Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage

Kisucka, Janka; Butterfield, Catherine; Duda, Dan G.; Eichenberger, Sarah; Saffaripour, Simin; Ware, Jerry; Ruggeri, Zaverio M.; Jain, Rakesh K.; Folkman, Judah; Wagner, Denisa D.

doi:10.1073/pnas.0510412103

Cited by 323 publications

(259 citation statements)

References 63 publications

(48 reference statements)

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“…For example, NETs have been shown to contain and activate matrix metalloproteinases, 28 preserve the enzymatic activity of elastase 29 and recruit platelets, 30 important cells for angiogenesis. 31 Neutrophils were described to suppress the cytotoxic CD8 C antitumoral response, which is associated with the generation of ROS. 32 ROS are inducers of NETs and thus NETs could be implicated.…”

Section: Discussionmentioning

confidence: 99%

Priming of neutrophils toward NETosis promotes tumor growth

et al. 2016

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Neutrophils play a major role in cancer biology and both pro-and antitumoral functions of tumorinfiltrating neutrophils have been described. We have shown that tumors, by releasing G-CSF into the bloodstream, prime circulating neutrophils to form neutrophil extracellular traps (NETs) and we have detected the presence of NETs within the tumor microenvironment. Here, we report, using PAD4-deficient mice with a defect in neutrophil chromatin decondensation and NET formation, that the priming of neutrophils toward NETosis favors tumor growth. Interestingly, in a tumor model that does not release G-CSF and in which neutrophils are not primed for NETosis, PAD4-deficiency did not reduce tumor growth. However, supplying exogenous G-CSF to the wild-type (WT) host promoted intratumoral NETosis and tumor growth. Taken together, our results suggest that the priming of neutrophils for NETosis by the tumor or its environment leads to the accumulation of intratumoral NETs and a growth advantage to the tumor. Our work unveiled a pro-tumoral role for NETs which strengthens their potential as a new target in the fight against cancer.

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Section: Discussionmentioning

confidence: 99%

Priming of neutrophils toward NETosis promotes tumor growth

et al. 2016

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“…Although the in vivo role of platelet GP Ib-IX in hemostasis and thrombosis is well established (26)(27)(28), its role in other biological events is only minimally appreciated. In the past decade, there has been a growing appreciation for the platelet in a variety of processes from tumorigenesis to inflammation (4,29,30).…”

Section: Discussionmentioning

confidence: 99%

“…In the past decade, there has been a growing appreciation for the platelet in a variety of processes from tumorigenesis to inflammation (4,29,30). One recent example is mice deficient in functional GP Ib-IX exhibiting impaired angiogenesis (27). A few reports have documented that GP Ib␣ can function as a counterreceptor for P-selectin (31) while supporting a platelet-leukocyte interaction via the integrin receptor, Mac-1 (32,33).…”

Section: Discussionmentioning

confidence: 99%

Platelet glycoprotein Ibα supports experimental lung metastasis

Jain

Zuka

Liu

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The platelet paradigm in hemostasis and thrombosis involves an initiation step that depends on platelet membrane receptors binding to ligands on a damaged or inflamed vascular surface. Once bound to the surface, platelets provide a unique microenvironment supporting the accumulation of more platelets and the elaboration of a fibrin-rich network produced by coagulation factors. The platelet-specific receptor glycoprotein (GP) Ib-IX, is critical in this process and initiates the formation of a platelet-rich thrombus by tethering the platelet to a thrombogenic surface. A role for platelets beyond the hemostasis/thrombosis paradigm is emerging with significant platelet contributions in both tumorigenesis and inflammation. We have established congenic (N10) mouse colonies (C57BL/6J) with dysfunctional GP Ib-IX receptors in our laboratory that allow us an opportunity to examine the relevance of platelet GP Ib-IX in syngeneic mouse models of experimental metastasis. Our results demonstrate platelet GP Ib-IX contributes to experimental metastasis because a functional absence of GP Ib-IX correlates with a 15-fold reduction in the number of lung metastatic foci using B16F10.1 melanoma cells. The results demonstrate that the extracellular domain of the ␣-subunit of GP Ib is the structurally relevant component of the GP Ib-IX complex contributing to metastasis. Our results support the hypothesis that platelet GP Ib-IX functions that support normal hemostasis or pathologic thrombosis also contribute to tumor malignancy.adhesion ͉ tumor ͉ hemostasis ͉ knockout ͉ melanoma C irculating blood platelets have an inherent adhesive potential long recognized as essential for hemostasis and thrombosis. Beyond the platelet paradigm for blood clotting and thrombosis, it is becoming apparent that the platelet's adhesive potential influences pathological events outside its role in hemostasis. Indeed, emerging hypotheses suggest the platelet paradigm in hemostasis and thrombosis, an accumulation of platelets and the elaboration of a fibrin matrix, may provide a mechanism for circulating tumor cells to metastasize. Experimental proof that platelets effect tumor metastasis was provided in models where an experimental lowering of circulating platelet counts reduced metastasis (1-3).Evidence suggests that carcinoma cells entering the circulation interact with both platelets and leukocytes to form tumor cell aggregates (1, 4). Data have suggested one mechanism linking the platelet to metastasis is a platelet ''cloak'' surrounding the tumor cell and protecting the tumor cell from immune surveillance (5, 6). Tumorigenesis has been linked to several molecules essential for blood coagulation and normal platelet function. These include thrombin, tissue factor, platelet P-selectin, fibrinogen, and lysophosphatidic acid (3,4,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Together, these results suggest that platelets and their procoagulant activity support tumor metastasis, possibly by aiding tumor cells to lodge in the microvasculature and either extravasate...

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“…At sites of blood vessel injury, platelets are activated and aggregate at the site of the damaged endothelium to prevent hemorrhage. Besides their role in hemostasis, platelets contribute to nonhemostatic processes such as immunity, tumor metastasis, and angiogenesis (9)(10)(11). Despite their content of both positive and negative regulators of blood vessel formation, platelets have in several different experimental settings been shown to stimulate angiogenesis (11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%