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Angiostatin inhibits monocyte/macrophage migration via disruption of actin cytoskeleton
Author(s) -
Perri Sabrina R.,
Annabi Borhane,
Galipeau Jacques
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-8158com
Subject(s) - microbiology and biotechnology , filopodia , lamellipodium , podosome , propidium iodide , macrophage , cell migration , actin cytoskeleton , chemistry , biology , cytoskeleton , actin , cell , in vitro , biochemistry , apoptosis , programmed cell death
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 an‐ giostatin (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 S.R., Annabi B., Galipeau J. Angiostatin inhibits monocyte/macrophage migration via disruption of actin cytoskeleton. FASEB J . 21, 3928–3936 (2007)