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The Pituitary Tgfβ1 System As a Novel Target for the Treatment of Resistant M V RECOUVREUX and others TGFb1 and resistant 228:3 R73–R83 Review prolactinomas The pituitary TGFb1 system as a novel target for the treatment of resistant prolactinomas M Victoria Recouvreux1,2, M Andrea Camilletti1, Daniel B Rifkin3 and Graciela Dı´az-Torga1 Correspondence 1Instituto de Biologı´a y Medicina Experimental, Consejo Nacional de Investigaciones Cientı´ficas y Te´ cnicas, should be addressed Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina to G Dı´az-Torga 2Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California 90048, USA Email 3Department of Cell Biology, New York University Medical Center, 550 First Avenue, New York, New York 10016, USA [email protected] Abstract Prolactinomas are the most frequently observed pituitary adenomas and most of them Key Words respond well to conventional treatment with dopamine agonists (DAs). However, a subset " resistant prolactinomas of prolactinomas fails to respond to such therapies and is considered as DA-resistant " dopamine prolactinomas (DARPs). New therapeutic approaches are necessary for these tumors. " estradiol Transforming growth factor b1 (TGFb1) is a known inhibitor of lactotroph cell proliferation " TGFb1 and prolactin secretion, and it partly mediates dopamine inhibitory action. TGFb1 is secreted to the extracellular matrix as an inactive latent complex, and its bioavailability is tightly regulated by different components of the TGFb1 system including latent binding proteins, Journal of Endocrinology local activators (thrombospondin-1, matrix metalloproteases, integrins, among others), and TGFb receptors. Pituitary TGFb1 activity and the expression of different components of the TGFb1 system are regulated by dopamine and estradiol. Prolactinomas (animal models and humans) present reduced TGFb1 activity as well as reduced expression of several components of the TGFb1 system. Therefore, restoration of TGFb1 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 TGFb1 important role as a local modulator of pituitary lactotroph function and to provide recent evidence of the restoration of TGFb1 activity as an effective treatment in experimental prolactinomas. Journal of Endocrinology (2016) 228, R73–R83 Pituitary tumors Despite their benign features, pituitary tumors can Pituitary tumors are commonly benign, slow growing cause considerably morbidity due to both hypersecretion adenomas, and account for 10–15% of all intracranial of pituitary trophic hormones and excessive tumor growth neoplasms (Farrell 2006, Melmed 2015). The prevalence of that can affect surrounding tissue. Common symptoms of these tumors is relatively high in the general population, a pituitary tumor compressive ‘mass effect’ include visual with w77 cases per 100 000 (Daly et al. 2009, Fernandez impairment, headaches, neurological disorders, and hypo- et al. 2010), and studies of autopsy specimens identified up pituitarism caused by disruption of the hypothalamic– to a 20% prevalence of clinically occult pituitary adeno- pituitary axis (Arafah & Nasrallah 2001, Melmed 2011). mas (Ezzat et al. 2004). Based on their size, pituitary adenomas are classified as http://joe.endocrinology-journals.org Ñ 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-15-0451 Printed in Great Britain Downloaded from Bioscientifica.com at 10/01/2021 02:33:00AM via free access Review M V RECOUVREUX and others TGFb1 and resistant 228:3 R74 prolactinomas microadenomas (!10 mm), macroadenomas (O10 mm), Prolactinoma treatment or giant adenomas (O40 mm). The major goals of treatment in patients with prolactino- Pituitary tumors usually present with monoclonal mas are to normalize serum PRL levels, to restore gonadal growth and can also be classified according to their cell- function, to reduce tumor size, and to preserve or improve type origin and hormone secretion. Thus, somatotropino- residual pituitary function. Prolactin secretion in the mas secrete growth hormone, prolactinomas secrete normal pituitary is tonically inhibited by hypothalamic prolactin (PRL), thyrotropinomas secrete thyroid-stimu- dopamine through dopamine D2 receptors (Drd2) lating hormone, and corticotropinomas secrete adreno- expressed on lactotroph cell membranes (Ben Jonathan corticotropin hormone. In contrast, the non-functioning & Hnasko 2001). The majority of prolactinomas retain pituitary adenomas (NFPAs) do not produce any hormone an intact response to dopamine inhibition; therefore, and usually derive from gonadotropes (Kovacs et al. 2001, medical treatment with dopamine agonists (DAs), such as Syro et al. 2015). cabergoline and bromocriptine, represents the first-line therapy for this tumors, including microprolactinomas, Prolactinomas macroprolactinomas, and giant prolactinomas (Wong et al. 2015b). DAs are highly effective in achieving Among functioning pituitary tumors, prolactinomas therapeutic aims with a favorable benefit/risk balance are the most frequently observed in the clinic (40%) compared with surgical treatment. (Ciccarelli et al. 2005). Excessive PRL secretion by these tumors leads to hyperprolactinemia, which primarily affects gonadal/reproductive function, causing hypogo- DA-resistant prolactinomas nadism, galactorrhea, decreased libido, and infertility both in men and women. Large macroprolactinomas can Despite the universal use of DAs and their high efficiency also cause neurological symptoms due to compression of in reducing PRL levels and decreasing tumor size, there is adjacent tissues. a subset of prolactinomas (10–15%) that do not respond Prolactinomas are usually benign, and although some appropriately to the treatment, even at high doses of DA tumors show invasion into the parasellar compartment (Vroonen et al. 2012). These tumors represent a major and/or sphenoid sinuses, malignant transformation and challenge for clinical management. DA-resistant prolacti- metastatic spread are extremely rare. Macroprolactinomas nomas (DARPs) are more prevalent in men than woman, Journal of Endocrinology tend to be more aggressive and resistant to therapies than occur most frequently as macroprolactinomas, and tend to microprolactinomas (Wong et al. 2015a). be invasive, exhibiting extension to the cavernous sinuses. Differences in prolactinoma incidence, tumor size, The molecular mechanisms underlying the escape and behavior have been described among genders. The from dopaminergic regulation in DARPs are not fully prevalence of prolactinomas is higher in women during elucidated. The main candidate thought to be responsible the fertile period (20–50 years), while the frequency is for resistance is the Drd2 itself. However, to date, no point similar between sexes after the fifth decade of life (Colao mutation in the Drd2 gene has been identified in DARPs et al. 2003, Gillam et al. 2006). Also, women usually (Friedman et al. 1994, Molitch 2003, 2014, Gillam et al. present with microprolactinomas whereas men more 2006, Vroonen et al. 2012). Nevertheless, several often present with macroprolactinomas (Delgrange et al. mechanisms that lead to reduced Drd2 sensitivity were 1997, Nishioka et al. 2003). These differences have been described in resistant prolactinomas, including evidence associated to the earlier diagnosis in woman due to the of decreased Drd2 mRNA expression, and differential readily detection of symptoms caused by high prolactin expression of short and long Drd2 isoforms (Caccavelli (amenorrea/galactorrea) (Delgrange et al. 1997, Colao et al. et al. 1994, Vasilev et al. 2011, Shimazu et al. 2012) reduced 2003, Nishioka et al. 2003, Gillam et al. 2006). However, Drd2 density and dopamine binding sites in plasma delayed diagnosis in men may not be the only explanation membranes of DARP cells (Pellegrini et al. 1989). Altera- for the differences in tumor size, since young men also tions in dopamine signaling, such as decreased expression present with macroprolactinomas, and prolactinomas in of the inhibitory alpha G protein subunit (Gai2), have also men tend to be more aggressive, with higher proliferative been described (Caccavelli et al. 1996), as well as decreased indexes and lower rates of surgical cure, suggesting a sex- expression of the nerve growth factor receptor, which specific behavior for these tumors (Delgrange et al. 1997, indirectly modulates Drd2 expression (Passos et al. 2009). Gillam & Molitch 2015). Histological studies on DARPs also revealed increased http://joe.endocrinology-journals.org Ñ 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-15-0451 Printed in Great Britain Downloaded from Bioscientifica.com at 10/01/2021 02:33:00AM via free access Review M V RECOUVREUX and others TGFb1 and resistant 228:3 R75 prolactinomas angiogenesis, cellular atypia (multinucleated cells, irregu- therapies. Many of these studies suggest that the dereg- lar nuclei), and increased proliferation index measured by ulation of local growth factors and extracellular matrix Ki67 staining, indicating an overall increase invasiveness (ECM) remodeling participate in the pathogenesis of (reviewed in Gurlek et al. (2007)). prolactinomas by promoting cell proliferation, angio- genesis, and invasiveness (Paez-Pereda et al. 2005, Cristina et al. et al. Alternative treatments for DARPs 2005, 2007, Recouvreux 2013). Transforming growth factor b1 (TGFb1), a well-known At present, there is no alternative medical treatment for inhibitor in lactotroph
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