Platelets actively sequester angiogenesis regulators
TL;DR: It is shown that accumulation of angiogenesis regulators in platelets of animals bearing malignant tumors exceeds significantly their concentration in plasma or serum, as well as their levels in Platelets from non-tumor-bearing animals.
About: This article is published in Blood.The article was published on 2009-03-19 and is currently open access. It has received 302 citations till now. The article focuses on the topics: Angiogenesis & Platelet activation.
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TL;DR: Contributions of platelets to tumour cell survival and spread suggest platelets as a new avenue for therapy.
Abstract: Experimental evidence suggests that platelets contribute to metastasis through adhesive and haemostatic functions that promote cancer cell survival, immune evasion and interactions with vascular cells to assist organ colonization from the bloodstream. Extensive experimental evidence shows that platelets support tumour metastasis. The activation of platelets and the coagulation system have a crucial role in the progression of cancer. Within the circulatory system, platelets guard tumour cells from immune elimination and promote their arrest at the endothelium, supporting the establishment of secondary lesions. These contributions of platelets to tumour cell survival and spread suggest platelets as a new avenue for therapy.
1,309 citations
Cites background from "Platelets actively sequester angiog..."
...Intriguingly, platelets specifically sequester regulators of angiogenesis (such as VEGF, platelet factor 4 (PF4) and THBS1) that are released from tumours, as seen in mouse model...
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TL;DR: The extrinsic regulation of angiogenesis by the tumour microenvironment is discussed, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.
Abstract: Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic programming of neoplastic tissue is a multidimensional process regulated by cancer cells in concert with a variety of tumour-associated stromal cells and their bioactive products, which encompass cytokines and growth factors, the extracellular matrix and secreted microvesicles. In this Review, we discuss the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.
1,145 citations
TL;DR: The role of alpha-granules in inflammation, atherosclerosis, antimicrobial host defense, wound healing, angiogenesis, and malignancy has become increasingly appreciated as the function of platelets in the pathophysiology of these processes has been defined.
901 citations
TL;DR: They are major players in atherosclerosis and related diseases, pathologies of the central nervous system (Alzheimers disease, multiple sclerosis), cancer and tumour growth, and participate in other tissue-related acquired pathologies such as skin diseases and allergy, rheumatoid arthritis, liver disease; while, paradoxically, autologous platelet-rich plasma and platelet releasate are being used as an aid to promote tissue repair and cellular growth.
Abstract: Blood platelets have long been recognised to bring about primary haemostasis with deficiencies in platelet production and function manifesting in bleeding while upregulated function favourises arterial thrombosis. Yet increasing evidence indicates that platelets fulfil a much wider role in health and disease. First, they store and release a wide range of biologically active substances including the panoply of growth factors, chemokines and cytokines released from a-granules. Membrane budding gives rise to microparticles (MPs), another active participant within the blood stream. Platelets are essential for the innate immune response and combat infection (viruses, bacteria, micro-organisms). They help maintain and modulate inflammation and are a major source of pro-inflammatory molecules (e.g. P-selectin, tissue factor, CD40L, metalloproteinases). As well as promoting coagulation, they are active in fibrinolysis; wound healing, angiogenesis and bone formation as well as in maternal tissue and foetal vascular remodelling. Activated platelets and MPs intervene in the propagation of major diseases. They are major players in atherosclerosis and related diseases, pathologies of the central nervous system (Alzheimers disease, multiple sclerosis), cancer and tumour growth. They participate in other tissue-related acquired pathologies such as skin diseases and allergy, rheumatoid arthritis, liver disease; while, paradoxically, autologous platelet-rich plasma and platelet releasate are being used as an aid to promote tissue repair and cellular growth. The above mentioned roles of platelets are now discussed.
650 citations
Cites background from "Platelets actively sequester angiog..."
...Platelets selectively accumulate angiogenesis regulators, in particular the pro-angiogenesis factors VEGF and angiopoietin-1 allowing them also to be released locally (reviewed in [20, 224])....
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TL;DR: The results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based “liquid biopsies”.
640 citations
References
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TL;DR: Tumors of epithelioma are composed of two discrete but interdependent compartments: the malignant cells themselves and the stroma that they induce and in which they are dispersed.
Abstract: SOLID tumors are composed of two discrete but interdependent compartments: the malignant cells themselves and the stroma that they induce and in which they are dispersed.1 , 2 In tumors of epitheli...
4,132 citations
TL;DR: These biomarkers demonstrated the potential to improve the detection of early stage ovarian cancer by demonstrating the sensitivity and specificity of a multivariate model combining the three biomarkers.
Abstract: Early detection remains the most promising approach to improve long-term survival of patients with ovarian cancer. In a five-center case-control study, serum proteomic expressions were analyzed on 153 patients with invasive epithelial ovarian cancer, 42 with other ovarian cancers, 166 with benign pelvic masses, and 142 healthy women. Data from patients with early stage ovarian cancer and healthy women at two centers were analyzed independently and the results cross-validated to discover potential biomarkers. The results were validated using the samples from two of the remaining centers. After protein identification, biomarkers for which an immunoassay was available were tested on samples from the fifth center, which included 41 healthy women, 41 patients with ovarian cancer, and 20 each with breast, colon, and prostate cancers. Three biomarkers were identified as follows: (a) apolipoprotein A1 (down-regulated in cancer); (b) a truncated form of transthyretin (down-regulated); and (c) a cleavage fragment of inter-alpha-trypsin inhibitor heavy chain H4 (up-regulated). In independent validation to detect early stage invasive epithelial ovarian cancer from healthy controls, the sensitivity of a multivariate model combining the three biomarkers and CA125 [74% (95% CI, 52-90%)] was higher than that of CA125 alone [65% (95% CI, 43-84%)] at a matched specificity of 97% (95% CI, 89-100%). When compared at a fixed sensitivity of 83% (95% CI, 61-95%), the specificity of the model [94% (95% CI, 85-98%)] was significantly better than that of CA125 alone [52% (95% CI, 39-65%)]. These biomarkers demonstrated the potential to improve the detection of early stage ovarian cancer.
1,000 citations
TL;DR: Using double immunofluorescence and immunoelectron microscopy, it is shown that pro- and antiangiogenic proteins are separated in distinct subpopulations of alpha-granules in platelets and megakaryocytes, which may provide a mechanism by which platelets can locally stimulate or inhibit angiogenesis.
811 citations
TL;DR: It is concluded that human megakaryocytes produce and secrete VEGF in an inducible manner and may contribute to the proliferation of endothelial cells within the bone marrow microenvironment.
Abstract: We have shown that coculture of bone marrow microvascular endothelial cells with hematopoietic progenitor cells results in proliferation and differentiation of megakaryocytes In these long-term cultures, bone marrow microvascular endothelial cell monolayers maintain their cellular integrity in the absence of exogenous endothelial growth factors Because this interaction may involve paracrine secretion of cytokines, we evaluated megakaryocytic cells for secretion of vascular endothelial growth factor (VEGF) Megakaryocytes (CD41a+) were generated by ex vivo expansion of hematopoietic progenitor cells with kit-ligand and thrombopoietin for 10 days and further purified with immunomagnetic microbeads Using reverse transcription–PCR, we showed that megakaryocytic cell lines (Dami, HEL) and purified megakaryocytes expressed mRNA of the three VEGF isoforms (121, 165, and 189 amino acids) Large quantities of VEGF (>1 ng/106 cells/3 days) were detected in the supernatant of Dami cells, ex vivo-generated megakaryocytes, and CD41a+ cells isolated from bone marrow The constitutive secretion of VEGF by CD41a+ cells was stimulated by growth factors of the megakaryocytic lineage (interleukin 3, thrombopoietin) Western blotting of heparin–Sepharose-enriched supernatant mainly detected the isoform VEGF165 In addition, immunohistochemistry showed intracytoplasmic VEGF in polyploid megakaryocytes Thrombin stimulation of megakaryocytes and platelets resulted in rapid release of VEGF within 30 min We conclude that human megakaryocytes produce and secrete VEGF in an inducible manner Within the bone marrow microenvironment, VEGF secreted by megakaryocytes may contribute to the proliferation of endothelial cells VEGF delivered to sites of vascular injury by activated platelets may initiate angiogenesis
702 citations
TL;DR: The presence of VEGF within platelets has implications for processes involving platelet and endothelial cell interactions, e.g. wound healing, and in tumour metastasis, when platelets adhering to circulating tumour cells may release V EGF at points of adhesion to endothelium, leading to hyperpermeability and extravasation of cells.
Abstract: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor with a key role in several pathological processes, including tumour vascularization. Our preliminary observations indicated higher VEGF concentrations in serum samples than in matched plasma samples. We have now demonstrated that this difference is due to the presence of VEGF within platelets and its release upon their activation during coagulation. In eight healthy volunteers, serum VEGF concentrations ranged from 76 to 854 pg ml(-1) and were significantly higher (P < 0.01) than the matched citrated plasma VEGF concentrations, which ranged from < 9 to 42 pg ml(-1). Using platelet-rich plasma, mean (s.d.) platelet VEGF contents of 0.56 (0.36) pg of VEGF 10(-6) platelets were found. Immunocytochemistry demonstrated the cytoplasmic presence of VEGF within megakaryocytes and other cell types within the bone marrow. From examination of the effects of blood sample processing on circulating VEGF concentrations, it is apparent that for accurate measurements, citrated plasma processed within 1 h of venepuncture should be used. Serum is completely unsuitable. The presence of VEGF within platelets has implications for processes involving platelet and endothelial cell interactions. e.g. wound healing, and in tumour metastasis, when platelets adhering to circulating tumour cells may release VEGF at points of adhesion to endothelium, leading to hyperpermeability and extravasation of cells.
607 citations