Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition

Nagy, Janice A.; Brown, Lawrence F.; Senger, Donald R.; Lanir, Naomi; Water, Livingston Van De; Dvorak, Ann M.; Dvorak, Harold F.

doi:10.1016/0304-419x(89)90004-8

Cited by 225 publications

(191 citation statements)

References 76 publications

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“…Studies from our laboratory (Nagy et al, 1988;Dvorak et al, 1991) support the hypothesis that VPF plays an important role in aiding growth of some tumors by promoting both tumor angiogenesis and stroma generation. In accord with earlier findings (Senger et al, 1986) .k-A w expression was correlated with tumorigenicity in matched pairs of cultured cell lines.…”

Section: Discussionmentioning

confidence: 62%

“…On a molar basis it is '50 000 times more potent than histamine at increasing microvascular permeability . In its capacity as both permeability and growth factor, VPF/VEGF very likely is responsible for fluid accumulation in solid and ascites tumors and for initiating and promoting tumor angiogenesis and stroma generation (Nagy et al, 1988). In vitro and at subpicomolar concentrations, VPF/VEGF rapidly increases free cytosolic Ca21 in endothelial cells, apparently by activating a phosphoinositide-specific phospholipase C (Brock et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors.

Berse

Brown

Water

et al. 1992

MBoC

796

423

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Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), increases microvascular permeability and is a specific mitogen for endothelial cells. Expression of VPF/VEGF previously was demonstrated in a variety of tumor cells, in cultures of pituitary-derived cells, and in corpus luteum. Here we present evidence, by Northern analysis and in situ hybridization, that the VPF/VEGF gene is expressed in many adult organs, including lung, kidney, adrenal gland, heart, liver, and stomach mucosa, as well as in elicited peritoneal macrophages. The highest levels of VPF/VEGF transcripts were found in epithelial cells of lung alveoli, renal glomeruli and adrenal cortex, and in cardiac myocytes. The prominence of VPF/VEGF mRNA in these tissues suggests a possible role for VPF/VEGF in regulating baseline microvascular permeability, which is essential for tissue nutrition and waste removal. We also demonstrate particularly high VPF/VEGF mRNA levels in several human tumors, where it may be involved in promoting tumor angiogenesis and stroma generation, both as an endothelial cell mitogen and indirectly by its permeability enhancing effect that leads to the deposition of a provisional fibrin gel matrix.

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Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors.

Berse

Brown

Water

et al. 1992

MBoC

796

423

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show abstract

“…It has been shown that greater numbers of tumour vessels increase the opportunity for tumour cells to enter the circulation (Liotta et al, 1976). Moreover, newly formed capillaries have fragmented basement membranes and are leaky, making them more penetrable by tumour cells than mature vessels (Nagy et al, 1989). Therefore, in the hypervascular tumours, the metastatic process may be enhanced by the 'leaky' nature of newly formed blood vessels facilitating vascular invasion.…”

Section: Discussionmentioning

confidence: 99%

Thymidine phosphorylase/platelet-derived endothelial cell growth factor expression associated with hepatic metastasis in gastric carcinoma

Maeda

Chung²,

Ogawa³

et al. 1996

Br J Cancer

138

108

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Summary It is known that angiogenesis plays an important role in the growth and metastasis of solid tumours. Several angiogenic factors have been identified and platelet-derived endothelial cell growth factor (PD-ECGF) is thought to be one such factor. Recently, it was reported that thymidine phosphorylase (dThdPase) is identical to PD-ECGF. Using immunohistochemical staining with an anti-dThdPase antibody, we investigated the correlation between dThdPase expression and the microvessel density in 120 gastric carcinomas. The microvessel density, determined by immunostaining for factor VIII-related antigen, was significantly higher in dThdPase-positive tumours than in dThdPase-negative tumours. There was a significant correlation between dThdPase expression and the increment of microvessel density. Moreover, regarding distant organ metastasis, the frequency of hepatic metastasis was significantly higher (P<0.01) in patients with dThdPase-positive tumours than in those with dThdPase-negative tumours. In summary, it was suggested that dThdPase expression is closely associated with the promotion of angiogenesis and hepatic metastasis in gastric carcinoma.

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“…VEGF-A also induces tissue factor on endothelium and tumour cells, activating coagulation and fibrin formation (Mechtcheriakova et al, 1999). This is of primary importance for angiogenesis and tumour growth (Nagy et al, 1989;. High serum levels of VEGF-A are predictive for tumour doubling time in patients with colorectal cancer.…”

mentioning

confidence: 99%

Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer

et al. 2002

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The circulating angiogenic factors vascular endothelial growth factor-A, interleukin-6 and the fibrin D-dimer fragment were measured in the mesenteric vein, the uterine vein, as well as in peripheral venous and arterial samples in 21 randomly selected patients with operable colorectal, ovarian and cervical carcinoma. In addition, immunohistochemistry for vascular endothelial growth factor-A and interleukin-6 was performed on colorectal tumours of such patients. Serum and plasma vascular endothelial growth factor-A were not significantly elevated in the vein draining the tumours, despite tumour cell expression of vascular endothelial growth factor-A. Serum vascular endothelial growth factor-A is therefore not all tumour-derived. In contrast, serum interleukin-6 was highly elevated in the draining veins in agreement with expression of interleukin-6 in the cytoplasm of tumour cells. In the megakaryoblastic cell line MEG-01, the expression of vascular endothelial growth factor-A was found to be regulated by interleukin-6. Thus, the higher platelet vascular endothelial growth factor-A load resulting in higher serum vascular endothelial growth factor levels in cancer patients may partly result from an interleukin-6 mediated upregulation of the expression of vascular endothelial growth factor-A in the precursor of the platelet, i.e. the megakaryocyte. We also confirmed by immunohistochemistry that platelets adhere and aggregate on tumour endothelium. We propose that interleukin-6 indirectly promotes tumour angiogenesis through its up-regulation of the vascular endothelial growth factor-A load in platelets. In addition, the correlations found between peripheral venous interleukin-6 and peripheral venous fibrinogen and D-dimers levels, and the high D-dimer levels found in the draining vein of the tumour, in agreement with fibrin deposits found in the tumour stroma, suggest an important role for interleukin-6 in extra-vascular fibrinogen metabolism. Our results suggest a pivotal role for interleukin-6 in the intrinsic link between haemostasis and angiogenesis. This might be of importance in the development of anti-angiogenic agents based on interference with haemostasis.

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Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition

Cited by 225 publications

References 76 publications

Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors.

Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors.

Thymidine phosphorylase/platelet-derived endothelial cell growth factor expression associated with hepatic metastasis in gastric carcinoma

Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer

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