Abstract
Genetic alterations of tumor suppressor genes (TSGs) are frequently observed to have cumulative or cooperative tumorigenic effects. We examined whether the TSGs Rb1, Trp53, Pten and Men1 have cooperative effects in suppressing neuroendocrine tumors (NETs) in mice. We generated pairwise homozygous deletions of these four genes in insulin II gene expressing cells using the Cre-LoxP system. By monitoring growth and examining the histopathology of the pituitary (Pit) and pancreas (Pan) in these mice, we demonstrated that pRB had the strongest cooperative function with PTEN in suppressing PitNETs and had strong cooperative function with Menin and TRP53, respectively, in suppressing PitNETs and PanNETs. TRP53 had weak cooperative function with PTEN in suppressing pituitary lesions. We also found that deletion of Pten singly led to prolactinomas in female mice, and deletion of Rb1 alone led to islet hyperplasia in pancreas. Collectively, our data indicated that pRB and PTEN pathways play significant roles in suppressing PitNETs, while the Menin-mediated pathway plays a significant role in suppressing PanNETs. Understanding the molecular mechanisms of these genes and pathways on NETs will help us understand the molecular mechanisms of neuroendocrine tumorigenesis and develop effective preclinical murine models for NET therapeutics to improve clinical outcomes in humans.
Highlights
Human pituitary neuroendocrine tumors (PitNETs) are the third most common intracranial neoplasms and represent approximately 10–25% of all primary intracranial tumors [1, 2]
We monitored the survival of a cohort of double homozygous deletions Men1flox/flox Rb1flox/flox RIP-Cre (MRbR) mice, alongside control mice—wildtype control Men1flox/flox Rb1flox/flox (MRb) without RIP-Cre transgene, the single homozygous deletion Men1flox/flox RIP-Cre (MR) and Rb1flox/flox RIP-Cre (RbR) (Figure 1C)
Wild-type control MRb and single deletion MR mice were viable during the study period of thirty-four weeks, as previously reported for MR mice [37]; Single deletion RbR mice started dying at sixteen weeks, had a median survival of twenty-one weeks and did not live beyond thirty-one weeks; double homozygous deletions MRbR mice started dying at ten weeks, had a median survival of thirteen weeks and did not live beyond twenty-one weeks
Summary
Human pituitary neuroendocrine tumors (PitNETs) are the third most common intracranial neoplasms and represent approximately 10–25% of all primary intracranial tumors [1, 2]. The pituitary gland sits at the pituitary fossa and contains anterior, intermediate and posterior lobes. The posterior lobe is considered an extension of the hypothalamus and secretes oxytocin and anti-diuretic hormone (ADH). The intermediate lobe is located between anterior and posterior lobes. It secretes melanocyte-stimulating hormone (MSH) during fetal life but is small or absent in adults. PitNETs are www.oncotarget.com generally benign monoclonal neoplasms, they can cause significant morbidity including visual disturbances caused by mass effects that lead to compression of adjacent structures, and/or deregulated hormone secretion, and mortality [3, 4]. The molecular mechanism of tumor progression in the pituitary remains unclear
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