Philipp Lachenmann: DELPHI Rationale


Schoeller Junkmann Preis 2003

Dr. Felix Beuschlein

Schwerpunkt Endokrinologie und Diabetologie, Medizinische Universitätsklinik Freiburg

Activin prevents luteinizing hormone-dependent adrenocortical tumor formation in inhibin deficient mice

Inhibin and activin are members of the TGF_ family of ligands produced and secreted primarily by the gonads and adrenals. Inhibin null (INH-/-) mice develop gonadal tumors and - when gonadectomized - adrenocortical carcinoma. As we could show in time course experiments on non-gonadectomized and gonadectomized INH-/- the adrenal phenotype in this mouse model is indicative of growth dysregulation of the x-zone: The x-zone, which serves as a functional equivalent of the fetal zone of the human adrenal cortex, regresses in the presence of activin secreting ovarian tumors, while gonadectomy is followed by unopposed x-zone growth and finally tumorigenesis.

However, the precise mechanisms underlying the dysregulated adrenocortical growth and ultimate carcinoma formation in gonadectomized INH-/- mice have yet to be elucidated. While a compensatory increase of pituitary LH following gonadectomy might promote the induction of adrenal tumorigenesis, it is equally plausible that the loss of a gonadal factor such as activin is responsible for the adrenal phenotype. In order to achieve elevation of gonadotropins without the concomitant loss of a gonadal hormone, we crossed INH-/- mice with a transgenic mouse strain that has chronically elevated LH levels (LH-CTP). Compound INH-/-:LH-CTP mice die within 6 weeks of age from severe cancer cachexia induced by large, activin secreting ovarian tumors.

Unexpectedly, INH-/-:LH-CTP mice not only fail to develop adrenal tumors, but have smaller adrenals with a regressed x-zone, indicating that elevated LH levels are not sufficient to induce adrenal tumor formation. However, following gonadectomy, INH-/-:LH-CTP mice develop large, sex steroid producing adrenal tumors indicating a direct growth promoting effect of LH on the adrenal cortex in the absence of ovarian tumors. In addition, in vivo and in vitro data indicate that activin induces apoptosis specifically in the adrenal x-zone.

The restricted expression of both activin receptor subunits (ActR-IA and ActR-IIB) and Smad2, which have a pivotal roles in the activin-signaling cascade, in cells of the adrenal x-zone, together with the elevated activin levels in INH-/-:LH-CTP mice, supports the conclusion that activin prevents adrenal tumor growth by inducing x-zone regression.



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