Enhanced Platelet Activation Mediates the Accelerated Angiogenic Switch in Mice Lacking Histidine-Rich Glycoprotein

Abstract

BackgroundThe 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 FindingsTo 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.ConclusionsOur 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.

Genetic Deficiency in Plasma Protein HRG Enhances Tumor Growth and Metastasis by Exacerbating Immune Escape and Vessel Abnormalization

“…Our data extend a recent report on enhanced tumor growth but unaffected angiogenesis in established pancreatic tumors in HRG-deficient Rip1-Tag2 mice (40), which were sensitive to treatment with a platelet-depleting antibody. HRG negatively affected the angiogenic switch as shown by the increased incidence of hemoglobin-containing pancreatic islets in the absence of HRG in the RipTag2 model (41).…”

Platelets Promote Mitochondrial Uncoupling and Resistance to Apoptosis in Leukemia Cells: A Novel Paradigm for the Bone Marrow Microenvironment

“…In contrast, in vitro and in vivo evidence supports the hypothesis that platelets promote solid tumor progression and dissemination [12][13][14][15], and may contribute to chemoresistance and exposed to increasing doses of ABT-737 or CDDO-Me for 16 h and apoptotic cells were quantified as above. *= p<0.05 from RPMI only control [14].…”

“…Megakaryopoiesis and thrombopoiesis occur in the bone marrow milieu ( [8] and reviewed in [9]), and although blood platelet counts are an important parameter (reviewed in [10,11]), and the scientific literature supports a solid tumor promoting effect of platelets [12][13][14][15], only few studies have investigated the interaction of platelets with leukemia cells in vitro (reviewed by Foss and Bruserud [10]). It is conceivable that multiple platelet-released mediators would promote the growth of leukemia cells -similar to the effects reported for mesenchymal stromal cells and solid tumors [16,17].…”

Platelet Regulation of Angiogenesis, Tumor Growth and Metastasis

“…Studies by Kisucka et al using the cornea micropocket assay in thrombocytopenic mice indicate that it is primarily the early stages in neovascularization that are affected by platelets (Kisucka et al, 2006). Moreover, mice lacking the endogenous angiogenesis inhibitor histidine-rich glycoprotein (HRG) have a coagulation defect and enhanced activation of platelets (Tsuchida-Straeten et al, 2005;Ringvall et al, 2011). HRG-deficient Rip1-Tag2 mice, a transgenic model of insulinoma, have a significantly increased number of angiogenic islets of Langerhans in their pancreas (Thulin et al, 2009).…”

“…reduced platelet count, two weeks before onset of the switch. However, thrombocytopenia had no effect on angiogenesis at a later stage when the angiogenic islets had developed into invasive carcinomas (Ringvall et al, 2011). In addition, negative regulation of angiogenesis by platelet-derived TSP was demonstrated to play a role during early stages of tumor vascularization (Zaslavsky et al, 2010).…”