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 142

Involvement of HA and HAase in Cancer: The Role of HA Binding Proteins
For several years, the involvement of the HA/HAase system in cancer have been the
subject of many research works. Indeed, many reports indicate elevated levels of both
HA and HAase in several tumors including carcinomas of the breast, colon, prostate,
bladder, lung, and ovary (Auvinen et al., 2000; Bertrand et al., 1997; Hautmann et al.,
2001; Lokeshwar and Selzer, 2008; Lokeshwar et al., 1996; Paiva et al., 2005; Simp-
son, 2006; Stern, 2008). According to various results, HA and HAase are involved
in cancer progression and invasion. Elevated levels of HAase in tumor are often cor-
related to tumor aggressiveness (Bertrand et al., 1997; Kovar et al., 2006; Lokeshwar
and Selzer, 2008; Lokeshwar et al., 1996; Stern, 2008). The activity of HAase is higher
in the most invasive forms of cancer and metastases than in primary tumors (Bertrand
et al., 1997; Delpech et al., 2002). For example, HAase activity is more elevated in
brain metastases than in primary tumors of the brain (Delpech et al., 2002). Identical
differences are found when primary breast tumors are compared to node or muscle me-
tastases of breast tumors (Bertrand et al., 1997). Moreover, cancer cells, which regu-
larly produce metastases when grafted to nude mice, are cells that produce high HAase
activity in culture (Delpech et al., 2001). Conversely, cell lines that do not express
HAase activity do not produce metastases when grafted to nude mice. Quantification
of HA in human breast carcinomas showed that it is significantly predominant in the
peripheral invasive area of the tumor (Bertrand et al., 1992). In addition, angiogenic
HA fragments were found in the saliva of patients with head and neck squamous cell
carcinoma, in the urine of patients with high-grade bladder cancer and in the tissue
extracts of high-grade prostate tumors (Franzmann et al., 2003; Lokeshwar and Selzer,
2008). All these results strongly suggest that the HA/HAase system plays an active
role in tissue invasion by cancer cells. The role of HAase in tumor invasion could be
related to the angiogenic switch (Folkman, 2002): high molar mass HA could form a
hydrated HA matrix appropriate for tumor cell attachment and enabling the flow of
nutriments at the primary site. When simple diffusion becomes no longer sufficient,
HAase activity generates angiogenic HA fragments that induce the neovascularization
required for tumor progression.
In order to investigate the behavior of a tumoral HAase as compared to that we
observed for BT-HAase, we performed experiments with a human cancer cell HAase
(H460M-HAase) purified from cultures of a lung carcinoma cell line (H460M) by
Delpech and his collaborators (Maingonnat et al., 1999). The substrate-dependence
curve obtained with the H460M-HAase (Figure 13) had exactly the same atypical
shape as that obtained with BT-HAase in the presence of 0.15 mol l -1 ionic strength
(Figure 4). This strongly suggests that, like BT-HAase, H460M-HAase has the abil-
ity to form electrostatic complexes with HA in which it is catalytically inactive. As a
consequence, the H460M-HAase activity decreases as the ratio of the H460M-HAase
concentration over the HA concentration is decreased. According to these results, with
a high HA concentration, as found in tumor tissues (Auvinen et al., 2000; Hautmann et
al., 2001; Paiva et al., 2005; Simpson, 2006), a high HAase level is required to obtain
a significant HAase activity.