Maryline Herbet
Insights into the role of genetic alterations in adrenocortical tumorigenesis
Published on 21 November 2008
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Thesis presented November 21, 2008
Abstract:
Although molecular genetic alterations of benign (adenoma; ACA) and malignant (carcinoma; ACC) sporadic adrenocortical tumors are well established, their involvement in each step of the tumoral process, from initiation to metastatic tumors, is still unclear. Moreover, whether adenoma represents a separate entity or is in fact part of a process of tumor progression leading to the emergence of an ACC is still an open question. Genetic alterations commonly found in carcinomas are mutation in the proto-oncogene
N-Ras (12.5%), mutation in the tumor suppressor gene
TP53 (25%), mutation in
ß-catenin gene (30%) and overexpression of
IGF-2 (90%). We reproduced these alterations by overexpressing the oncogene
RasG12V, the dominant negative
p53DD, the mutant
ß-cateninS37A and
IGF-2 wild type. We thought to define a minimal genetic combination triggering fully tumorigenic transformation of primary bovine adrenocortical cells (BAC) in an
in vivo tissue reconstruction model where cells are transplanted beneath the kidney capsule of immunodeficiente mice. Once transplanted into animals, cells overexpressing
IFG-2 or
ß-cateninS37A induced the formation of a murine tumor. Then, we failed to determine a combination using these two genes. Nevertheless, we showed that the simultaneous expression of RasG12V and p53DD is sufficient to convert primary cells into a fully tumorigenic state and that these genes cooperate through a precise sequence: only cells expressing first RasG12V and then p53DD become tumorigenic. Into this process, RasG12V induces an hyperplasic phenotype which progress into a malignant tumor after introduction of p53DD.
All together, our data have shown that the overexpression of an oncogene and the alteration of a tumor suppressor gene is sufficient to trigger ACC development (RasG12V and p53DD) and that the adrenocortical tumorigenesis is possibly a multi-step process. The mouse model proposed by this study could be a useful tool to define markers of malignancy and to design new therapeutic options for CCS treatments.
Keywords:
Adrenocortical tumorigenesis, adrenocortical carcinoma,
in vivo model, RasG12V, p53DD, multi-step process
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