Dysregulation of cell cycle in animal models and human neuroendocrine pituitary tumors (PitNET)

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HMGA2 cooperates with either p27kip1 deficiency or Cdk4R24C mutation in pituitary tumorigenesis

Human pituitary tumors are frequent brain tumors displaying different tumor behaviors and endocrine symptoms. Most are benign but many are invasive. Some show multiple recurrences and resistance to conventional treatment (surgery, radiotherapy, standard medical treatment) and are considered as clinically aggressive [1]. In the absence of markers of malignancy, only pituitary tumors with metastasis are classified as malignant. Despite numerous attempts, establishment of a human pituitary cell line has always been unsuccessful. Animal models are thus essential to identify factors involved in both pathogenesis and tumor progression and also to test new drugs. Examples include rats with spontaneous transplantable pituitary tumors [2] and transgenic mice overexpressing Hmga1, Hmga2, or a truncated form of Hmga2 (Hmga2/T), described in 2002 by Fedele et al [3]. The proteins of the HMGA family (HMGA1a, HMGA1b and HMGA2) are chromatin-regulating factors. When overexpressed, they act at the transcription level as cellular oncogenes. Dysregulation of cyclin/cyclin-dependent kinase (Cdk) complexes, including cyclin D-binding Cdk4 and its inhibitor INK4 as well as cyclin E-binding Cdk2 and its inhibitor p27^Kip1, has been found in human tumors displaying cell cycle alterations [4]. In their elegant experiment in transgenic mice, Fedele et al investigated the possible synergistic expression between Hmga2 and these two cell cycle regulators, Cdk4 and P27^kip1 [5]. The authors crossed Hmga2/T mice, overexpressing the truncated/active form of Hmga2, either with knock-out mice displaying functional deficiency of p27, or with Cdk4^R24C knock-in mice bearing a mutation leading to the expression of a Cdk4 protein insensitive to INK4 inhibitor. Based on Kaplan-Meier survival curves, the size of the pituitary tumor, and the histological signs of invasion and proliferation (ki-67 index) used in the classification of human pituitary tumors, they observed different tumor behaviors and demonstrated a cooperation between Hmga2 overexpression and either p27^kip1 or Cdk4 impairment in these double transgenic mice.

As in this study, the animal models have to be compared to the human pathology and the experimental results similar to that in humans. Such dysregulation of the cell cycle, molecular and genetic markers have indeed been demonstrated in human pituitary tumors (Review in [6]). The term pituitary “adenoma”, commonly used, which defines a tumor as benign, seems inappropriate to define tumors with aggressive or invasive behavior and genetic abnormalities. Indeed, it has been recently proposed, that pituitary tumors should no longer be considered as simply endocrine diseases, but classified as pituitary neuroendocrine tumors (PitNET) with endocrine manifestations [7].

Disclosure of Potential Conflicts of Interest

No potential conflict of interest was reported by the authors