J. Endocrinol. Invest. 25: 663-664, 2002
LETTER TO THE EDITOR
The mystery of nm23H1 in thyroid cancer
The product of the nm23 gene was held for a long
time to be an important anti-metastatic factor. We
found, instead, in a group of well-characterized
patients with thyroid carcinomas an increase in
nm23 transcripts, the more advanced the tumor
stage. These findings could not be accounted for
by mutations or amplification of the nm23 gene
loss or indeed subversion of restraining influences
in the process (3, 6).
It turns out that nm23 is an GTP ase-activating protein
of Rad, a small ras-related protein. nm23 is reported
to be specific for Rad, affecting GDPꢂGTP Rad ex-
change by way of its dinucleotide kinase activity. In
turn Rad enhances nm23 enzymatic activity (7).
By contrast to earlier studies Zafon et al. (8) recently
reported not only a significant inverse association
between metastatic disease and nm23 immunore-
activity on thyroid tumor tissue sections but also a
strong evidence for improved survival in those with
greater nm23 expression.
(
1). Our findings were upheld in studies of nm23
protein abundance in thyroid cancer tissues (2).
Furthermore, other studies raised doubts about
the role of nm23 as an anti-metastasis factor as
opposed to its involvement in cell proliferation (3).
Because of these considerations we explored the
roles of nm23 in fetal development as well as a
malignancy-associated factor. We found nm23 not
to be particularly highly expressed in invasive tis-
sues e.g. placenta, early in mouse embryonic de-
velopment. Compared to normal human term pla-
centa cells, the highly metastatic choriocarcinoma
cell line JAR expressed much more nm23 (4).
Moreover, cytokines known to modulate tumor
growth and spread had no influence on JAR nm23
levels (4).
When the nm23 gene was transfected into the
highly malignant and metastatic B16F10 murine
melanoma cell line, there was significant suppres-
sion of invasiveness and metastatic ability of the
melanoma cells and longer survival of tumor- bear-
ing animals (5). Interestingly B16F10 cells trans-
fected with nm23 produced less ICAM-1 than did
non-transfected cells. Treatment of transfected cells
with PGE2, TNFꢀ and INFꢁ resulted in down-regu-
lation of nm23 expression and this was reflected in
the tumor-bearing mice in increased pulmonary
metastases and reduced survival (5).
How can these discrepancies between studies be
accommodated?
Given the tandem regulatory relationship of nm23 to
Rad, it is conceivable that for example an increase in
nm23 expression might be compensatory of a muta-
tion on deletion in Rad, which has now been de-
scribed in some malignancies (9). Moreover, nm23
may also indirectly regulate rac-1, another ras-related
GTPase-regulating protein, and thus the c Jun-kinase
pathway (10), thus adding complexity to the involve-
ment of nm23 in cancer cell proliferation and in con-
stitutive activity conducive to metastatic behavior. It
is also clear that cytokines and other biological me-
diators have an important impact on nm23 expres-
sion and possibly on metastatic potential (5). These
factors and others yet to be uncovered, may cause
variation in the abundance of nm23 transcripts and
protein at the time of tumor resection. As an example,
estrogen acting through its ꢀ-receptor can activate
the transcription of nm23 (11). Is it conceivable that
the thyroid hormone may exercise similar control on
nm23 transcripts?
It thus seemed that nm23, in addition to its metas-
tasis suppressor function, could be involved in mod-
ulating tumor target structure expression, in down-
regulating invasive potential and in the regulation
of adhesion molecules. Disquietingly, some ele-
ments of tumor immunotherapeutic protocols may
have deleterious influence on tumor metastases
suppression mediated by nm23 (5).
We feel strongly that much might be gained from
an in depth study of the characteristics, including
genetic and environmental backgrounds as well as
the pre-surgical treatment schedules, of the pa-
tients donating tumor tissue as well as the molecu-
lar genetic attributes of the tumors, where nm23
abundance appears to show markedly divergent re-
lationship to tumor behavior.
It was thus apparent that the relationship of nm23
to metastatic behavior in thyroid cancer might not
be simple. We speculated that nm23 might be as-
sociated with enhanced malignant cell growth and
the ability to form distant metastases may reflect
Y. Shi, M. Zou and N.R. Farid
Osnacor Biotech Inc., Watford, Herts, U.K.
663
Palkin
