Biomedical Engineering Reference
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to its concentration, HN was able to either enhance or suppress the H460M-HAase
activity (Maingonnat et al., 1999). In other words, it means that a hyaladherin behave
exactly in the same way as a polycationic non-catalytic protein, such as BSA, with
respect to the enzymatic activity of a human tumoral HAase towards HA.
When studying HN, Delpech and his collaborators also obtained interesting results
about the involvement of HN in tumors. They found that HN concentrations were
lower (i) in invasive tumors and metastases as compared to poorly-invasive tumors
(Delpech et al., 1993) and (ii) in invasive peripheral areas than in the central areas of
breast cancer (Bertrand et al., 1992). Similarly, using H460M cells transfected by hu-
man HN cDNA, it was shown that the HN-rich clones developed much fewer metas-
tases than HN-poor clones (Paris et al., 2006). In addition, HN was shown to be able
to reduce the tumor growth rate of grafted human glioblastoma, while it was unable
to do so when previously heat-inactivated so that it was unable to bind HA (Girard et
al., 2000).
Altogether these results strongly suggest that, at rather low concentration, by form-
ing complexes with HA, HN could prevent the formation of electrostatic complexes
between HA and tumoral HAase and thus, enable tumoral HAase to be active. HA
hydrolysis catalyzed by tumoral HAase would thus generate angiogenic HA fragments
which in turn would enhance tumor progression. On the contrary, high levels of HN,
leading to the formation of dense HA-HN complexes, would hinder tumoral HAase
accessibility to HA b(1,4) bonds. Under such conditions, even though tumoral HAase
would be present, it could not catalyze HA hydrolysis and, as a consequence, tumor
progression would be reduced. So, by modulating tumoral HAase activity through the
formation of HA-HN complexes, HN could act either as a promoter of tumor growth
and metastasis or as a metastatic spread suppressor.
The HN is not the only protein that can play a role in the HAase hydrolytic activ-
ity associated with tumor progression. Indeed, like HN, metastatin, and HA-binding
complex from cartilage, inhibited angiogenesis, tumor growth, and metastasis (Liu et
al., 2001). These inhibitions were not observed with heat-inactivated metastatin and
with metastatin preincubated with HA, which suggests that metastatin must bind to
HA to exhibit inhibition. In addition, it was shown that the binding of the link protein
on HA molecules of the proteoglycan aggregates from cartilage protected HA from
degradation by HAase (Rodriguez and Roughley, 2006). Inhibition of tumor growth
and metastasis was also reported with the soluble form of CD44 and RHAMM. Over-
expression of soluble CD44 in mouse mammary carcinoma cells or in human malig-
nant melanoma cells led
in vivo
to inhibition of growth, local invasion and metastasis,
while no significant effects were obtained if the soluble CD44 was mutated such that
it could not bind to HA (Toole, 2002). All these results strongly support the idea that
binding of various proteins to HA can control its hydrolysis catalyzed by HAase and
thus are involved in the aggressiveness of tumors. Indeed, tumor progression and me-
tastasis is dependent on the HA size distribution, which is related to HAase activity,
and, according to our results, the HAase activity is itself dependent on the relative
levels of HA, HAase and proteins.
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