Angiostatin inhibits monocyte/macrophage migration via disruption of actin cytoskeleton.
In light of the involvement of tumor-associated macrophages (TAM) in the promotion of tumor growth and metastasis, strategies to prevent TAM recruitment within the tumor microenvironment are currently under investigation. The recent observation that angiostatin reduces macrophage infiltration in an atherosclerosis model prompted our laboratory to further explore the use of human plasminogen angiostatin (hK1-3) protein as a macrophage modulatory agent. We demonstrate that hK1-3 blocks migration of murine peritoneal macrophages (91% decrease, P<0.00005) and human monocytes (85% decrease, P<0.05) in vitro. Cell viability of hK1-3-treated cells is not affected, as determined by fluorochrome-labeled inhibitors of caspase-propidium iodide (FLICA/PI) flow cytometry analysis. Furthermore, confocal microscopy of phalloidin-stained cells reveals that hK1-3 leads to disruption of actin filopodia/lamellipodia in human monocytes and induces distinct podosome accumulation in mature differentiated macrophages. Paradoxically, we observed a 3.5-fold increase in secretion and a 3- to 5.5-fold increase in gelatinolytic activity of macrophage-produced matrix metalloproteinase-9, which we suggest is a cellular response to compensate for the dominant static effect of hK1-3 on actin. We also demonstrate that hK1-3 induces the phosphorylation of extracellular signal-regulated kinase (ERK1/2) in human monocytes. hK1-3-mediated macrophage immobilization has the potential to be exploited therapeutically in pathological conditions associated with cellular hypoxia, such as cancer and atherosclerosis.
Perri
Sabrina R
SR
Division of Experimental Medicine, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada H3T 1E2.
Annabi
Borhane
B
Galipeau
Jacques
J
D000199:Actins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043168:Angiostatins / Q000502:physiology*; D000818:Animals; D002464:Cell Migration Inhibition / Q000502:physiology*; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018082:Kringles / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000502:physiology
D000199:Actins; D010446:Peptide Fragments; D043168:Angiostatins