NG2 targets tumorigenic Rb inactivation in Pit1-lineage pituitary cells

Abstract

The proteoglycan neuron-glial antigen 2 (NG2) is expressed by oligodendrocyte progenitors, pericytes, and some cancerous cells where it is implicated in tumor development. We examined mice with NG2-driven pRb inactivation. Unexpectedly, NG2-Cre:pRb flox/flox mice developed pituitary tumors with high penetrance. Adenohypophysial neoplasms developed initially as multifocal lesions; by 1 year, large tumors showed brain invasion. Immunohistochemistry identified these as Pit1-lineage neoplasms, with variable immunoreactivity for growth hormone, prolactin, thyrotropin, and α-subunit of glycoprotein hormones. Other than modest hyperprolactinemia, circulating hormone levels were not elevated. To determine the role of NG2 in the pituitary, we investigated NG2 expression. Immunoreactivity was identified in anterior and posterior lobes but not in the intermediate lobe of the mouse pituitary; in the adenohypophysis, folliculostellate cells had the strongest NG2 immunoreactivity but showed no proliferation in response to Rb inactivation. Pit1-positive adenohypophysial cells were positive for NG2, but corticotroph and gonadotroph cells were negative. RT-PCR revealed NG2 expression in normal human pituitary and human pituitary tumors; immunohistochemistry localized NG2 in nontumorous human adenohypophysis with strongest positivity in folliculostellate cells, and in tumors of all types except corticotrophs. Functional studies in GH4 mammosomatotrophs showed that NG2 increases prolactin (PRL), reduces growth hormone (GH) expression, and enhances cell adhesion without influencing proliferation. In conclusion, NG2-driven pRb inactivation results in pituitary tumors that mimic endocrinologically inactive Pit1-lineage human pituitary tumors. This model identifies a role for NG2 in pituitary cell-type-specific functions and unmasks a protective role from Rb inactivation in folliculostellate cells; it can be used for further research, including preclinical testing of novel therapies.

Increased NG2 and SOX2 expression is associated with high-grade choroid plexus tumors

“…To the best of our knowledge there are no previous studies investigating NG2 or SOX2 expression levels in CPTs but they have been previously associated with cancer development (15)(16)(17)(18)(19)(20)(21)(22). Increased expression of NG2 has been demonstrated in a variety of head and neck cancers, glioma and pituitary cells (15)(16)(17)(18).…”

“…Increased expression of NG2 has been demonstrated in a variety of head and neck cancers, glioma and pituitary cells (15)(16)(17)(18). SOX2 overexpression or gene amplification has been associated with the development of lung, esophageal, breast and gastric cancers (19-22).…”

The “game” of glial fibrillary acidic and S100 proteins in pituitary adenomas: two players or several?

“…In pathological situations, this marker is exhibited by all tumour types of the adenohypophysis except for the ACTH type [19]. It has also been demonstrated that NG2 modulates the prolactin type and the GH type adenomas through enhancement of cell adhesion but without influencing proliferation [19]. Previous data available in literature regarding pituitary pathology shows that a molecular mapping of the normal hypophysis, and of the various tumour types that emerge from it, serves as a useful tool for differential diagnosis and for the diagnosis of ectopic hormone-producing tissue and of metastases [20].…”

“…Besides protein S100 and GFAP, the neuroglial antigen 2 (NG2) is another controversial marker in tumours of the pituitary gland. Normally, NG2 is expressed by oligodendrocytes progenitors, pericytes, and tumour cells [19]. In pathological situations, this marker is exhibited by all tumour types of the adenohypophysis except for the ACTH type [19].…”

“…Normally, NG2 is expressed by oligodendrocytes progenitors, pericytes, and tumour cells [19]. In pathological situations, this marker is exhibited by all tumour types of the adenohypophysis except for the ACTH type [19]. It has also been demonstrated that NG2 modulates the prolactin type and the GH type adenomas through enhancement of cell adhesion but without influencing proliferation [19].…”