Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid and adrenocortical tumors, and neuroendocrine tumors (NETs) of the pancreas and pituitary. The pancreatic NETs are predominantly gastrinomas and insulinomas, and the pituitary NETs are mostly prolactinomas and somatotrophinomas. We postulated that the different types of pancreatic and pituitary NETs may be partly due to differences in their proliferation rates, and we therefore assessed these in MEN1-associated tumors and gonadal tumors that developed in mice deleted for an Men1 allele (Men1(+/-)). To label proliferating cells in vivo, Men1(+/-) and wild-type (Men1(+/+)) mice were given 5-bromo-2-deoxyuridine (BrdU) in drinking water from 1-12 wk, and tissue sections were immunostained using anti-BrdU and hormone-specific antibodies. Proliferation in the tumors of Men1(+/-) mice was significantly (P < 0.001) increased when compared with the corresponding normal Men1(+/+) tissues. Pancreatic, pituitary and adrenocortical proliferation fitted first- and second-order regression lines in Men1(+/+) tissues and Men1(+/-) tumors, respectively, R(2) = 0.999. Apoptosis was similar in Men1(+/-) pancreatic, pituitary, and parathyroid tumors when compared with corresponding normal tissues, decreased in Men1(+/-) adrenocortical tumors, but increased in Men1(+/-) gonadal tumors. Mathematical modeling of NET growth rates (proliferation minus apoptosis rates) predicted that in Men1(+/-) mice, only pancreatic β-cells, pituitary lactotrophs and somatotrophs could develop into tumors within a murine lifespan. Thus, our studies demonstrate that Men1(+/-) tumors have low proliferation rates (<2%), second-order kinetics, and the higher occurrence of insulinomas, prolactinomas, and somatotrophinomas in MEN1 is consistent with a mathematical model for NET proliferation.