Scientists Identify Unique Cell in Rare Tumor Tied to Ectopic Cushing’s

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A clinical researcher views samples through a microscope in this illustration.

A team of researchers in China have identified, for the first time, a tumor cell that produces both adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) — two hormones that promote excess cortisol levels and the development of Cushing’s syndrome.

Specifically, this unique cell type was found in a rare adrenal gland tumor called pheochromocytoma that is often associated with ectopic Cushing’s.

The study also pinpointed galanin, a nerve cell chemical messenger, as a potential marker of the rare ACTH-CRH-producing pheochromocytoma in cases of suspected Cushing’s.

The study, “Single-cell transcriptome analysis identifies a unique tumor cell type producing multiple hormones in ectopic ACTH and CRH secreting pheochromocytoma,” was published in the journal eLife.

Cushing’s syndrome is characterized by abnormally high levels of the hormone cortisol in the bloodstream.

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Consider Possibility of Cushing’s Disease in Patients With Adrenal Tumor

A tumor in the brain’s pituitary gland that secretes higher-than-normal amounts of ACTH, which stimulates cortisol production by the adrenal glands, is the most common cause of endogenous Cushing’s syndrome. The adrenal glands are located above the kidneys.

However, tumors outside the pituitary gland can cause the body to produce abnormally high levels of cortisol, in which case a patient is said to have ectopic Cushing’s. In rare cases, ectopic Cushing’s may be caused by pheochromocytoma, a rare adrenal gland tumor that is capable of producing several hormones, such as ACTH.

Pheochromocytoma “becomes even rarer when it is capable of both secreting ACTH and CRH,” the researchers wrote, adding that only two cases of ACTH-CRH-producing pheochromocytoma had been reported by 2020.

Given its rarity, there is limited knowledge about its diagnosis and management, as well as about whether a unique cell type produces both hormones in these tumors.

To address this, a team of researchers at the Chinese Academy of Medical Sciences & Peking Union Medical College, in China, analyzed the gene activity of single tumor cells of a new rare case ectopic Cushing’s caused by an ACTH-CRH-producing pheochromocytoma.

For comparison, samples from other adrenal tumor subtypes — common pheochromocytoma (without ACTH or CRH secretion) and adrenocortical adenoma — also were collected and studied from two other patients.

The analysis identified a total of 16 different cell types in the tumor microenvironment from all specimens.

One of these cells, only present in the ACTH-CRH-producing pheochromocytoma, was found to have high activity in the genes that code for proopiomelanocortin (POMC), the precursor of ACTH, and CRH, a hormone that stimulates the production and release of ACTH in the pituitary gland.

Further molecular analyses confirmed that this cell type was producing multiple hormones, including POMC, ACTH, and CRH.

Based on these findings, the researchers hypothesized that the newly identified tumor cell type was behind the rare case of ectopic Cushing’s. They theorized that the secretion, or release, of ACTH directly stimulated the adrenal glands to produce cortisol, and CRH production indirectly stimulated cortisol production by promoting ACTH secretion from the pituitary gland.

Notably, the team also found that this unique cell type produced galanin, a neuronal chemical messenger that can regulate multiple physiologic functions, such as hormone secretion by the adrenal glands.

A previous study showed that galanin and ACTH were co-produced in human pituitary glands and pituitary tumors, and suggested that galanin may be locally involved in the regulation of the hypothalamic-pituitary-adrenal axis, which controls cortisol levels in the body. As such, galanin could be a new biomarker of ACTH-CRH-producing pheochromocytoma.

After the surgical removal of the ACTH-CRH-producing pheochromocytoma, the patient showed complete remission of Cushing’s symptoms.

The team now plans to conduct additional experiments to identify the molecular mechanisms behind this cell’s ability to secrete multiple hormones.