Lumen Formation and Other Angiogenic Activities of Cultured Capillary Endothelial Cells Are Inhibited by Thrombospondin-1

Tolsma, Sara Sybesma; Stack, M. Sharon; Bouck, Noël

doi:10.1006/mvre.1997.2015

Cited by 59 publications

(36 citation statements)

References 56 publications

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“…B, survival curves of patients with resected colorectal liver metastases categorized into tumors that express and do not expressTSP-1in the stroma. (19,20). It has been found to suppress capillary formation in vitro (20,21), possibly by inhibiting chemotaxis, proliferation (3,22), and the formation of focal adhesions in endothelial cells (23).…”

Section: Discussionmentioning

confidence: 99%

Expression of Thrombospondin-1 in Resected Colorectal Liver Metastases Predicts Poor Prognosis

Sutton¹,

O’Byrne²,

Goddard³

et al. 2005

Clinical Cancer Research

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Purpose: The aim of this study was to examine the expression and prognostic relevance of thrombospondin-1 (TSP-1) in tumor biopsies taken from a consecutive series of liver resections done at the University Hospitals of Leicester and the Royal Liverpool Hospital. Experimental Design: Patients having undergone a liver resection for colorectal liver metastases at our institutions between 1993 and 1999 inclusive were eligible. Inclusion criteria were curative intent, sufficient tumor biopsy, and patient follow-up data. One hundred eighty-two patients were considered in this study. Standard immunohistochemical techniques were used to study the expression of TSP-1 in 5-Am tumor sections from paraffin-embedded tissue blocks. TSP-1 was correlated with survival using the Kaplan-Meier method and log-rank test for univariate analysis and the Cox proportional hazard model for multivariate analysis. Results: One hundred eighty-two patients (male, n = 122 and female, n = 60) ages between 25 and 81 years (mean, 61 years) were included. TSP-1 was expressed around blood vessels (n = 45, 25%) or in the stroma (n = 59, 33%). No expression was detected in the remaining tumors. TSP-1 significantly correlated with poor survival on univariate (P = 0.01 for perivascular expression and P = 0.03 for stromal expression) and multivariate analysis (P = 0.01 for perivascular expression). Conclusion: TSP-1 is a negatively prognostic factor for survival in resected colorectal liver metastases.Thrombospondin-1 (TSP-1) is a multidomain glycoprotein that modulates platelet aggregation, wound healing, protease activity, and cellular functions such as adhesion, motility, and growth (1). However, the precise function of TSP-1 in the growth of tumors is not straightforward. Evidence suggests that different fragments of the large TSP-1 molecule may individually facilitate different and opposing tumor-modulating properties, such as proangiogenic and antiangiogenic activity (2) and promotion/inhibition of tumor cell migration (3).In colorectal cancer, TSP-1 has been shown to have both an antiangiogenic effect (4, 5) and conversely be associated with venous invasion and tumor progression (6). However, expression of TSP-1 has been associated with increased disease-free survival rates: 84% 5-year survival in primary colorectal tumors expressing TSP-1 compared with 55% in TSP-1-negative tumors in one study (4) and 91% survival versus 44% in TSP-1-negative tumors in another study (5). Studies in breast cancer have described reduced TSP-1 levels in association with more aggressive tumors (3). It is noteworthy that these figures pertain to studies carried out in primary tumors. The aim of this study was to examine the expression and prognostic relevance of TSP-1 in resected colorectal liver metastases.

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Section: Discussionmentioning

confidence: 99%

Expression of Thrombospondin-1 in Resected Colorectal Liver Metastases Predicts Poor Prognosis

Sutton¹,

O’Byrne²,

Goddard³

et al. 2005

Clinical Cancer Research

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“…In this respect, TSP2 differs from TSP1 in that TSP1 is more prominently expressed in endothelial cells during embryogenesis (Iruela-Arispe et al, 1993) and is synthesized in significant amounts by cultured ECs (McPherson et al, 1981;Mosher et al, 1982). Thus, unlike TSP2, TSP1 seems to be an autocrine inhibitor of EC function (Iruela-Arispe et al, 1991;DiPietro et al, 1994;Tolsma et al, 1997). Our findings that TSP2 and TSP1 have similar effects on proliferation and cell death in endothelial cells support the concept that the different distributions, rather than intrinsic biochemical properties, of TSP2 and TSP1 determine the differences in antiangiogenic functions of the proteins in vivo.…”

Section: Tsp2 Inhibits Ec Proliferationmentioning

confidence: 99%

Thrombospondin 2 Inhibits Microvascular Endothelial Cell Proliferation by a Caspase-independent Mechanism

Armstrong¹,

Björkblom²,

Hankenson³

et al. 2002

MBoC

103

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The matricellular protein thrombospondin 2 (TSP2) regulates a variety of cell-matrix interactions. A prominent feature of TSP2-null mice is increased microvascular density, particularly in connective tissues synthesized after injury. We investigated the cellular basis for the regulation of angiogenesis by TSP2 in cultures of murine and human fibroblasts and endothelial cells. Fibroblasts isolated from murine and human dermis synthesize TSP2 mRNA and secrete significant amounts of immunoreactive TSP2, whereas endothelial cells from mouse lung and human dermis did not synthesize TSP2 mRNA or protein. Recombinant mouse TSP2 inhibited growth of human microvascular endothelial cells (HMVECs) mediated by basic fibroblast growth factor, insulin-like growth factor-1, epidermal growth factor, and vascular endothelial growth factor (VEGF). HMVECs exposed to TSP2 in the presence of these growth factors had a decreased proportion of cells in S and G 2 /M phases. HMVECs cultured with a combination of basic fibroblast growth factor, insulin-like growth factor-1, and epidermal growth factor displayed an increased proportion of nonviable cells in the presence of TSP2, but the addition of VEGF blocked this TSP2-mediated impairment of cell viability. TSP2-mediated inhibition of DNA synthesis by HMVECs in the presence of VEGF was not affected by the broadspectrum caspase inhibitor zVAD-fmk. Similar findings were obtained with TSP1. Taken together, these observations indicate that either TSP2 or TSP1 can inhibit HMVEC proliferation by inhibition of cell cycle progression and induction of cell death, but the mechanisms responsible for TSP2-mediated inhibition of cell cycle progression are independent from those leading to cell death. INTRODUCTIONThe process of wound healing is highly dependent on angiogenesis to provide a vascular network for the regenerating tissue. The study of mechanisms governing vascularization of healing connective tissues has primarily focused on proangiogenic factors occurring early in the wound-healing process. Degranulating platelets and a fibrin clot provide growth and chemotactic factors and an adhesive substrate for initial influx of endothelial cells (ECs) (Singer and Clark, 1999;Tonnesen et al., 2000). Infiltrating inflammatory cells, such as macrophages, appear at the wound site shortly after the wounding event and are also potent sources of proangiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) (Sunderkö tter et al., 1994). A number of these factors also induce migration of fibroblasts into the wound area and stimulate fibroblasts to deposit extracellular matrix (Kalluri and Sukhatme, 2000). The direct influence of fibroblasts on ECs in determining the vascularity of the healing wound is less clear. Regression of blood vessels seen in the resolution phase of a wound, in which fibroblasts become the predominant cell type, suggests an inhibitory role for fibroblasts in the angiogenic process (Kyriakides et al., 1999b).A large number of factors...

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“…First discovered in platelets as a thrombin-sensitive protein (1), THBS1 was later shown to be a major component of platelet ␣-granules, comprising some 25% of the total protein (2). Once released, THBS1 exerts various functions on the vascular system under physiological and pathophysiological conditions causing platelet activation (3,4) and adhesion (5) in addition to endothelial cell adhesion (6), promotion of angiogenesis (7), and inhibition of angiogenesis (8), wound healing (9) as well as pathological states such as tumor progression and metastasis (10,11). THBS1 is important not only in cancer progression but also in inflammatory autoimmune diseases such as rheumatoid arthritis (12).…”

mentioning

confidence: 99%

Thrombin Modulates the Expression of a Set of Genes Including Thrombospondin-1 in Human Microvascular Endothelial Cells

McLaughlin¹,

Mazzoni

Cleator

et al. 2005

Journal of Biological Chemistry

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Lumen Formation and Other Angiogenic Activities of Cultured Capillary Endothelial Cells Are Inhibited by Thrombospondin-1

Cited by 59 publications

References 56 publications

Expression of Thrombospondin-1 in Resected Colorectal Liver Metastases Predicts Poor Prognosis

Expression of Thrombospondin-1 in Resected Colorectal Liver Metastases Predicts Poor Prognosis

Thrombospondin 2 Inhibits Microvascular Endothelial Cell Proliferation by a Caspase-independent Mechanism

Thrombin Modulates the Expression of a Set of Genes Including Thrombospondin-1 in Human Microvascular Endothelial Cells

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