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

Abstract

Prolactinomas are the most frequently observed pituitary adenomas and most of them respond well to conventional treatment with dopamine agonists (DAs). However, a subset of prolactinomas fails to respond to such therapies and is considered as DA-resistant prolactinomas (DARPs). New therapeutic approaches are necessary for these tumors. Transforming growth factor β1 (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, 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 and to provide recent evidence of the restoration of TGFβ1 activity as an effective treatment in experimental prolactinomas.

Keywords: TGFβ1; dopamine; estradiol; resistant prolactinomas.

Figure 1. The biology of TGFβ system

TGFβ is synthesized as homodimeric precursor containing a pro-peptide sequence LAP, (1), and then processed by furin. LAP remains associated with the mature TGFβ by non-covalent interactions in a small latent complex (2), which in turn is linked by disulfide bonds to one of the latent TGFβ binding proteins (LTBP1–4) (3). TGFβ is secreted as part of this large latent TGFβ complex (LLC) (3), and it is incorporated as component of the extracellular matrix (ECM), which acts as a reservoir of the cytokine (4). TGFβ must undergo a highly regulated activation process by which mature cytokine is released (5) to enable binding to its receptor complex (TβRI and TβRII) (6) and signal through Smad2/Smad3 pathway (7). Known TGFβ activators are listed in the upper left.

Figure 2. Alterations of TGFβ1 system in prolactinomas

Decreased expression of different components of pituitary TGFβ1 system in prolactinoma models are represented with down-pointed arrows. Gray arrows indicate findings in human prolactinoma specimens; black arrows indicate findings in Drd2^−/− mice; white arrows indicate findings in estradiol induced prolactinomas in rats.

Figure 3. Recovery of TGFβ1 activity emerges as a novel therapeutic target for treatment of dopamine agonist resistant prolactinomas

Treatment with Thrombospondin-1 analogs (ABT-510, ABT-898) recover pituitary TGFβ1 activity, reduce tumor size, tumor angiogenesis and proliferation markers, as well as serum