Аннотация
EphB receptors and their ephrinB ligands play a key role in the formation
of a regular vascular system. Recent studies have also shown the
involvement of Eph/ephrin interactions in malignant tumor progression
and angiogenesis. We have generated soluble monomeric EphB4 (sEphB4)-expressing
A375 melanoma cells to study the effect of dominant negatively acting
sEphB4 on tumor growth and angiogenesis. Soluble EphB4-expressing
A375 tumors grown subcutaneously in nude mice show dramatically reduced
tumor growth compared to control tumors. The proliferative capacity
of sEphB4-expressing cells in monolayer culture is not altered. Yet,
sEphB4-expressing A375 cells cannot establish proper cell-cell contacts
in three-dimensional spheroids. However, sEphB4 transfectants have
reduced proliferation and apoptosis rates when grown in three-dimensional
culture in vitro or in subcutaneous tumors in vivo. Analysis of the
vascular phenotype of the tumors revealed a reduction of intratumoral
microvessel density in sEphB4-expressing tumors. Corresponding to
these mouse experiments, a matched pair analysis of EphB4 and ephrinB2
expression in human colon carcinomas revealed significantly upregulated
levels of EphB4 expression compared to adjacent normal tissue. Taken
together, the data identify dual effects of sEphB4 on the tumor and
the vascular compartment that collectively inhibit tumor growth.
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