Thrombospondin-1 and transforming growth factor-betal promote breast tumor cell invasion through up-regulation of the plasminogen/plasmin system

Albo, Daniel; Berger, David H.; Wang, Thomas N; Hu, Xiaolong; Rothman, Vicki L.; Tuszynski, George P.

doi:10.1016/s0039-6060(97)90043-x

Cited by 62 publications

(60 citation statements)

References 18 publications

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“…Tuszynski and colleagues have shown that TSP-1's ability to increase the formation of plasmin and to serve as an adhesive protein can create an environment that promotes cell invasion in vitro [24-26, 30,63,64]. Interestingly, the regulation of plasmin activity was reportedly mediated by TGF-β in breast cancer cells [25,30]. Thus, the activation of TGF-β by TSP-1 that we have observed in the tumor microenvironment may promote tumor cell migration, invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…These residues fall in the region that has the highest degree of homology between the members of the thrombospondin gene family [23]. However, in vitro studies suggest that TSP-1 promotes MDA-MB-435 and MDA-MB-231 cell migration and invasion [24,25]. Over-expression of TSP-1 results in an approximately 50% increase in cellassociated plasmin.…”

Section: Introductionmentioning

confidence: 99%

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The effect of thrombospondin-1 on breast cancer metastasis

Yee

Connolly

Duquette

et al. 2008

Breast Cancer Res Treat

112

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Thrombospondin-1 (TSP-1) has been proposed to have both pro-metastatic and anti-metastatic properties. To elucidate its role in breast cancer metastasis, we compared tumor progression in the polyomavirus middle T antigen (Pyt) transgenic mouse and the TSP-1-null Pyt transgenic mouse. We characterized the tumors in these mice at 45, 60 and 90 days of age. Tumor size, areas of necrosis, macrophage infiltration, levels of active and total TGF-β, vessel morphology, and lung and blood metastasis were measured in these mice. Mammary tumors were larger in the TSP-1-null mouse, and vessels were larger, but fewer in number in these tumors. The level of total TGF-β was significantly higher in the Pyt tumors at 90 days of age. Importantly, significantly fewer metastases were observed in the lungs of the TSP-1-null/Pyt mouse. Primary Pyt tumor cells were more migratory than TSP-1-null Pyt tumor cells on collagen. Treatment of Pyt mice with recombinant proteins that contain the type-1 repeats of TSP-1 resulted in decreased primary tumor growth and metastasis. Sequences that are involved in CD36 binding and those required for TGF-β activation mediated the inhibition of primary tumor growth. Thus, TSP-1 in the mammary tumor microenvironment inhibits angiogenesis and tumor growth, but promotes metastasis to the lung in the Pyt transgenic mouse. The ability of TSP-1 to support metastasis correlates with its ability to promote tumor cell migration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The effect of thrombospondin-1 on breast cancer metastasis

Yee

Connolly

Duquette

et al. 2008

Breast Cancer Res Treat

112

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“…TGFb is known to modulate cell adhesion and motility in a variety of cell types (Albo et al, 1997;Cai et al, 2000;Loganadane et al, 1999;Merzak et al, 1994;Teti et al, 1997), including prostate (Festuccia et al, 1999). Finally, endoglin contains the tripeptide motif, arg-glyasp (RGD) in its extracellular domain (Altomonte et al, 1996;Gougos and Letarte, 1990).…”

Section: Introductionmentioning

confidence: 99%

Over expression of endoglin in human prostate cancer suppresses cell detachment, migration and invasion

et al. 2002

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The regulation of cell adhesion and motility in human prostate is not well understood. We have previously shown that the endoglin gene is differently expressed during changes in prostate cell adhesion. Endoglin is a transmembrane transforming growth factor b binding protein typically expressed by endothelial cells. In this report we demonstrate that endoglin over expression increases prostate cell attachment, while decreasing migration and invasion. Engineered decreases in endoglin expression have opposite effects. While endoglin exerted only relatively small effects upon cell adhesion, large effects upon cell migration and invasion were observed. Endoglin was shown to localize to focal adhesion plaques, consistent with its role in regulating cell adhesion and motility. Loss of endoglin expression in cancer, as compared to normal prostate, was seen in human prostate cell lines. Suppression of endoglin expression in a panel of normal human prostate cell lines led to cell detachment. Endoglin is identified as a regulator of cell adhesion, motility and invasion in human prostate. Loss of endoglin expression appears to be associated with prostate cancer progression, at least in vitro.

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“…A growing body of evidence has recently implicated that members of TGF-␤ family are potent regulators of multiple cellular functions, including cell proliferation, differentiation, migration, organization, and death (4,12,13). TGF-␤1 is produced by host cells and/or tumor cells in a latent form and is activated by proteases in a cell-dependent manner.…”

mentioning

confidence: 99%

“…TGF-␤1 is produced by host cells and/or tumor cells in a latent form and is activated by proteases in a cell-dependent manner. TGF-␤1 produced by tumor cells including prostate cancer (4) and breast cancer (12)(13)(14) is a candidate responsible for the induction of PA system expression. Thus, TGF-␤1 had a positive effect on cell proliferation and increased uPA or uPAR expression (15).…”

mentioning

confidence: 99%

A Kunitz-type Protease Inhibitor, Bikunin, Inhibits Ovarian Cancer Cell Invasion by Blocking the Calcium-dependent Transforming Growth Factor-β1 Signaling Cascade

Kobayashi

Suzuki

Tanaka

et al. 2003

Journal of Biological Chemistry

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Bikunin is a Kunitz-type protease inhibitor, acting at the level of tumor invasion and metastasis. The goal of this study was to investigate the effect of bikunin-dependent signal transduction involved in the expression of a plasminogen activator (PA) system and invasion. We report here the following. 1) The human ovarian cancer cell line HRA produced secreted and cell-associated urokinase-type PA (uPA) and PA inhibitor type 1 (PAI-1). The plasma membrane of the cells showed enzymatically active uPA even in the presence of high level of PAI-1, as measured by zymography, Western blot, chromogenic assay, enzyme-linked immunosorbent assay, and Northern blot. Tumor cell invasion is dependent on finely regulated extracellular proteolytic activity, which allows tumor cells to invade the extracellular matrix (1). Among the proteolytic enzymes involved in this process are PAs, 1 whose expression in cultured cells is regulated by several types of growth factors and cytokines (2). Invasive tumor cells not only express cell-associated proteases but also secrete anti-proteases, preventing the overdigestion of the extracellular matrix, which leads to a loss of cell attachment. The balance between proteolytic activity and inhibition is crucial in the invasive and metastatic event (3). Indeed, the increment of a specific PA inhibitor, PAI-1, could have an important regulatory role on the extracellular proteolysis and might explain the decrease of net PA and gelatinolytic activities measured in the medium (3, 4). Even in the high levels of PAI-1 in the medium, however, several growth factors, including TGF-␤1, induced the increase of net PA and gelatinolytic activities on the plasma membrane, which results in strong proteolytic activity in some specific sites, such as areas of cell-to-cell or cell-to-extracellular matrix contacts. For this reason, drugs that manipulate or suppress signal transduction on the PA system in malignant cells offer a potentially new approach to anti-cancer therapy. One prototype signal transduction therapy agent is bikunin, which is a Kunitz-type protease inhibitor with tumor-suppressive potential in several malignant cell types, acting at the level of tumor invasion and metastasis (5-7). It was subsequently demonstrated that bikunin inhibits tumor invasion, at least in part, by a direct inhibition of plasmin activity as well as by inhibiting uPA (5, 6) and uPAR (7) expression at the gene and protein levels. Interestingly, in cell-free solutions, bikunin does not inhibit uPA activity effectively. Mechanistic studies in several cell types demonstrated that bikunin interferes with an upstream target(s) of selected MAP kinase signaling processes such as phosphorylation of MEK and ERK, leading to overexpression of uPA (6). A recent study in our laboratory demonstrated that bikunin could interfere with selected calcium-sensitive signaling processes such as agonist-induced cytokine expression in several types of cells, including human umbilical vein endothelial cells, uterine myometrial cells, vascular endo...

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Thrombospondin-1 and transforming growth factor-betal promote breast tumor cell invasion through up-regulation of the plasminogen/plasmin system

Cited by 62 publications

References 18 publications

The effect of thrombospondin-1 on breast cancer metastasis

The effect of thrombospondin-1 on breast cancer metastasis

Over expression of endoglin in human prostate cancer suppresses cell detachment, migration and invasion

A Kunitz-type Protease Inhibitor, Bikunin, Inhibits Ovarian Cancer Cell Invasion by Blocking the Calcium-dependent Transforming Growth Factor-β1 Signaling Cascade

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