Recombinant soluble betaglycan is a potent and isoform-selective transforming growth factor-β neutralizing agent

Vilchis-Landeros, M. Magdalena; Montiel, José Luis; Mendoza, Valentín; Mendoza‐Hernández, Guillermo; López‐Casillas, Fernando

doi:10.1042/bj3550215

Cited by 60 publications

(72 citation statements)

References 41 publications

(62 reference statements)

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“…This cell line produces active TGFb 1 and TGFb 2 , and is resistant to TGFb's growth inhibitory activity (Chen et al, , 2001). The sRIII has been shown to act as a TGFb antagonist (Lopez-Casillas et al, 1994;Vilchis-Landeros et al, 2001). Consequently, the expression of a sRIII in the MDA-MB-231 cells resulted in the sequestration of the active TGFbs and antagonization of their biological activity (Bandyopadhyay et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Autocrine TGFβ supports growth and survival of human breast cancer MDA-MB-231 cells

Lei

Bandyopadhyay

et al. 2002

Oncogene

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Using a cell model system established by ectopic expression of a soluble TGFb type III receptor (sRIII) containing the whole extracellular domain of the type III receptor in human breast cancer MDA-MB-231 cells, we observed that the expression of sRIII antagonized TGFb activity and inhibited both anchorage-dependent and anchorage-independent cell growth. Further studies revealed that sRIII expression induced apoptosis both in vitro and in vivo. Treatment with TGFb neutralizing antibodies or a recombinant human sRIII also induced apoptosis in the MDA-MB-231 parental cells, suggesting that the increased apoptosis after sRIII expression was specifically due to antagonization of autocrine TGFb signaling. Western blotting showed that sRIII clones had a higher PTEN expression level than the control cells did. Treatment with TGFb 1 decreased PTEN and inhibited apoptosis in sRIII cells to a level similar to that in the control cells. sRIII clones also showed a lower level of phosphorylated-Akt than the control cells, consistent with the inhibitory activity of PTEN on Akt activation. Treatment with LY294002, a specific inhibitor of Akt activator, phosphatidylinositol 3-kinase, also induced apoptosis in a dose dependent manner in the control cells. Our results suggest that autocrine TGFb signaling is necessary for the growth and survival of MDA-MB-231 cells.

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Section: Discussionmentioning

confidence: 99%

Autocrine TGFβ supports growth and survival of human breast cancer MDA-MB-231 cells

Lei

Bandyopadhyay

et al. 2002

Oncogene

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“…Baculoviral recombinant soluble betaglycan was purified as described before (22). Amounts of soluble betaglycan sBG-90 were determined by Western blot.…”

Section: Methodsmentioning

confidence: 99%

“…As a reference for comparison, we also tested the baculoviral recombinant soluble betaglycan (Fig. 8B), which binds TGF-␤ similar to the wild type membrane receptor (22). Binding of 125 I-TGF-␤2 to sBG-90 (Fig.…”

Section: Overexpression Of Mt1-or Mt3-mmps Augments the Shedding Of Smentioning

confidence: 99%

“…In contrast to membrane betaglycan, soluble betaglycan inhibits TGF-␤ binding to cell surface receptors in vitro (21,22). Thus, betaglycan could be a dual modulator of TGF-␤ activities: as a membrane protein it is an enhancer of TGF-␤ actions, and as a soluble protein it is an inhibitor (21,22). This latter property has been exploited therapeutically to block TGF-␤ actions in a carcinogenesis animal model using a recombinant soluble betaglycan (23).…”

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The Shedding of Betaglycan Is Regulated by Pervanadate and Mediated by Membrane Type Matrix Metalloprotease-1

Velasco-Loyden

Arribas

López‐Casillas

2004

Journal of Biological Chemistry

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126

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Betaglycan is a membrane-anchored proteoglycan that binds transforming growth factor-␤ (TGF-␤) via its core protein. A soluble form of betaglycan can be released by proteolytic cleavage (also known as shedding) of the membrane-bound form, yielding soluble betaglycan. The mechanism leading to the generation of soluble betaglycan is poorly understood. Because the membrane and soluble forms of betaglycan have opposite effects regulating the availability of TGF-␤, it is important to characterize the shedding of betaglycan further. Here we present evidence showing that in certain cell types, pervanadate, a general tyrosine phosphatase inhibitor, induces the release of the previously described fragment that encompasses almost the entire extracellular domain of betaglycan (sBG-120). In addition, treatment with pervanadate unveils the existence of a novel 90-kDa fragment (sBG-90). Noticeably, the cleavage that generates sBG-90 is mediated by a tissue inhibitor of metalloprotease-2-sensitive protease. Overexpression of all membrane type matrix metalloproteases (MT-MMPs) described to date indicates that MT1-MMP and MT3-MMP are endowed with ability to generate sBG-90. Furthermore, the patterns of expression of different MTMMPs in the cell lines used in this study suggest that MT1-MMP is the protease involved in the shedding of sBG-90. Overexpression of MT1-MMP in COS-1 cells, which do not express detectable levels of this metalloprotease, confirms the feasibility of this hypothesis. Unexpectedly, during the course of these experiments, we observed that MT2-MMP decreases the levels of MT1-MMP and betaglycan. Finally, binding competition experiments indicate that, similar to the wild type membrane betaglycan, sBG-90 binds the TGF-␤2 isoform with greater affinity than TGF-␤1, suggesting that once released, it could affect the cellular availability of TGF-␤.

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“…It is a membrane bound proteoglycan that is expressed in most cell types and tissues, and has been shown to generate, upon ectodomain shedding, a soluble form of the receptor (Andres et al, 1989;Lopez-Casillas et al, 1991). While the membrane receptor enhances the TGFb e ects, the soluble form is a potent TGFb neutralizing agent (Esparza-Lopez et al, 2001;Vilchis-Landeros et al, 2001). In our previous studies, we have shown that expression of the extracellular domain of RIII in its soluble form (sRIII) in human breast cancer MDA-MB-231 cells can sequester endogenous TGFb isoforms and antagonize their activity.…”

Section: Introductionmentioning

confidence: 99%

Extracellular domain of TGFβ type III receptor inhibits angiogenesis and tumor growth in human cancer cells

et al. 2002

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TGFb overexpression in human cancer cells has been shown to promote tumor progression. In the present study, we sought to determine whether sequestration of endogenous TGFb by the expression of a soluble TGFb type III receptor (sRIII), can reduce malignancy in human carcinoma cells and whether the tumor-suppressive activity of sRIII is associated with the inhibition of angiogenesis. Ectopic expression of sRIII signi®cantly inhibited the growth of tumors formed by human colon carcinoma HCT116 and breast carcinoma MDA-MB-435 cells in nude mice. It also reduced the metastatic potential of the MDA-MB-435 cells. Thus, endogenous TGFb appears to be necessary for the progression of these two carcinomas. Furthermore, when the tumor cells were mixed with Matrigel and embedded subcutaneously in nude mice, the blood volume in Matrigel plugs containing sRIII-expressing cells as indicated by hemoglobin levels was signi®cantly lower than that in Matrigel plugs containing the respective control cells. Blood vessel counts in para n sections of the Matrigel plugs containing sRIII-expressing cells were also signi®cantly lower than those in para n sections of the Matrigel plugs containing control cells. Treatment of human endothelial cells with a recombinant sRIII signi®cantly inhibited their ability to form a capillary web structure on Matrigel. These results for the ®rst time indicate that the sRIII-induced tumor suppression appears to be in part due to the inhibition of angiogenesis.

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Recombinant soluble betaglycan is a potent and isoform-selective transforming growth factor-β neutralizing agent

Cited by 60 publications

References 41 publications

Autocrine TGFβ supports growth and survival of human breast cancer MDA-MB-231 cells

Autocrine TGFβ supports growth and survival of human breast cancer MDA-MB-231 cells

The Shedding of Betaglycan Is Regulated by Pervanadate and Mediated by Membrane Type Matrix Metalloprotease-1

Extracellular domain of TGFβ type III receptor inhibits angiogenesis and tumor growth in human cancer cells

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