(2024/03/28)

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New insights into how tumors on adrenal glands develop
Researchers identify a new type of tumor cell population that leads to cortisol-producing
adenomas, noncancerous tumors that produce excessive cortisol
Fukuoka, Japan—Researchers from Kyushu University's Faculty of Medical Sciences report on
new insights into the mechanisms of how adrenal gland tumors are formed. The team
identified a new type of tumor cell population that they termed 'steroids-producing nodules'
or SPNs, that exhibits the unique characteristic of producing two different hormones. Specificstructures in SPNs were found to lead to cortisol-producing adenomas, or CPAs,
noncancerous tumors that produce excessive cortisol.
Their findings, published in eBioMedicine, provide clues into the formation and maintenanceof the human adrenal cortex, which can lead to better treatments in diseases linked to its
dysfunction.
Nobody likes the feeling of being under stress, your heart rate rises, your muscles tense, andyour body starts twitching with energy. One of the key chemical compounds behind this iscortisol, known colloquially as the 'stress hormone.' Cortisol is a family of steroid hormones
known as 'adrenal steroid hormones' and are produced within the small glands above thekidneys called the adrenal cortex.
The adrenal cortex is critical in producing the vital hormones regulating everything from yoursleep-wake cycle, blood pressure, and even sexual development. Naturally, disruptions in theadrenal gland have been linked to a wide range of diseases.
"For example, tumors that can develop in the adrenal cortex can lead to the production ofexcessive amounts of certain hormones. One type of tumor we study are cortisol-producing
adenomas, or CPAs, which are noncancerous tumors that produce excessive cortisol,"
explains Research Fellow Tazuru Fukumoto, the first author of the study. "While researchers
have found several genetic mutations linked to CPA, how exactly these tumors develop
remained unclear."
The human adrenal cortex is made of three layers, with each layer producing specifichormones: the zona glomerulosa that produce aldosterone, zona fasciculata (zF) that produce
cortisol, and the zona reticularis (zR) that produce adrenal androgens.
The team began by collecting tissue samples from patients with adrenal tumors andconducted histopathologic tests along with the latest genetic analysis. They found structuresthat exhibited a unique two-layered zF and zR-like structure, producing both cortisol andadrenal androgens.
"We called these structures steroids-producing nodules, or SPNs. SPNs had mutations in thegene GNAS, that is known to cause CPAs. Further analyses showed that the zF-like quality
enhanced cell proliferation, but the zR-like structure had a tumor suppressive effect. We also
found that this zF-like structure was the main cause for the development of CPAs" continues
Fukumoto. "In summary, when cells of the adrenal cortex acquire the GNAS gene mutation,
they develop into SPNs, wherein their zF-like structure contributes to them becoming CPAs."
The team hopes their findings can lead to better understanding and treatment ofadrenocortical tumors and the diseases they are linked to.
"Steroid based drugs are vital in the treatment of many diseases including autoimmune
diseases like rheumatoid arthritis, and allergic diseases like asthma. However, long-term use
will atrophy of the adrenal cortex," concludes Professor Yoshihiro Ogawa who led the study.
"We hope our results will advance our understanding of the layered structure of the adrenal
cortex and can lead to the prevention and treatment of adrenal cortex atrophy in the future."###For more information about this research, see "Steroids-producing nodules: a two-layered
adrenocortical nodular structure as a precursor lesion of cortisol-producing adenoma," Tazuru
Fukumoto, Hironobu Umakoshi, Norifusa Iwahashi, Tatsuki Ogasawara, Maki YokomotoUmakoshi, Hiroki Kaneko, Masamichi Fujita, Naohiro Uchida, Hiroshi Nakao, NamikoKawamura, Yayoi Matsuda, Ryuichi Sakamoto, Takashi Miyazawa, Masahide Seki, Masatoshi
Eto, Yoshinao Oda, Yutaka Suzuki, Seishi Ogawa, and Yoshihiro Ogawa eBioMedicine,
https://doi.org/10.1016/j.ebiom.2024.105087
About Kyushu University
Kyushu University is one of Japan's leading research-oriented institutes of higher education
since its founding in 1911. Home to around 19,000 students and 8,000 faculty and staff,
Kyushu U's world-class research centers cover a wide range of study areas and research
fields, from the humanities and arts to engineering and medical sciences. Its multiple
campuses—including one of the largest in Japan—are located around Fukuoka City, a coastal
metropolis on the southwestern Japanese island of Kyushu that is frequently ranked among
the world's most livable cities and historically known as Japan's gateway to Asia. Through its
Vision 2030, Kyushu U will 'Drive Social Change with Integrative Knowledge.' Its synergistic
application of knowledge will encompass all of academia and solve issues in society while
innovating new systems for a better future.

Fig. 1. Graphical abstract of the study. Steroids-producing nodules, or SPNs, exhibit a twolayered zona fasciculata (zF) and zona reticularis (zR) like structure, where two distinct cell
populations might contribute differently to adrenocortical tumorigenesis.

[Contact]
Yoshihiro Ogawa, Professor
Department of Medicine and Bioregulatory Science
Graduate School of Medical Sciences
Tel: +81-92-642-5275
E-mail: ogawa.yoshihiro.828@m.kyushu-u.ac.jp