Lung neuroendocrine tumors (NET) or carcinoids constitute 1% of all lung cancers. Patients with metastatic carcinoid disease have a poor 5-year survival of 14-25%. Lung carcinoids originate from lung neuroendocrine cells (PNEC). Knowledge about the basic biology of lung NET is incomplete. We first described PNEC and their role as key airway oxygen sensors. PNEC produce the chemical serotonin (5-hydroxytryptamine, 5-HT), responsible for carcinoid syndrome, a major cause of morbidity in patients. We found that 5-HT secretion is induced by low oxygen and high carbon dioxide/acidosis. We found that lung carcinoids express carbonic anhydrases (CA), proteins specialized in sensing carbon dioxide. One CA subtype, CAIX, is up-regulated by low oxygen and high carbon dioxide/acidosis, conditions correlating with tumor aggressive behavior and metastasis. We found that the drug, acetazolamide, a blocker of CA activity, inhibits 5-HT secretion from carcinoid cells. We postulate that CAIX plays a key role in the malignant behavior of carcinoids. We will investigate how carcinoids sense oxygen and carbon dioxide and provide proof-of-principle evidence in an animal model that therapeutic targeting of CAIX with drugs can abolish the carcinoid syndrome and eliminate malignant transformation.

This grant is jointly funded by CNETS (Carcinoid NeuroEndocrine Tumor Society of Canada) and the Cancer Research Society.