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.