Kyushu University researchers have revealed a surprising layer of complexity in aldosterone-producing adenomas (APAs), adrenal gland tumors that contribute to high blood pressure. By employing advanced analysis methods, they found evidence that these tumors consist of at least four distinct cell types, including those responsible for cortisol production—the primary stress hormone in the body.
Published in PNAS during the week commencing 24 February, their discoveries shed light on why some APA patients experience unexpected health issues such as weakened bones and open new avenues for treatment. Currently, surgery is the sole cure for APAs; however, this approach has remained unchanged for decades. To develop innovative treatments like medication, there’s an urgent need to comprehend how these tumors function at a molecular level and understand the interactions among their various cell types.
Maki Yokomoto-Umakoshi, first author of the study and an Assistant Professor from Kyushu University Hospital’s Department of Endocrine and Metabolic Diseases, emphasized that “To develop new treatment models such as drug treatments, we urgently need to understand how these tumors work at the molecular level, and how the different cell types interact with each other.”
Aldosterone-producing adenomas (APAs) are benign tumors originating on adrenal glands—small glands located atop kidneys responsible for producing essential hormones including aldosterone, cortisol, and sex hormones. Due to their positioning, APAs are a significant cause of primary aldosteronism—a condition marked by excessive production of the hormone aldosterone leading to high blood pressure.
Primary aldosteronism is accountable for approximately 5-10% of hypertension cases; individuals with APAs have an increased risk of developing heart and vascular diseases compared to those affected by common high blood pressure. “Without adequate treatment, patients can encounter serious health issues like heart disease, diabetes, and bone weakness,” Yokomoto-Umakoshi added.
In this study, the researchers concentrated on APAs caused by mutations in a gene called KCNJ5. This mutation is linked to around 40-70% of all APA cases and usually leads to larger tumors forming at an earlier age with more severe symptoms that can’t be explained simply through overproduction of aldosterone.
The cellular composition and other hormones secreted by KCNJ5 tumors have been challenging to study. To gain deeper insights into APAs, the research team led by Professor Yoshihiro Ogawa from Kyushu University collaborated with Osaka University, Kyoto University, and Tokyo University. They utilized a combination of advanced techniques to provide unprecedented detail on APA structure.
The researchers were able to map different cell types within these tumors along with their interactivity. Additionally, the techniques revealed diverse genetic variations across various regions in APAs and identified specific hormones being produced by the tumors. Their study highlighted that APAs are more complex than previously thought, comprising at least four distinct cell types.
The tumor initiates with stress-responsive cells which can evolve into either aldosterone-producing or cortisol-producing cells. Cortisol-producing cells may further develop into stromal-like ones facilitating tumor growth. Researchers also discovered an abundance of special immune cells called lipid-associated macrophages within the tumors, potentially influencing hormone production and tumor development.
“Overall, these tumors contain diverse hormone-producing cell types that can impact patient health in various ways—not just through high blood pressure but also via other symptoms caused by excess cortisol like bone weakness,” Yokomoto-Umakoshi explained.
In future research, the team plans to apply their techniques to explore other APA variants and different tumors secreting excessive hormones. They hope these findings will pave the way for new drug treatments targeting lipids-associated macrophages or surplus cortisol. “Now that we understand more about APAs, it opens up promising new treatment strategies,” Yokomoto-Umakoshi concluded.
