Masahide Ota

Cancer cells contain a small population of cancer stem cells or cancer initiating cells, which can be enriched in the side population (SP) after fluorescence activated cell sorting. To examine the members of the ADAM, ADAMTS and MMP gene families related to phenotypes of the SP and the main population (MP), we screened the expression of all the members in the propagated SP and MP of A549 lung adenocarcinoma cells, and found that the relative expression ratio of ADAM23 in the MP to the SP is most highly increased, but none of them are increased in the SP. A similar result on the ADAM23 expression was obtained with another cell line, Calu-3 cells. Overexpression of ADAM23 inhibited colony formation, cell adhesion and migration, and knockdown of ADAM23 by shRNA showed the reverse effects. ADAM23-mediated suppression of colony formation, cell adhesion and migration was greatly reduced by treatment with neutralizing anti-ADAM23 antibody, anti-αvβ3 integrin antibody and/or ADAM23 disintegrin peptide. Expression of cancer stem cell-related genes, including AKRC1/2, TM4SF1 and NR0B1, was increased by knockdown of ADAM23. In addition, lung metastasis of A549 transfectants with different levels of ADAM23 expression was negatively regulated by the ADAM23 expression levels. Our data provide evidence that ADAM23 plays a role in suppression of cancer cell progression through interaction with αvβ3 integrin, and suggest that downregulation of ADAM23 in SP cells may contribute toward providing a cancer stem cell phenotype by facilitating the activity of integrin αvβ3.

SUMMARY: Ectopic ACTH (adrenocorticotrophic hormone) syndrome (EAS) is rarely associated with small-cell lung cancer (SCLC). Although chemotherapy is initially effective for SCLC, complicated EAS scarcely improves. Recently, immune checkpoint inhibitors have been used to treat SCLC. Atezolizumab plus chemotherapy for SCLC improved progression-free survival compared to conventional chemotherapy. However, little has been reported on the efficacy of the combination therapy for SCLC with EAS. We report a 72-year-old male who presented with 4-week history of leg oedema, proximal myopathy, weight loss, and worsened symptoms of diabetes and hypertension. Laboratory findings revealed hypokalaemia, increased plasma ACTH, and serum cortisol levels. Cortisol levels were not suppressed by the high-dose dexamethasone test. Chest and abdominal CT revealed a right lower lobe tumour with multiple metastases on the hilar lymph nodes, liver, lumbar spine, and bilateral enlarged adrenal glands. The patient was diagnosed with stage 4B SCLC with EAS. Hypercortisolaemia was then treated with metyrapone and atezolizumab plus chemotherapy, which was started for SCLC. After 10 days, the tumour shrank noticeably, and the ACTH level drastically decreased concomitantly with low cortisol levels with symptoms of fever, appetite loss, and general fatigue. Hydrocortisone treatment was initiated, and the symptoms resolved immediately. We describe a case of SCLC with EAS treated with atezolizumab plus chemotherapy, presenting with adrenal insufficiency. Close observation is required for patients with adrenal insufficiency receiving atezolizumab plus chemotherapy because of its stronger effect. Furthermore, advances in cancer therapy and care for endocrine paraneoplastic syndrome needs to be adapted. LEARNING POINTS: The immune checkpoint inhibitor atezolizumab has recently been approved for the treatment of small-cell lung cancer (SCLC). Approximately 1-6% of tumour ectopically produce ACTH and cause ectopic ACTH syndrome (EAS) as an endocrine paraneoplastic syndrome. The use of combined chemotherapy and atezolizumab in the ectopic ACTH syndrome secondary to small-cell lung cancer may cause a precipitous fall in circulating ACTH/cortisol, resulting in symptomatic adrenal insufficiency The advances in cancer therapy and treatment for endocrine paraneoplastic syndrome need to be adapted.