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In vitro release and biosynthesis of tumor ACTH in ectopic ACTH producing tumors
Abstract:
Tumor tissues obtained from 4 patients with the ectopic ACTH syndrome were studied for release and synthesis of tumor ACTH, using an in vitro incubation system. The effect of various agents on release of tumor ACTH was evaluated in three cases; beta-MSH released and adenosine 3',5'-monophosphate (cyclic AMP) formed in the tissue were determined in one. Biosynthetic experiments using labeled amino acid incorporation were performed in two cases. Secretion of tumor ACTH was significantly stimulated in all cases by crude rat median eminence extract which was also effective in stimulating beta-MSH secretion associated with elevated tissue cyclic AMP levels in one. Addition of cyclic AMP and dibutyryl cyclic AMP caused a significant increase in release of both tumor ACTH and beta-MSH in one. Biogenic amines (norepinephrine and serotonin) markedly elevated tussie cyclic AMP levels without a corresponding increase of hormone release in one. Incorporation experiments revealed that 3H- or 14C-phenylalanine was incorporated into immunoreactive ACTH of a larger molecular size (big ACTH) in both cases by chromatographic procedures. However, biological activity of big ACTH was found to be undetectable by an in vivo steroidogenic assay. A mild tryptic digestion of the big forms resulted in the appearance of little ACTH to which the major radioactive peak shifted. These data suggest that the mechanism of release of tumor ACTH and beta-MSH is very similar to that of the pituitary, and that intracellular cyclic AMP may in part play some role in release of both hormones. It is also suggested that some ectopic ACTH producing tumors predominantly synthesize big ACTH, a possible precursor of ACTH, with less bioactivity.
Insights
Tumor tissues from ectopic ACTH syndrome patients release adrenocorticotropic hormone (ACTH) similarly to the pituitary. Cyclic adenosine monophosphate (cAMP) may influence this release, and tumors can produce a less active ACTH precursor.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Ectopic ACTH syndrome is caused by tumors producing ACTH.
- Understanding ACTH release mechanisms in these tumors is crucial.
Purpose of the Study:
- To investigate ACTH release and synthesis in tumors from patients with ectopic ACTH syndrome.
- To evaluate the role of cyclic adenosine monophosphate (cAMP) and other agents in tumor ACTH secretion.
- To characterize the biosynthesis of ACTH in these tumors.
Main Methods:
- In vitro incubation of tumor tissues.
- Measurement of ACTH and beta-MSH release.
- Determination of cyclic AMP levels.
- Biosynthetic experiments using labeled amino acid incorporation.
- Chromatographic and enzymatic digestion procedures.
Main Results:
- Crude rat median eminence extract stimulated ACTH secretion and beta-MSH release, associated with elevated cAMP.
- Exogenous cAMP and dibutyryl cAMP increased ACTH and beta-MSH release.
- Biogenic amines increased cAMP but not hormone release.
- Tumors synthesized a larger, less bioactive form of ACTH ('big ACTH'), which could be converted to a smaller, active form.
- The release mechanism appears similar to the pituitary.
Conclusions:
- Tumor ACTH and beta-MSH release mechanisms resemble those of the pituitary.
- Intracellular cAMP may play a role in the release of both hormones.
- Some ectopic ACTH-producing tumors synthesize a bioactive precursor ('big ACTH') of ACTH.