Little is known about the molecular mechanisms that control adrenomedullin (AM) production in human cancers. We demonstrate here that the expression of AM mRNA in a variety of human tumor cell lines is highly induced in a time-dependent manner by reduced oxygen tension (

Objective: Our aim was to validate the prognostic relevance in NSCLC of potential residual tumor (R) descriptors, including the proposed International Association for the Study of Lung Cancer definition for uncertain resection, referred to as R(un).Methods: A total of 14,712 patients undergoing resection with full R status and survival were analyzed. The following were also evaluated: whether fewer than three N2 stations

Harnessing the immune system by blocking the programmed cell death protein 1 (PD-1) pathway has been a major breakthrough in non-small-cell lung cancer treatment. Nonetheless, many patients fail to respond to PD-1 inhibition. Using three syngeneic models, we demonstrate that short-term starvation synergizes with PD-1 blockade to inhibit lung cancer progression and metastasis. This antitumor activity was linked to a reduction in circulating insulin-like growth factor 1 (IGF-1) and a downregulation of IGF-1 receptor (IGF-1R) signaling in tumor cells. A combined inhibition of IGF-1R and PD-1 synergistically reduced tumor growth in mice. This effect required CD8 cells, boosted the intratumoral CD8/T reg ratio and led to the development of tumor-specific immunity. In patients with non-small-cell lung cancer, high plasma levels of IGF-1 or high IGF-1R expression in tumors was associated with resistance to anti-PD-1-programmed death-ligand 1 immunotherapy. In conclusion, our data strongly support the clinical evaluation of IGF-1 modulators in combination with PD-1 blockade.

The present study reports the developmental patterns of expression of adrenomedullin (AM) in rat and mouse embryos. AM is a novel multifunctional peptide recently isolated from a human pheochromocytoma, which has been shown to promote growth in a variety of mammalian cell lines. We have applied several techniques to investigate the localization of both the AM peptide and its receptor throughout development. Immunocytochemical detection has been performed using different specific antibodies against AM and its generelated peptide pro-AM N-terminal 20 peptide. In situ hybridization showed the localization of the messenger RNAs for AM and its receptor. Western blot analysis together with reverse transcription-PCR gave further support to the localization of AM and its receptor in a variety of embryonic tissues. The localization of the receptor paralleled that of AM itself, suggesting an autocrine or paracrine mode of action. The spatio-temporal pattern of expression of AM in cardiovascular, neural, and skeletal-forming tissues as well as in the main embryonic internal organs is described. The primitive placenta, especially the giant trophoblastic cells, shows high levels of AM and AM receptor. The heart is the first organ that expresses AM during development. The kidney, lung, and developing tooth, in which epithelial-mesenchymal interactions are taking place, show specific patterns of AM expression. In several regions of the embryo, the patterns of AM expression correspond to the degree of differentiation. The possible involvement of AM in the control of embryonic invasion, proliferation, and differentiation is discussed. (Endocrinology 138: 440 -451, 1997) A DRENOMEDULLIN (AM) is a multifunctional peptide that has been identified from extracts of human pheochromocytoma (18). It is comprised of 52 amino acids and shows slight structural homology with calcitonin gene-related peptide (CGRP). Initial characterization demonstrated AM as a potent mediator of hypotension when injected iv into rats (18). AM and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), are the two known bioactive amidated peptides generated by posttranslational enzymatic processing of the 185-amino acid prepro-AM molecule (19). AM elevates intracellular cAMP levels in several cell types, and a receptor for AM (AM-R) has recently been cloned and sequenced (16). PAMP has no sequence homology with AM or CGRP and seems to act via a different receptor system (30). The expression of AM has been shown in a variety of adult rat, human, and porcine tissues, including heart, adrenals, brain, kidney, pancreas, aorta, lung, and brain-and lung-derived tumors (10,23,24,31).Apart from the vasorelaxant effect, several other functions have been reported for this peptide hormone. AM has been implicated in the regulation of renal function by means of its potent natriuretic and diuretic properties (14), has bronchodilatory effects (15), and inhibits the release of aldosterone, ACTH, and insulin (24,28). Recent data suggest the involv...