The biology of gonadotropin hormone-releasing hormone: role in the control of tumor growth and progression in humans

It is now well known that different forms of GnRH coexist in the same vertebrate species. In humans, two forms of GnRH have been identified so far. The first form corresponds to the hypophysiotropic decapeptide, and is now called GnRH-I. The second form has been initially identified in the chicken brain, and it is referred to as GnRH-II. GnRH-I binds to and activates specific receptors, belonging to the 7 transmembrane (7TM) domain superfamily, present on pituitary gonadotropes. These receptors (type I GnRH receptors) are coupled to the Gq/11/PLC intracellular signalling pathway. A receptor specific for GnRH-II (type II GnRH receptor) has been identified in non-mammalian vertebrates as well as in primates, but not yet in humans. In the last 10-15 years experimental evidence has been accumulated indicating that GnRH-I is expressed, together with its receptors, in tumors of the reproductive tract (prostate, breast, ovary, and endometrium). In these hormone-related tumors, activation of type I GnRH receptors consistently decreases cell proliferation, mainly by interfering with the mitogenic activity of stimulatory growth factors (e.g., EGF, IGF). Recent data seem to suggest that GnRH-I might also reduce the migratory and invasive capacity of cancer cells, possibly by affecting the expression and/or activity of cell adhesion molecules and of enzymes involved in the remodelling of the extracellular matrix. These observations point to GnRH-I as an autocrine negative regulatory factor on tumor growth progression and metastatization. Extensive research has been performed to clarify the molecular mechanisms underlying the peculiar antitumor activity of GnRH-I. Type I GnRH receptors in hormone-related tumors correspond to those present at the pituitary level in terms of cDNA nucleotide sequence and protein molecular weight, but do not share the same pharmacological profile in terms of binding affinity for the different synthetic GnRH-I analogs. Moreover, the classical intracellular signalling pathway mediating the stimulatory activity of the decapeptide on gonadotropin synthesis and secretion is not involved in its inhibitory activity on hormone-related tumor growth. In these tumors, type I GnRH receptors are coupled to the Gi-cAMP, rather than the Gq/11-PLC, signal transduction pathway. Recently, we have reported that GnRH-I and type I GnRH receptors are expressed also in tumors not related to the reproductive system, such as melanoma. Also in melanoma cells, GnRH-I behaves as a negative regulator of tumor growth and progression. Interestingly, the biochemical and pharmacological profiles of type I GnRH receptors in melanoma seem to correspond to those of the receptors at pituitary level. The data so far reported on the expression and on the possible functions of GnRH-II in humans are still scanty. The decapeptide has been identified, together with a 'putative' type II GnRH receptor, both in the central nervous system and in peripheral structures, such as tissues of the reproductive tract (both normal and tumoral). The specific biological functions of GnRH-II in humans are presently under investigation.