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Enhanced platelet activation mediates the accelerated angiogenic switch in mice lacking histidine-rich glycoprotein.

Ringvall M, Thulin Å, Zhang L, Cedervall J, Tsuchida-Straeten N, Jahnen-Dechent W, Siegbahn A, Olsson AK - PLoS ONE (2011)

Bottom Line: Mice lacking the HRG gene are viable and fertile, but have an enhanced coagulation resulting in decreased bleeding times.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry and Microbiology, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden.

ABSTRACT

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.

Methodology/principal findings: 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.

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Related in: MedlinePlus

Tumor volume is increased in RT2/HRG−/− compared to RT2/HRG+/+ mice.Tumors were dissected and measured. Tumor volumes were calculated by the formula ((π/6)×width2×length). Each dot represents the summarized tumor volume in mm3 from one mouse at (A) 12 weeks of age (n+/+ = 16; n−/− = 16) and at (B) 15 weeks of age (n+/+ = 11; n−/− = 12). Statistical analyses were performed with a two-tailed Mann-Whitney test, vertical bars represent standard deviation, * p≤0.05.
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pone-0014526-g002: Tumor volume is increased in RT2/HRG−/− compared to RT2/HRG+/+ mice.Tumors were dissected and measured. Tumor volumes were calculated by the formula ((π/6)×width2×length). Each dot represents the summarized tumor volume in mm3 from one mouse at (A) 12 weeks of age (n+/+ = 16; n−/− = 16) and at (B) 15 weeks of age (n+/+ = 11; n−/− = 12). Statistical analyses were performed with a two-tailed Mann-Whitney test, vertical bars represent standard deviation, * p≤0.05.

Mentions: Analysis of tumor growth in RT2/HRG+/+ and RT2/HRG−/− mice was performed on gender-matched groups at two ages, 12 and 15 weeks. The total tumor burden was assessed by two parameters; total tumor volume and number of tumors. At 12 weeks of age, the mean total tumor volume in the HRG−/− group was two times higher than in the HRG+/+ group (Fig. 2A, table 1). Three weeks later, at 15 weeks of age, the difference between the two groups was further enhanced. At this time point the mean total tumor volume in the HRG−/− group was more than three times higher than in the HRG+/+ group (Fig. 2B, table 1). The number of tumors did not differ between the groups at any age (data not shown).


Enhanced platelet activation mediates the accelerated angiogenic switch in mice lacking histidine-rich glycoprotein.

Ringvall M, Thulin Å, Zhang L, Cedervall J, Tsuchida-Straeten N, Jahnen-Dechent W, Siegbahn A, Olsson AK - PLoS ONE (2011)

Tumor volume is increased in RT2/HRG−/− compared to RT2/HRG+/+ mice.Tumors were dissected and measured. Tumor volumes were calculated by the formula ((π/6)×width2×length). Each dot represents the summarized tumor volume in mm3 from one mouse at (A) 12 weeks of age (n+/+ = 16; n−/− = 16) and at (B) 15 weeks of age (n+/+ = 11; n−/− = 12). Statistical analyses were performed with a two-tailed Mann-Whitney test, vertical bars represent standard deviation, * p≤0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3022027&req=5

pone-0014526-g002: Tumor volume is increased in RT2/HRG−/− compared to RT2/HRG+/+ mice.Tumors were dissected and measured. Tumor volumes were calculated by the formula ((π/6)×width2×length). Each dot represents the summarized tumor volume in mm3 from one mouse at (A) 12 weeks of age (n+/+ = 16; n−/− = 16) and at (B) 15 weeks of age (n+/+ = 11; n−/− = 12). Statistical analyses were performed with a two-tailed Mann-Whitney test, vertical bars represent standard deviation, * p≤0.05.
Mentions: Analysis of tumor growth in RT2/HRG+/+ and RT2/HRG−/− mice was performed on gender-matched groups at two ages, 12 and 15 weeks. The total tumor burden was assessed by two parameters; total tumor volume and number of tumors. At 12 weeks of age, the mean total tumor volume in the HRG−/− group was two times higher than in the HRG+/+ group (Fig. 2A, table 1). Three weeks later, at 15 weeks of age, the difference between the two groups was further enhanced. At this time point the mean total tumor volume in the HRG−/− group was more than three times higher than in the HRG+/+ group (Fig. 2B, table 1). The number of tumors did not differ between the groups at any age (data not shown).

Bottom Line: Mice lacking the HRG gene are viable and fertile, but have an enhanced coagulation resulting in decreased bleeding times.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry and Microbiology, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden.

ABSTRACT

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.

Methodology/principal findings: 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.

Show MeSH
Related in: MedlinePlus