SIGNIFICANCE: An anti-semaphorin-4D vascular targeting agent demonstrates antitumor and prosurvival effects but also unravels a novel promalignant effect involving macrophage-derived SDF1 that promotes tumor invasion and metastasis, both in animal models and patients.<b>Graphical Abstract:</b> http://cancerres.aacrjournals.org/content/canres/79/20/5328/F1.large.jpg.<i>See related commentary by Tamagnone and Franzolin, p. 5146</i>.
In human trophoblast HTR8/SVneo cell line, sema4D could promote Met and Erk phosphorylation as well as enhance trophoblast cell invasion and tubulogenesis with endothelial cells.
We used computational methods based upon correlated evolution of sequences of interacting proteins, mutational analysis and in vitro and in vivo measurements of tumor aggressiveness to show that when bound to PB1, transmembrane S4D associates with the Rac GTPase exchange factor T lymphoma invasion and metastasis (Tiam) 1, which activates Rac and promotes proliferation, invasion and metastasis in oral squamous cell carcinoma (OSCC) cells.
We evaluated Sema4D expression, density of lymphatic vessels, and invasion of lymphatic vessels with immunohistochemical methods in 232 human cervical cancers with long-term follow-up.