Thrombospondin-1 and Transforming Growth Factor-β<sub>1</sub> Levels in Prolactinoma and their Clinical Significance

Prolactinomas are the most frequently observed pituitary adenomas and most of them respond well to conventional treatment with dopamine agonists. However, a subset of prolactinomas fails to respond to such therapies and is considered as dopamine agonist-resistant prolactinomas (DARPs). New therapeutic approaches are necessary for these tumors. TGFβ1 is a known inhibitor of lactotroph cell proliferation and prolactin secretion, and it partly mediates dopamine inhibitory action. TGFβ1 is secreted to the extracellular matrix as an inactive latent complex, and its bioavailability is tightly regulated by different components of the ‘TGFβ1 system including latent binding proteins (LTBPs), local activators (Thrombospondin-1, matrix metalloproteases, integrins, among others), and TGFβ receptors. Pituitary TGFβ1 activity and the expression of different components of the TGFβ1 system, are regulated by dopamine and estradiol. Prolactinomas (animal models and humans) present reduced TGFβ1 activity as well as reduced expression of several components of the TGFβ1 system. Therefore, restoration of TGFβ1 inhibitory activity represents a novel therapeutic approach to bypass dopamine action in DARPs. The aim of this review is to summarize the large literature supporting TGFβ1 important role as a local modulator of pituitary lactotroph function; as well to provide recent evidence of the restoration of TGFβ1 activity as an effective treatment in experimental prolactinomas.

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“…TSP-1 expression was also found down-regulated in invasive vs . non-invasive prolactinomas in humans (Jiang et al 2012). …”

Section: Alterations In the Components Of The Tgfβ1 System During Promentioning

confidence: 99%

The pituitary TGFβ1 system as a novel target for the treatment of resistant prolactinomas

Recouvreux¹,

Camilletti²,

Rifkin³

et al. 2015

Journal of Endocrinology

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“…Our data concerning MMP2 concentrations were controversial. These results were not unexpected, as fibrosis was limited only to the cardiac valvular apparatus and the percentage of subjects with advanced (53). Although the term 'aggressiveness' should not be used synonymously with 'invasiveness' concerning prolactinomas, almost all aggressive tumors are invasive.…”

Section: Discussionmentioning

confidence: 83%

Transforming growth factor β1 is not a reliable biomarker for valvular fibrosis but could be a potential serum marker for invasiveness of prolactinomas (pilot study)

Еленкова¹,

Atanassova²,

Кirilov³

et al. 2013

European Journal of Endocrinology

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Background: Transforming growth factor b1 (TGFb1) signaling pathway is crucial for both human fibrogenesis and tumorigenesis. Objective: This study aimed to investigate the usefulness of TGFb1 and matrix metalloproteinase 2 (MMP2) as potential circulating markers for fibrotic valvular heart disease (FVHD) and invasiveness as well as of Fetuin A as a marker for calcification in patients with prolactinomas. Design: The study population consisted of 147 subjects divided into four groups: 30 dopamine agonist (DA)-treated prolactinoma patients with proven FVHD and three control groups with normal echocardiograms: 43 DA-treated patients, 26 naïve patients, and 48 healthy subjects. Results: We observed significantly higher serum TGFb1 levels in all three patient groups than in the healthy subjects (21.4G8.86 vs 19.1G9.03 vs 20.7G11.5 vs 15.8G7.2 ng/ml; PZ0.032). Moreover, TGFb1 levels were significantly higher in patients with macroprolactinomas and invasive prolactinomas than in those with microprolactinomas and noninvasive tumors respectively. In addition, a strong positive linear relationship between TGFb1 levels and invasiveness score (rZ0.924; P!0.001) and a moderate correlation between TGFb1 levels and tumor volume (rZ0.546; P!0.002) were observed in patients with invasive prolactinomas. By contrast, prolactin (PRL) levels exhibited a better correlation with tumor volume (rZ0.721; P!0.001) than with invasiveness score (rZ0.436; P!0.020). No significant difference was observed in Fetuin A levels between patients with FVHD and healthy controls. Results concerning MMP2 were unclear. Conclusions: TGFb1, MMP2, and Fetuin A are not reliable biomarkers for valvular fibrosis and calcification in DA-treated patients with prolactinomas, but TGFb1 may represent a useful serum marker for tumor invasiveness. The simultaneous determination of TGFb1 and PRL levels could improve the noninvasive assessment of prolactinoma behavior.

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“…Previous studies have demonstrated that TSP-1 inhibits tumor angiogenesis and invasion in melanoma and breast, prostate, and pancreatic cancers (3–6,15–17). However, Elpek et al (18) observed that TSP-1 promotes angiogenesis during chronic liver injury and did not identify a correlation between TSP-1 expression and MVD in pituitary tumors (19). In the present study, it was demonstrated that TSP-1 is negatively correlated with the MVD in the gliomas, and TSP-1 immunoreactivity decreases with increasing tumor grade, suggesting that TSP-1 may inhibit tumor angiogenesis and progression in gliomas.…”

Section: Discussionmentioning

confidence: 99%

Correlation between TSP-1, TGF-β and PPAR-γ expression levels and glioma microvascular density

Zhang

Zhao

et al. 2013

Oncology Letters

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Gliomas are the most common type of primary tumor in the central nervous system and are characterized by abundant capillary angiogenesis. It is important to study the underlying molecular mechanisms of angiogenesis in order to aid the identification of potential therapeutic targets. The aim of the current study was to investigate the expression levels of thrombospondin-1 (TSP-1), transforming growth factor-β (TGF-β) and peroxisome proliferator-activated receptor-γ (PPAR-γ) in gliomas, and determine their relationships with angiogenesis. Immunohistochemical methods were used to detect TSP-1, TGF-β and PPAR-γ expression levels and to assess microvascular density (MVD) in 99 glioma tissue samples of various grades. The total positive expression rates of TSP-1 and PPAR-γ were 78.4 and 94.1% in low-grade gliomas and 45.8 and 39.6% in high-grade gliomas. These values suggest that their expression negatively correlated with tumor grade. However, TGF-β expression positively correlated with tumor grade; the total positive expression rate of TGF-β in high-grade gliomas (93.8%) was significantly increased compared with that in low-grade gliomas (43.1%). The MVD in the low-grade group was 28±7.2 vessels/field, which was significantly lower than in the high-grade group (45±6.2 vessels/field). TSP-1 and PPAR-γ expression levels were negatively correlated with MVD (P<0.05), while the TGF-β expression level was positively correlated with MVD (P<0.05). These results indicate that the TSP-1, TGF-β and PPAR-γ expression levels in gliomas are correlated with MVD, which suggests that these proteins may be involved in the regulation of glioma angiogenesis.

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Thrombospondin-1 and Transforming Growth Factor-β₁ Levels in Prolactinoma and their Clinical Significance

Cited by 7 publications

References 41 publications

The pituitary TGFβ1 system as a novel target for the treatment of resistant prolactinomas

The pituitary TGFβ1 system as a novel target for the treatment of resistant prolactinomas

Transforming growth factor β1 is not a reliable biomarker for valvular fibrosis but could be a potential serum marker for invasiveness of prolactinomas (pilot study)

Correlation between TSP-1, TGF-β and PPAR-γ expression levels and glioma microvascular density

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Thrombospondin-1 and Transforming Growth Factor-β1 Levels in Prolactinoma and their Clinical Significance

Cited by 7 publications

References 41 publications

The pituitary TGFβ1 system as a novel target for the treatment of resistant prolactinomas

The pituitary TGFβ1 system as a novel target for the treatment of resistant prolactinomas

Transforming growth factor β1 is not a reliable biomarker for valvular fibrosis but could be a potential serum marker for invasiveness of prolactinomas (pilot study)

Correlation between TSP-1, TGF-β and PPAR-γ expression levels and glioma microvascular density

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Thrombospondin-1 and Transforming Growth Factor-β₁ Levels in Prolactinoma and their Clinical Significance