Control of the Hyaluronidase Activity Towards Hyaluronan by Formation of Electrostatic Complexes: Fundamental and Application Relevance - Natural Polymers, Biopolymers, Biomaterials, and Their Composites, Blends, and IPNs - page 145

CoNClusioN
The main conclusion of our study of the HA/HAase system is that the HA hydrolysis
catalyzed by HAase is strongly modulated by the formation of electrostatic complexes.
Indeed, on one hand, polyanions, such as HA, other GAGs and synthetic polyanions,
by forming electrostatic complexes with HAase, can suppress its enzymatic activity. In
such a case, HAase is present but is catalytically inactive. On the other hand, polyca-
tions, such as proteins or synthetic polycations, able to compete with HAase for the
formation of electrostatic complexes with HA, can either enhance or suppress HAase
activity according to their concentration. At rather low concentrations, by preventing
HAase to undergo electrostatic complex formation with HA, polycations allow HAase
to be free and thus active. At high concentrations, the electrostatic HA-polycation
complexes are too much dense to allow the formation of catalytic complexes between
HA and HAase. In that case, while HAase is present and catalytically active, no HAase
activity can be detected. Moreover, it should be noted that, as shown in the present
study, the modulation of the HAase activity by formation of electrostatic complexes
can occur in a large pH domain, including pH 7, and at an ionic strength at least equal
to 0.15 mol l -1 , ionic strength value usually considered as the physiological one.
The role played by the formation of electrostatic complexes involving either HA
or HAase or both in the behavior of the HA/HAase system allows to explain some
of the difficulties encountered in attempts to detect HAase activity and some of the
discrepancies in the results obtained when quantifying and characterizing the HAase
activity. This knowledge about the behavior of the HA/HAase system should be useful
for improving the selection of the experimental conditions used to detect, quantify and
characterize the HAase activity. Concerning the use of HAase, we showed that this
knowledge was really useful for developing efficient enzymatic methods allowing us
to produce HA fragments of well-defined size.
The results described in the present report also allow to suggest that the process
of enhancement/suppression of the HAase activity by formation of electrostatic com-
plexes could be of importance in vivo , as for example, in cancer invasion. Indeed, it
was shown that the activity of a human tumoral HAase can be either enhance or sup-
press by a hyaladherin according to its concentration. Through the data related to the
levels of HAase, HA, and the considered hyaladherin in tumors, this result was well
correlated to tumor aggressiveness. Similar correlations, between tumor invasion and
hyaladherin levels, were also established for several other hyaladherins. According
to these results, rather low levels of hyaladherins would thus allow HAase to be
able to produce angiogenic HA fragments required for tumor progression, while high
levels of hyaladherins would suppress HAase activity and prevent tumor progession.
If hyaladherins play such a role in the control of tumoral HAase activity and, as a
consequence, in tumor progression, they could constitute the basis of new therapeutic
possibilities.