doi: 10.1006/ scbi.2000.0303, available online at http:/ / www.idealibrary.com on seminars in CANCER BIOLOGY, Vol. 10, 2000: pp. 15–23 Histamine as an autocrine growth factor: an unusual role for a widespread mediator Elena S. Rivera a , ∗ , Graciela P. Cricco a , Nora I. Engel b , Carlos P. Fitzsimons a , Gabriela A. Mart´ ın a and Rosa M. Bergoc a The involvement of histamine in cancer growth represents an old controversy and direct experimental evidence proving this hypothesis is not still available. In this paper we review the most relevant mechanisms referring to the role of histamine receptors, histidinedecarboxylaseand histaminereleasein the onset of an autocrine loop, that enables histamine to act as an autocrine growth factor. We postulate that this autocrine loop, that has been studied in an experimental mammary carcinoma model induced in rats, may be present in different human neoplasias. Therefore, thebetter understanding of this novel regulatory pathway that is controlled by histamine may contribute to identifying new therapeutic targets. Key words: histamine / histamine receptors / histidine decarboxylase (HDC) / growth factors / NMU-induced carcinomas c  2000 Academic Press Introduction Histamine is so widely distributed in the animal and plant kingdoms, and its effects are so pleiotropic, that there has been a long-standing effort to describe its role in pathological, and more recently, in physiolog- ical processes. The hypothesis that histamine could be involved in cell proliferation was postulated manyyears ago 1, 2 and it still remains controversial. Many investigations From the a Laboratory of Radioisotopes and b Laboratory of Genetic and Molecular Biology, University of Buenos Aires, School of Pharmacy and Biochemistry, Junin 956 PB, 1113 Buenos Aires, Argentina. *Corresponding author. c 2000 Academic Press 1044–579X / 00 / 000015+ 09 / $35.00 / 0 related histamine to cell proliferation and tumor growth, attributing this action to different physiologi- cal functions. Biological functions of mast cells, which are a rich source of histamine, appear to include modulation of the immune system, tissue repair and angiogenesis, 3 a critical step for tumor progression and invasion. The described function for histamine in cytokine-mediated regulation of inflammatoryand immune cascades, 4 has led manyauthors to postulate that the therapeutic action of H 2 antagonistsreported in patients with different neoplasias is due to their capacity to stimulate immune response. 5 The fact that histamine is a widespread mediator virtually ubiquitous in the tissues and body fluids makes the state-of-the art a complex situation. The interesting observation that histamine synthe- sis can be induced and made available in an unstored diffusible form in tissues undergoing rapid growth or repair, suggested additional physiological roles for this biogenic amine. 1, 6 Furthermore, high histamine biosynthesis and content has been reported in differ- ent human malignant tissuesaswellasin experimental tumors induced in rodents. 2, 7, 8 Histamine receptors are expressed in multiple malignant cell types, with the additional finding that theycan activate multiple signalling pathways. 6, 9 All these data support the hypothesis that histamine and its receptors maybe involved in cell growth. The question is: do these changes genuinely contribute to malignancy or are they simply by-products of the process? This review focuses on our studies of the role of histamine as an autocrine growth factor in an experimental model of mammary adenocarcinoma induced in rats by ip administration of N -nitroso-N - methylurea (NMU) 10, 11 and the possible expression of this autocrine regulation loop in different human neoplasias. 15