Tumor-induced inverted vasculogenesis from mesenchymal stem cells is the origin of tumor lymphovascular invasion
Barsky, S.H.
FASEB Journal 17(4-5): Abstract 861
2003
ISSN/ISBN: 0892-6638 Accession: 035991555
Tumor lymphovascular invasion (LVI) is a rate-limiting step in metastasis yet its molecular mechanisms are unknown. We have developed a human inflammatory breast carcinoma/scid mouse xenograft (MARY-X) which exhibits florid LVI within murine stroma. The xenograft produces tumor cell spheroids in suspension culture which when reinjected exhibit tumor emboli showing LVI. Green fluorescence protein (GFP)-labelled murine embryonal fibroblasts co-injected with the spheroids reproduce the MARY-X phenotype in which GFP is present within both the stroma as well as the endothelial cells which surround the tumor emboli. Injected GFP-labelled spheroids also reproduce the MARY-X phenotype but one in which the GFP is present only within the tumor cells and not the stroma nor the surrounding endothelial cells. Two derived mutants of MARY-X, one containing a dominant negative E-cadherin mutant (H-2Kd-E-cad) which disrupts the E-cadherin-mediated homotypic adhesion of the spheroids and the other containing alpha-1,3-fucosyltransferase III (FucT-III), which increases surface sialyl Lewis x/a which also disrupts the E-cadherin homotypic adhesion, do not exhibit LVI. When these mutant spheroids are co-injected with GFP-murine embryonal fibroblasts, GFP is detected within stroma but not within surrounding endothelial cells. Our studies indicate that spheroid-induced inverted vasculogenesis from mesenchymal stem cells is the origin of tumor lymphovascular invasion.