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2016 ; 7
(42
): 68527-68545
Nephropedia Template TP
gab.com Text
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Twit Text #
English Wikipedia
Heparins that block VEGF-A-mediated von Willebrand factor fiber generation are
potent inhibitors of hematogenous but not lymphatic metastasis
#MMPMID27602496
Goertz L
; Schneider SW
; Desch A
; Mayer FT
; Koett J
; Nowak K
; Karampinis I
; Bohlmann MK
; Umansky V
; Bauer AT
Oncotarget
2016[Oct]; 7
(42
): 68527-68545
PMID27602496
show ga
Von Willebrand factor (VWF) serves as a nidus for platelet aggregation and
thrombosis. We hypothesize that VWF fibers contribute to the development of
venous thromboembolism (VTE) and to metastasis formation. Here, we show that
vascular and lymphatic endothelial cells (ECs) express VWF in vitro and release
VWF fibers after activation by tumor cell supernatants. In contrast, an ex vivo
analysis of primary mouse tumors revealed the presence of VWF fibers in the blood
microvasculature but not in lymphatic vessels. Unlike the anticoagulant
Fondaparinux, an inhibitor of thrombin generation, the low-molecular-weight
heparin (LMWH) Tinzaparin inhibited VWF fiber formation and vessel occlusion in
tumor vessels by blocking thrombin-induced EC activation and vascular endothelial
growth factor-A (VEGF-A)-mediated VWF release. Intradermal tumor cell inoculation
in VWF- and ADAMTS13-deficient mice did not alter lymph node metastases compared
with wild type animals. Interestingly, multiple tumor-free distal organs
exhibited hallmarks of malignancy-related VTE, including luminal VWF fibers,
platelet-rich thrombi and vessel occlusions. Furthermore, ADAMTS13 deficiency,
characterized by prolonged intraluminal VWF network lifetimes, resulted in a
severely increased number of metastatic foci in an experimental model of
hematogenous lung seeding. Treatment with Tinzaparin inhibited tumor-induced
release of VWF multimers, impeded platelet aggregation and decreased lung
metastasis. Thus, our data strongly suggest a critical role of luminal VWF fibers
in determining the occurrence of thrombosis and cancer metastasis. Moreover, the
findings highlight LMWHs as therapeutic strategy to treat thrombotic
complications while executing anti-metastatic activities.