Abstract
BackgroundPERK eIF2α kinase is required for the proliferation of the insulin-secreting beta- cells as well as insulin synthesis and secretion. In addition, PERK signaling has been found to be an important factor in determining growth and angiogenesis of specific types of tumors, and was attributed to PERK-dependent regulation of the hypoxic stress response. In this report we examine the role of PERK in regulating proliferation and angiogenesis of transformed beta-cells in the development of insulinomas.MethodologyThe SV40 Large T-antigen (Tag) was genetically introduced into the insulin secreting beta-cells of Perk KO mice under the control of an inducible promoter. Tumor growth and the related parameters of cell proliferation were measured. In late stage insulinomas the degree of vascularity was determined.Principal FindingsThe formation and growth of insulinomas in Perk-deficient mice was dramatically ablated with much fewer tumors, which averaged 38-fold smaller than seen in wild-type control mice. Beta-cell proliferation was ablated in Perk-deficient mice associated with reduced tumor growth. In the small number of large encapsulated insulinomas that developed in Perk-deficient mice, we found a dramatic reduction in tumor vascularity compared to similar sized insulinomas in wild-type mice. Although insulinoma growth in Perk-deficient mice was largely impaired, beta-cell mass was increased sufficiently by T-antigen induction to rescue the hypoinsulinemia and diabetes in these mice.ConclusionsWe conclude that PERK has two roles in the development of beta-cell insulinomas, first to support rapid cell proliferation during the initial transition to islet hyperplasia and later to promote angiogenesis during the progression to late-stage encapsulated tumors.
Highlights
In the small number of large encapsulated insulinomas that developed in Perk-deficient mice, we found a dramatic reduction in tumor vascularity compared to similar sized insulinomas in wild-type mice
We conclude that PERK has two roles in the development of beta-cell insulinomas, first to support rapid cell proliferation during the initial transition to islet hyperplasia and later to promote angiogenesis during the progression to late-stage encapsulated tumors
Tumor growth is dependent upon high rates of protein synthesis, and previous studies had shown that control of protein synthesis mediated by phosphorylation of the translation initiation factor eIF2a is important for tumor progression [1,2,3,4]
Summary
Tumor growth is dependent upon high rates of protein synthesis, and previous studies had shown that control of protein synthesis mediated by phosphorylation of the translation initiation factor eIF2a is important for tumor progression [1,2,3,4]. Previous studies have shown that tumors that lack PERK-mediated signaling tend to be smaller and this was found to be correlated with smaller hypoxic microenvironments [5,6,7]. The resultant tumors were found to be smaller and less vascular compared to control implants that were wild type for Perk [6,7] In these studies, the dramatic reduction in growth of the Perk-deficient tumors was attributed to increased rates of apoptotic cell death and impaired angiogenesis but, inexplicably, tumor cell proliferation rates were not examined [6,7]. In this report we examine the role of PERK in regulating proliferation and angiogenesis of transformed beta-cells in the development of insulinomas
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