Abstract B91: A novel role for the secreted growth factor progranulin in angiogenesis

Progranulin (also called PC cell-derived growth factor, acrogranin or proepithelin), is a secreted glycoprotein with growth factor-like activities. It is often highly over-expressed in tumors including cancers of the breast, ovary, endometrium, kidney, prostate, bladder and liver. It stimulates cellular proliferation, migration and survival and increases the growth of cancers in mice. Recent work suggests that progranulin has, in addition, potentially important roles in fibroblast activation during the formation of tumor stroma. An elevated progranulin level has been observed in endothelial cells in some cancers including ovarian tumors, esophageal carcinomas and gliomas. Since progranulin is not expressed in normal quiescent endothelia, its presence in endothelial cells from cancers prompted us to propose that progranulin may have a novel role in tumor angiogenesis. It is, however, unknown at present, how, if at all, progranulin modulates angiogenesis in vivo . To address this question we created transgenic models in which progranulin expression is specifically targeted to endothelial cells under the control of the Tie2 promoter. Three independent transgenic lines were obtained, with lower ( Tie2-GrnLo ), intermediate ( Tie2-GrnMid ) and higher ( Tie2-GrnHi ) transgene copy number. Increased mortality was observed in heterozygotic crosses from all three transgenic lines, with the highest mortality and lowest germline transmission ratio in the Tie2-GrnHi line; at three weeks after birth the germline transmission ratios of Tie2-Grn positive mice were 26.01%, 19.61% and 4.72% for PgrnLo, PgrnMid and PgrnHi respectively. Premature deaths occurred during the perinatal period after embryonic day 17.5 and before post-natal day 3. Importantly, we observed an array of vascular abnormalities in Tie2-Grn transgenic neonates. These include extensive bleeding into body cavities such as the pericardial space as well as smaller localized hemorrhages in multiple organs. The abnormal blood vessels had dramatically enlarged diameters with irregular edges; several had an incomplete basement membranes and, typically, the perivascular cell coverage was reduced or absent when compared to Tie2-Grn negative litter mates. To establish the developmental timing of vascular disruption, we examined Tie2-GrnHi mice from embryonic day 10.5 to fetal age 17.5. An apparently normal primitive vasculature was established at E10.5 in Tie2-Grn positive embryos suggesting that vasculogenesis proceeded normally. The earliest onset of vascular impairment was observed at E15.5, after vasculogenesis has occurred but during active angiogenesis. As with neonates, from E15.5 and later, vessels became enlarged and perivascular cell investiture was reduced contributing to loss of structural integrity and causing the blood vessels to be prone to hemorrhaging. Given the vessel dilation in Tie2-Grn positive late-stage fetuses and neonates we conclude that progranulin is a novel regulator of angiogenesis. The elevated expression of progranulin by endothelial cells is observed in some cancers in vivo, and, as we report here, in transgenic mice results in the development of enlarged, disorganized, thin-walled vessels that resemble to some extent the disorganized blood vessels in tumors. We suggest, therefore, that progranulin may be significant in regulating tumor angiogenesis. Citation Format: Huishi Toh, Ming Cao, Yonghua Zhang, Eugene Daniels, Andrew Bateman. A novel role for the secreted growth factor progranulin in angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B91.