title: Metastatic growth progression caused by PSGL-1-mediated recruitment of monocytes to metastatic sites.
abstract: Tumor cell-derived selectin ligands mediate contact to the endothelium, platelets, and leukocytes through binding to selectins that facilitates metastasis. Here, we describe the mechanism of how endogenous (non-tumor derived) selectin ligands contribute to metastasis using α(1,3)fucosyltransferase 7 (Fuc-TVII(-/-))-deficient mice. Experimental metastasis of MC-38GFP and Lewis lung (3LL) carcinoma cells was attenuated in Fuc-TVII(-/-) mice, which express minimal amount of selectin ligands. We show that metastasis is dependent on selectin ligands carried on hematopoietic cells. P-selectin glycoprotein ligand-1 (PSGL-1) was identified as the major ligand facilitating monocyte accumulation at metastatic sites. Reduced recruitment of monocytes to metastasizing tumor cells in Fuc-TVII(-/-) mice correlated with attenuated metastasis. Adoptive transfer of Fuc-T7(+) monocytes rescued metastasis in Fuc-TVII(-/-) mice, indicating that selectin ligand-dependent recruitment of monocytes is required for cancer progression. Cytokine analysis in metastatic lungs revealed high expression of CCL2 in C57BL/6 mice that was significantly lower in Fuc-TVII(-/-) mice. The absence of monocyte recruitment in Fuc-TVII(-/-) mice correlated with increased apoptosis of tumor cells. Thus, the recruitment of monocytes to metastasizing tumor cells is facilitated by endogenous selectin ligands on monocytes that enable efficient tumor cell survival, extravasation, and metastasis.
authors: Authors' Affiliation: Institute of Physiology, University of Zürich and Zürich Center for Integrative Human Physiology, Zurich, Switzerland.
authors: Alexandra
authors: A
authors: Hoos
authors: Darya
authors: D
authors: Protsyuk
authors: Lubor
authors: L
authors: Borsig
mesh_terms: D000818:Animals; D002450:Cell Communication; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D022423:Myeloid Cells / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*
chemical_list: D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein