Abstract
Targeting immune cells that support tumor growth is an effective therapeutic strategy in tumor entities such as melanoma. M2-like tumor-associated macrophages (TAM) sustain tumor growth by secreting anti-inflammatory cytokines, proteases and growth factors. In this study, we show that a protein derived from M2-like macrophages namely the shedded ectodomain of Lyve-1 (sLyve-1) decreases human HT144 and murine B16F1 melanoma cell proliferation significantly by acting as a decoy receptor for low-molecular weight hyaluronic acid (LMW-HA) although the LMW-HA/Lyve-1 interaction on lymphatic endothelial cells has been described to induce lymphangiogenesis. This is in line with our finding that the number of LYVE-1+ TAM decreases in higher human melanoma stages and that the early growth of B16 transplant tumors is enhanced in Lyve-1 knockout mice when compared to wild-type mice due to an increased melanoma cell proliferation. LYVE-1 expressing TAM are however true M2 macrophages as they co-express typical M2-markers such as CD163 and CD206. The results of the present study highlight the necessity to carefully determine the net effect particular TAM subpopulations have on tumors before establishing a treatment to target these immune cells.
Highlights
Hyaluronic acid (HA) is a structural component of the extracellular matrix necessary for hydration and protection against mechanical forces
We show that a protein derived from M2-like macrophages namely the shedded ectodomain of lymphatic vessel endothelial hyaluronan receptor-1 (Lyve-1) decreases human HT144 and murine B16F1 melanoma cell proliferation significantly by acting as a decoy receptor for lowmolecular weight hyaluronic acid (LMW-HA) the LMW-HA/Lyve-1 interaction on lymphatic endothelial cells has been described to induce lymphangiogenesis
This is in line with our finding that the number of LYVE-1+ tumor-associated macrophages (TAM) decreases in higher human melanoma stages and that the early growth of B16 transplant tumors is enhanced in Lyve-1 knockout mice when compared to wild-type mice due to an increased melanoma cell proliferation
Summary
Hyaluronic acid (HA) is a structural component of the extracellular matrix necessary for hydration and protection against mechanical forces. It binds to a wide range of different receptors - amongst them the lymphatic vessel endothelial hyaluronan receptor-1 (Lyve-1) - and exerts various functions which depend on the size of the polymer. Lyve-1 is a type I transmembrane glycoprotein belonging to the link domain superfamily with 43 % sequence homology to the hyaluronan receptor CD44. It has first been identified as a lymphatic endothelial cellspecific HA receptor [5,6,7]. The biological effect of a HA/Lyve-1-binding in these myeloid cells has not yet been examined
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