in blood vascular
endothelial cells (BECs). This suggests that the distinct phenotypes of
cells in the adult vascular endothelium are plastic and sensitive to
transcriptional reprogramming, which might be useful for future
therapeutic applications involving endothelial cells.

Vascular endothelial growth factor-C (VEGF-C) and VEGF-D are peptide
growth factors capable of inducing the growth of new lymphatic vessels
in vivo in a process called lymphangiogenesis. They belong to the
larger family which also includes VEGF, placenta growth factor (PlGF)
and VEGF-B, VEGF-C and VEGF-D are ligands for the endothelial cell
specific tyrosine kinase receptors VEGFR-2 and VEGFR-3. In adult human
as well as mouse tissues VEGFR-3 is expressed predominantly in
lymphatic endothelial cells which line the inner surface of lymphatic

While VEGFR-2 is thought to be the main mediator of angiogenesis,
VEGFR-3 signaling is crucial for the development of the lymphatic
vessels. Heterozygous inactivation of the VEGFR-3 tyrosine kinase leads
to primary lymphedema due to defective lymphatic drainage in the limbs.
Other factors that seem to be involved in lymphangiogenesis include the
Tie/angiopoietin system, neuropilin-2 and integrin alpha 9. VEGF-C
induces lymphatic vessel growth, but high levels of VEGF-C also
resulted in blood vessel leakiness and growth.

The VEGFR-3-specific mutant form of VEGF-C called VEGF-C156S lacks
blood vascular side effects but is sufficient for therapeutic
lymphangiogenesis in a mouse model of lymphedema. As VEGF-C156S is a specific lymphatic endothelial growth factor in the skin, it provides
an attractive molecule for pro-lymphangiogenic therapy.

Publication Types:

PMID: 12888864 [PubMed - indexed for MEDLINE]

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