Plasma thrombospondin levels in patients with colorectal carcinoma

Yamashita, Yuichi; Kurohiji, Toshihiko; Tuszynski, George P.; Sakai, Toshimi; Shirakusa, Takayuki

doi:10.1002/(sici)1097-0142(19980215)82:4<632::aid-cncr3>3.0.co;2-n

Cited by 46 publications

(41 citation statements)

References 30 publications

(2 reference statements)

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“…Circulating plasma TSP1 levels were 0.3-15 nM in tumor-bearing animals (45), and mean values of 0.6-2.3 nM were reported in patients with colon carcinomas (46). These are clearly adequate concentrations to completely inhibit NO-stimulated endothelial responses.…”

Section: Discussionmentioning

confidence: 82%

Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner

Isenberg

Ridnour

Perruccio

et al. 2005

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

242

261

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Redox signaling plays an important role in the positive regulation of angiogenesis by vascular endothelial growth factor, but its role in signal transduction by angiogenesis inhibitors is less clear. Using muscle explants in 3D culture, we found that explants from mice lacking the angiogenesis inhibitor thrombospondin-1 (TSP1) exhibit exaggerated angiogenic responses to an exogenous NO donor, which could be reversed by providing exogenous TSP1. To define the basis for inhibition by TSP1, we examined the effects of TSP1 on several proangiogenic responses of endothelial cells to NO. NO has a biphasic effect on endothelial cell proliferation. The positive effect at low doses of NO is sensitive to inhibition of cGMP signaling and picomolar concentrations of TSP1. NO stimulates both directed (chemotactic) and random (chemokinetic) motility of endothelial cells in a cGMP-dependent manner. TSP1 potently inhibits chemotaxis stimulated by NO. Low doses of NO also stimulate adhesion of endothelial cells on type I collagen in a cGMP-dependent manner. TSP1 potently inhibits this response both upstream and downstream of cGMP. NO-stimulated endothelial cell responses are inhibited by recombinant type 1 repeats of TSP1 and a CD36 agonist antibody but not by the N-terminal portion of TSP1, suggesting that CD36 or a related receptor mediates these effects. These results demonstrate a potent antagonism between TSP1 and proangiogenic signaling downstream of NO. Further elucidation of this inhibitory signaling pathway may identify new molecular targets to regulate pathological angiogenesis.angiogenesis ͉ cell adhesion ͉ chemotaxis ͉ proliferation ͉ CD36 R edox signaling plays a central role in both developmental and pathological angiogenesis (1). Low to moderate concentrations of NO act on endothelial cells to stimulate angiogenesis by activating soluble guanylyl cyclase (sGC), thereby increasing cGMP, which activates cGMP-dependent protein kinases (2) and other cGMP-dependent pathways (3, 4). These responses lead to downstream activation of the Ras-Raf-extracellular-regulated kinase (ERK) (5), vasodilator-stimulated phosphoprotein (6), and phosphatidylinositol 3-kinase-Akt pathways (7). At specific doses, NO donors induce endothelial cell chemotaxis (7,8), permeability (9), and proliferation in vitro (10, 11) and angiogenesis in vivo (12).Consistent with these observations, endogenous NO synthesis in endothelial cells is induced by some angiogenic factors, including vascular endothelial growth factor (VEGF) (13). VEGF receptor signaling activates Akt in a phosphatidylinositol 3-kinase-and PKC-dependent manner, which phosphorylates endothelial NO synthase (eNOS) on Ser-1177 (14, 15). This modification increases eNOS activity and NO synthesis. eNOS activation plays a crucial role in VEGF-induced angiogenesis and vascular permeability (16,17). Conversely, NO induces VEGF transcription by inducing synthesis and stabilization of . These data suggest a positive feedback loop between NO and VEGF signaling. However, inhibitory effects of ...

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Section: Discussionmentioning

confidence: 82%

Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner

Isenberg

Ridnour

Perruccio

et al. 2005

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

242

261

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“…Venous invasion has been argued as resulting in increased thrombospondin levels, most likely from platelet activations or from the endothelium; however, the authors argue that another source must exist to account for the increase levels in patients with no venous invasion. They further argue that high plasma TSP-1 levels may promote metastatic disease as high TSP-1 has stimulated cell invasion in experimental models and indirectly, because patients with venous invasion have been shown to be at greater risk of developing hepatic metastases (6). Therefore, TSP-1 has been proposed as a marker of possible hepatic dissemination and may support the perivascular and stromal localization of TSP-1 in our series of liver metastases which contrasts the expression of TSP-1 in the primary tumor.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

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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“…The protocol that we followed quite closely mimics the conditions likely to occur in naturally-arising human tumors that develop despite their continuous production in the tumor bed of high levels of inhibitors of angiogenesis (Chen et al 1995;Ohtani et al 1999;Volpert et al 1998;Yamashita et al 1998). Thus our results strongly support the idea that antiangiogenic agents will ultimately be most effective when used in conjunction with cytotoxic therapies, not only because of their demonstrated synergistic action in killing endothelial cells (Kerbel et al 2000), but also because they directly reduce tumor burden and thus lessen the possibility that resistant tumor cells will emerge.…”

Section: Discussionmentioning

confidence: 99%

“…In humans, anti-angiogenic properties of TSP1 have been reported in bladder cancer (Campbell et al 1998), melanoma , and gastro-intestinal tumors (Morelli et al 1998). Conversely, in colorectal cancer, high TSP1 level in plasma is associated with increased angiogenesis (Yamashita et al 1998) and with lymph node metastasis in gallbladder cancers (Ohtani et al 1999). In breast cancer, both pro-and antiangiogenic correlations to TSP-1 are reported (Bertin et al 1997;Clézardin et al 1993;Morelli et al 1998;Zabrenetzky et al 1994).…”

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confidence: 99%

In vivo mechanisms by which tumors producing thrombospondin 1 bypass its inhibitory effects

Filleur¹,

Volpert²,

Degeorges³

et al. 2001

Genes Dev.

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Thrombospondin 1 (TSP1) is a multifunctional protein able to activate TGF␤ and to inhibit angiogenesis in vivo. Although usually thought of as an inhibitor of tumor growth, TSP1 may sometimes be present at high levels during tumor progression, suggesting that tumors can eventually overcome their anti-tumor effects. Using a tet-repressible expression system, we demonstrate that murine TSP1 delayed the onset of tumor growth when produced in the tumor bed by rat fibrosarcoma tumor cells or by stromal fibroblasts coinjected with unmodified C6 glioma tumor cells. Yet upon prolonged exposure to TSP1, tumors came to grow at the same rate in the presence as in the absence of TSP1 and transplantation experiments showed that they had become insensitive to inhibition by TSP1 in both syngeneic and immune compromised hosts. Tumor resistance to TSP1 developed as a result of the in vivo outgrowth of pre-existing tumor cell variants that (1) secreted increased amounts of angiogenic factors that counterbalanced the inhibitory effect of TSP1 on neovascularization and (2) grew more efficiently in the presence of TSP1-activated TGF␤. These results indicate that prolonged and continuous local delivery of a single multifunctional angiogenesis inhibitor like TSP1 to fast-growing tumors can lead to tumor resistance in vivo by fostering the outgrowth of subpopulations that are a by-product of the genetic instability of the tumor cells themselves.

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Plasma thrombospondin levels in patients with colorectal carcinoma

Abstract: Venous invasion by colorectal carcinoma was found to play an important role in the elevation of the plasma thrombospondin level. Alternatively, a high concentration of thrombospondin may support metastasis and progression of this malignancy.

Cited by 46 publications

References 30 publications

Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner

Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner

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

In vivo mechanisms by which tumors producing thrombospondin 1 bypass its inhibitory effects

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