The pituitary is a small endocrine gland that controls vital homeostatic functions. It is called the “master gland” because it directs other organs and endocrine glands, such as the thyroid, the adrenals and the liver to suppress or induce hormone production. Under control of growth factors and transcription factors, pituitary progenitor cells differentiate into five types of hormone-secreting cells: lactotrophs (prolactin secreting), somatotrophs (growth-hormone (GH) secreting), gonadotrophs (follicle-stimulating hormone and luteinizing-hormone secreting), thyrotrophs (thyroid-stimulating hormone secreting) and corticotrophs (adrenocorticotrophic-hormone (ACTH) secreting).
Role of Somatostatin Receptors in Pituitary Function
Anat Ben-Shlomo, MD, studies regulatory factors for pituitary tumorigenesis, as well as novel treatment approaches to pituitary disease with somatostatin receptors. She has shown ligand-independent constitutive somatostatin receptor activity regulating ACTH and GH synthesis. She analyzes genetic aberrations in human pituitary tumors that underlie unique patterns for tumor development.
Growth Hormone and Colon Cancer
Vera Chesnokova, PhD, studies the relationship between GH and colon cancer development. Recognizing that GH excess in acromegaly is associated with high rates of colon cancer, while genetic mutations leading to GH deficiency protect against cancer development, she studies mechanisms underlying protective effects of GH deficiency for colon tumor growth. GH-targeted therapeutic approaches may disrupt preneoplastic colon changes.
Figure 1. Two-month-old normal and GH-deficient Prop1-/- mice (left). Cross-breeding of APCmin+/- mice genetically predisposed to intestinal tumors with GH-deficient Prop1-/- mice resulted in a marked decrease in the number of mice bearing colon tumors (right).
Figure 2. Immunofluorescent confocal images of GH immunoreactivity in colon tumor of APCmin+/− stroma and epithelium are immunopositive for GH (red), whereas no GH is detected in the colon of APCmin+/−Prop1−/− mice. Upper images, magnification, 20X; scale bar, 200 μm. Lower images, magnification, 63X; scale bar, 100 μm.
To enable pituitary discovery and develop new treatments for pituitary diseases, the Melmed Lab uses an integrative genomics approach to develop a pituitary biomarker database for storing information of high-throughput studies, analyses and detected biomarkers.
- Gene expression microarray to determine differentially expressed genes in pituitary disorders
- SNP/CGH microarray to determine the contribution of genetic variations to pituitary tumor development
- Whole exome sequencing to determine the contribution of somatic mutations to pituitary tumor development
Figure 3. Microarray analysis of prolactinomas. (A) Microarray data derived from pituitaries of vehicle- or DES-treated ACI and BN rats. (B) Differentially expressed genes were identified and a Venn diagram generated to unmask overlapping genes. (C) Genes related to invasion, recurrence, and drug resistance were identified and applied to the Venn diagram. (D) A total of 38 genes were selected from 4,545 differentially expressed genes in DES-treated ACI rats (empty bar) and expression was validated using real-time PCR (solid bar) in prolactinomas from estrogen-treated Fischer rats.
The Role of Epidermal Growth Factor Receptor in Pituitary Tumor Progression
Odelia Cooper, MD, explores the role of the epidermal growth factor receptor (EGFR) pathway in pituitary tumor growth. She demonstrated that EGFR expression in pituitary tumors correlates with invasion and higher hormone levels. Translating these findings to the clinic, she is testing treatment with the EGFR tyrosine kinase inhibitor lapatinib to reduce prolactin levels and tumor size in a Phase IIa multicenter clinical trial.
Molecular Pathogenesis and Treatment for Pituitary Adenomas
Cuiqi Zhou, PhD, studies molecular pathogenesis and treatment of pituitary adenomas, utilizing cellular and animal models. She studies regulatory mechanisms and functions of pituitary tumor-transforming gene (PTTG), as well as hormone regulation. She has investigated PTTG regulatory mechanisms mediated by cell cycle regulator Rb/E2F1 and STAT3, thereby extending our knowledge of tumor cell cycle control to support anti-tumor therapeutic approaches.
Vertebrate Hypothalamic-Pituitary Axis
Ning-Ai Liu, MD, PhD, uses zebrafish to investigate hypothalamic-pituitary development and function, as well as to screen for new therapeutic strategies for pituitary disorders. Using our zebrafish models of human pituitary disease, novel investigative molecules have been discovered to treat patients with Cushing disease.
In vivo time-lapse imaging of embryonic pituitary lactotroph (red) and corticotroph (green) development in transgenic zebrafish at 18–26 hours post fertilization.