NEUROENDOCRINE ALTERATIONS IN NUDE MICE WITH A HUMAN LUNG CARCINOMA PRODUCING PRO‐OPIOMELANOCORTIN, CORTICOTROPHIN‐RELEASING HORMONE AND ARGININE VASOPRESSIN

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Abstract
A mucoepidermoid carcinoma of the lung (ICD classification 8430/3) resected from a patient with no clinical signs of pituitary—adrenal alterations was transplanted into 2-month-old athymic nu/nu nude mice, with the purpose of studying the effects exerted by the human tumour on the host hypothalamo—pituitary—adrenal axis. The tumour produces peptides derived from different regions of pro-opiomelanocortin (POMC: ACTH, 7.6±0.7; N-terminal POMC, 6.6±0.6; β-LPH/endorphin, 7.3±0.7; and α-MSH, 3.8±0.5 pmol/g wet tissue) and the neuropeptides corticotrophin-releasing hormone and arginine vasopressin (CRH: 3.6±0.4 and AVP: 1-1±0.2 pmol/g wet tissue). Immunohistochemical staining of consecutive sections of the tumour indicated that staining of tumour cells for the different peptides was not uniform and although some cells co-stained with CRH and AVP, POMC-positive cells appeared to be distinct from CRH and AVP cells. Tumour extracts were chromatographed on Sephadex G-75 and fractions monitored for POMC derived peptides. A single peak with characteristics of α-MSH was detected. The ACTH, N-POMC and β-LPH/endorphin radioimmunoassays (RIA) detected a peak at large molecular weight, eluting at the position expected for POMC. These RIA systems also revealed an ACTH(1-39) peak and another peak which probably correspond to 13 kDa ACTH, a peak eluting at the position of hN-POMC(1-48), a β-LPH-like peak, and a smaller sized peak which may represent α or γ-endorphin. The ACTH, N-POMC and β-LPH/endorphin contents of anterior lobe (AL) extracts, but not neutrointermediate lobe (NIL) extracts, showed a striking decrease in tumour-bearing (TB) nude mice. However, while no difference was seen in the α-MSH content of AL extract between TB and control (C) nude mice, it decreased in NIL extracts of TB animals. The contents of CRH and AVP in stalk—median eminence extracts of TB nude mice was significantly lower than that of C nude mice. Basal plasma corticosteroids were raised in TB nude mice at levels comparable to those in stressed C nude mice, and although adrenal weights did not vary between TB and C nude mice, morphological changes indicating hypertrophy were found in the adrenal glands of the host animals. It was concluded that the tumour dramatically alters the hypothalamo—pituitary—adrenal axis of the host, and that it may be a useful model for studying tumour—host interactions in ectopic hormone-producing tumours.