OR16-6 Order of acquisition of genetic changes leads to distinct adrenocortical tumor phenotypes

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR16-Cancers of Endocrine Organs: Mechanisms of Tumorigenesis & Progression
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:30 PM
Room 206 (Moscone Center)
Maryline Herbet1, Aude Salomon1, Jean-Jacques Feige2 and MichaŽl Thomas*1
1Inserm U1036, Grenoble, France, 2INSERM U1036, Grenoble, France
Sporadic adrenocortical carcinomas (ACCs) are rare endocrine neoplasms with a dismal prognosis. By contrast, benign tumors of the adrenal cortex are common in the general population. Whether benign tumors represent a separate entity or are in fact part of a process of tumor progression ultimately leading to ACC is still an unresolved issue. Moreover, many of the significant advances in identifying genes involved in ACCs development derive from the study of human tumor specimens. To complement these studies, several laboratories including ours have developed murine models of ACCs. Such models provide an important basis for understanding the specific genetic alterations that lead to particular phenotypes. To this end, we have developed a mouse model of tumor progression by transplanting bovine adrenocortical cells successively transduced by genes altered in adrenocortical tumors beneath the kidney capsule of adrenalectomized ICR-SCID mice. The use of such techniques permits the phenotypes of individual genes and combination of genes to be observed in an in vivo environment more suitable for the engraftment of the cells than the subcutaneous space.  The introduction in different orders of the activated allele of Ras (H-RasG12V) and the mutant p53DD that disrupts the p53 pathway yielded tumors displaying major differences in histological features, tumorigenicity, and metastatic behavior. Whereas the successive expression of RasG12V and p53DD lead to highly malignant tumors with metastatic behavior, reminiscent of those formed after the simultaneous introduction of p53DD and RasG12V, the reverse sequence only gave rise to benign tumors. Microarray profiling revealed that 157 genes related to cancer development and progression were differentially expressed. Of these genes, 40 were up-regulated and 117 were down-regulated in malignant cell populations as compared with benign cell populations. We further validated these malignant to benign tumor transcriptome changes by real-time quantitative PCR and immunohistochemical analyses on 5 genes, namely secreted protein, acidic, cysteine-rich (Sparc), leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1), tumor protein D52 (TPD52), Egl nine homolog 2 (EglN2) and cyclinD1 (CCND1). This is the first evidence-based observation that ACC development follows a multistage progression and that the tumor phenotype is directly influenced by the order of acquisition of genetic alterations.

Nothing to Disclose: MH, AS, JJF, MT

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Fondation de France Grant 2004012837; Association pour la Recherche sur le Cancer Grant 5106
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