What are the markers of aggressiveness in prolactinomas? Changes in cell biology, extracellular matrix components, angiogenesis and genetics

Abstract

Prolactinoma is the most common pituitary tumour in adults. Macroprolactinomas, particularly in men, may occasionally exhibit a very aggressive clinical course as evidenced by progressive growth, invasion through bone into the sphenoid sinus, cavernous sinus, suprasellar region or the nasopharynx. Some may even progress to pituitary carcinoma with craniospinal or systemic metastases. Aggressive tumours have low cure rates despite appropriate medical and surgical treatment. The mechanisms underlying this aggressive biological behaviour have not yet been fully clarified. Recent immunohistochemical, molecular and genetic studies have provided some insight in this respect. Invasive prolactinomas may be associated with a high Ki-67/MIB-1 labelling index indicating increased cell proliferation, although this is not a universal finding. The AA polymorphism in the cyclin adenine (A)/guanine (G) gene is more frequently detected in invasive prolactinomas. Increased expression of the polysialylated neural cell adhesion molecule (NCAM) and reduced expression of the E-cadherin/catenin complex implies a contribution of altered cell-to-cell adhesion and cellular migration. Extracellular matrix components (ECM), matrix metalloproteinases (MMPs) and their inhibitors play important roles in the context of angiogenesis and invasion. The induction of fibroblast growth factor and vascular endothelial growth factor via oestrogen-induced overexpression of novel genes (PTTG, hst and Edpm5) enhance cell growth, proliferation and angiogenesis contributing to invasiveness in prolactinomas. Although mutations in proto-oncogenes like Ras are uncommon, loss of tumour suppressor genes at loci 11q13, 13q12-14, 10q and 1p seem to be associated with invasiveness. Of the described mechanisms, only reduced E-cadherin/catenin expression and overexpression of hst gene seem to be relatively specific markers for prolactinoma invasiveness compared with other pituitary adenomas. Further research is needed to clarify the molecular mechanisms behind the aggressive course of some prolactinomas to predict those with a potentially poor clinical outcome, and to devise treatments that will eventually enable the cure of these challenging tumours.

Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients

“…Additional factors involved in the aggressiveness of prolactinomas may interfere with D2R signaling or exert opposing biological effects on lactotroph cells. These include abnormalities in growth factors signaling (18,23) and in extracellular matrix components (24,25), the increased expression of genes involved in cell proliferation (25,26), and loss of tumor suppressor genes at various loci (24). The promoting effects of estrogens on prolactinoma formation are well known (27), and gender-related differences in sex steroid receptor expression, especially the estrogen receptors (ERs), and in the steroid milieu, may contribute to the aggressiveness of prolactinomas in men (28).…”

Differential gene expression profiles of invasive and non-invasive non-functioning pituitary adenomas based on microarray analysis

“…Microarray technology has previously been used to evaluate gene expression during pituitary tumorigenesis, but most studies compared pituitary adenomas to normal pituitary tissues (Evans et al 2001, Moreno et al 2005, Morris et al 2005, Farrell 2006, Gurlek et al 2007, Shorts-Cary et al 2007, Wierinckx et al 2007 in order to identify genes associated with tumor pathogenesis. To gain insight into the mechanisms involved in pituitary adenoma invasiveness, we sought to identify genes that were differentially expressed in invasive and non-invasive forms.…”

Extracellular Matrix Proteins in the Anterior Pituitary Gland

“…The potential importance of cadherin in pituitary pathophysiology has been noted [69]. In other cancer sites it is thought that E-cadherin may act to retain potentially invasive tumour cells at the primary lesion [70,71].…”