Syndromes of ectopic ACTH secretion: Recent pathophysiological progresses and their clinical implications

The pituitary hormone ACTH occasionally is produced by nonpituitary tumors, leading to ectopic ACTH secretion. Whereas the ectopic ACTH syndrome was c lassically seen as a rather uniform condition, there is increasing evidence that it actually includes distinct pathological entities. Various types of tumors, most often originating in the lung, can secrete ACTH. Among them a re the well-differentiated and rather indolent carcinoids and, by contrast, the highly aggressive small cell cancers. The former tumors often respond in an unanticipated, "pituitary-like" manner to the modulators of the corti cotroph function. The recent cloning of the V3 vasopressin receptor, and th e demonstration of its close association with the corticotroph phenotype, o ffered a new molecular tool with which to explore ACTH-secreting nonpituita ry tumors. The high levels of V3 receptor gene expression in most carcinoid s reveal that ACTH production by these tumors is but one aspect of a wider program of corticotroph differentiation. In contrast, ACTH-secreting small cell lung carcinomas do not exhibit a clear corticotroph phenotype: proopio melanocortin (POMC) gene transcription occurs at a low rate and generates a ltered POMCmRNA, and POMC processing is often abnormal, often resulting in large concentrations of circulating intact precursor, In these aggressive t umors, POMC gene expression is triggered by E2F factors: it was recently fo und that POMC gene promoter is a target of such factors that participate in cell proliferation and become active when the retinoblastoma protein is ab sent, as is the case in most small cell carcinomas of the lung.