Enhanced platelet activation mediates the accelerated angiogenic switch in mice lacking histidine-rich glycoprotein.
BACKGROUND
The heparin-binding plasma protein histidine-rich glycoprotein (HRG; alternatively, HRGP/HPRG) can suppress tumor angiogenesis and growth in vitro and in vivo. Mice lacking the HRG gene are viable and fertile, but have an enhanced coagulation resulting in decreased bleeding times. In addition, the angiogenic switch is significantly enhanced in HRG-deficient mice.


RESULTS
To address whether HRG deficiency affects tumor development, we have crossed HRG knockout mice with the RIP1-Tag2 mouse, a well established orthotopic model of multistage carcinogenesis. RIP1-Tag2 HRG(-/-) mice display significantly larger tumor volume compared to their RIP1-Tag2 HRG(+/+) littermates, supporting a role for HRG as an endogenous regulator of tumor growth. In the present study we also demonstrate that platelet activation is increased in mice lacking HRG. To address whether this elevated platelet activation contributes to the increased pathological angiogenesis in HRG-deficient mice, they were rendered thrombocytopenic before the onset of the angiogenic switch by injection of the anti-platelet antibody GP1bα. Interestingly, this treatment suppressed the increase in angiogenic neoplasias seen in HRG knockout mice. However, if GP1bα treatment was initiated at a later stage, after the onset of the angiogenic switch, no suppression of tumor growth was detected in HRG-deficient mice.


CONCLUSIONS
Our data show that increased platelet activation mediates the accelerated angiogenic switch in HRG-deficient mice. Moreover, we conclude that platelets play a crucial role in the early stages of tumor development but are of less significance for tumor growth once angiogenesis has been initiated.
Department of Medical Biochemistry and Microbiology, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden.
Maria
M
Ringvall
Åsa
Å
Thulin
Lei
L
Zhang
Jessica
J
Cedervall
Nobuko
N
Tsuchida-Straeten
Willi
W
Jahnen-Dechent
Agneta
A
Siegbahn
Anna-Karin
AK
Olsson
D000818:Animals; D001777:Blood Coagulation; D006023:Glycoproteins; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000209:etiology; D009389:Neovascularization, Pathologic; D015539:Platelet Activation; D011506:Proteins / Q000235:genetics*; D047368:Tumor Burden / Q000235:genetics; D000099053:Histidine-Rich Glycoprotein
D006023:Glycoproteins; D011506:Proteins; D000099053:Histidine-Rich Glycoprotein
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