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Lee and Welch (1997b) attributed the peptide with the ability to regulate cell-sub-
stratum adhesion possibly involving cytoskeletal proteins. Loss of both receptor and
gene expression was reported to relate to and predictive of the presence of lymph
node metastases (Ikeguchi et al., 2004) who also pointed out their potential clini-
cal value. Recently, Kisspeptin-10 has been found to inhibit osteotropic invasion of
breast cancers carrying GPCR54 (Olbrich et al., 2010). The metastasis and invasion
suppressor function has been attributed to the suppression of expression of MMPs
(Bilban et al., 2004; Hesling et al., 2004; Yan et al., 2001). At the phenotypic level,
Kisseptin can inhibit invasive behaviour by inhibiting the DNA-binding activity of
NF-κB and leading to a loss of MMP activity (Takeda et al., 2012). The inhibition of
migration occurs via paxillin focal adhesion protein, FAK, MAPK and Rho A media-
tion. The focal adhesions and stress fibres induced by Kisseptin are inhibited by Rho
kinases inhibitors (Shoji et al., 2009, 2010).
Historically, loss of Kisseptin with associated progression to the metastatic state
has been reported in many human neoplasms (Shoji et al., 2010). Compatibly, its
expression in metastatic tumours is downregulated in comparison with the corre-
sponding primary tumours. More recently patients with endometrial cancers with
high expression of GPCR54 showed higher overall survival and GPR54 expression
was related to FIGO (International Federation of Gynecology and Obstetrics) stage
and grade and myometrial invasion (Kang et al., 2011b). Earlier Nagai et al. (2009)
had identified pancreatic tumours expressing Kisseptin with less frequent recurrence.
High expression of the ligand and GPCR54 was predictive of significantly longer
survival. But many dissenting voices have also been heard. No differences have been
found in serum Kisseptin between normal subjects and NSCLC patients and between
patients with and without metastatic disease (Karapanagiotou et al., 2011). Indeed,
plasma levels were similar in prostate cancer patients and in gastric and pancreatic
cancer plasma levels were higher than in normal subjects (Curtis et al., 2010; Ergen
et al., 2012; Katagiri et al., 2009).
Kisseptin in Clinical Medicine
Some clinical trials involving the administration of kisspeptin 112-121 are currently
being carried out to examine its effectiveness in subjects with reproductive disor-
ders. Kisseptin agonists TAK-448 and TAK-683 have been developed for evaluation
and are currently being tested for tolerability, toxicity and pharmacological features.
Both these analogues have been tested in animal models for their biological proper-
ties, for example responsiveness of hypothalamic gonadotoropin-releasing hormone
(GnRH) neurons (Matsui et al., 2010). Scott et al. (2013) have successfully tested
TAK-683 for tolerability by normal subjects.
With the present background of the biology of the gene, possibly it would be pre-
mature to expect similar clinical trials with cancer patients. Whilst the primary target
is clearly defined by various studies, we are at the observation stage rather than one of
active intervention. In any event, this has to be preceded by both
in vitro
and
in vivo
testing. It would also be helpful to address the question of potential secondary targets.
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