**4. Diagnostic and therapeutic values**

Overexpression of particular CS chains can be used to develop diagnostic tests predicting tumor behavior or for prognostic purposes. In this regard, further attempts should be made to link the expression of a combination of genes that define GAG remodeling to the initiation and outcome of the disease in clinical setting.

Expression of CS can also be used for drug delivery purposes. Polyethylene glycol coated liposomes, containing a cationic lipid with CS specificity were used to deliver cisplatin to metastatic tumor cells (Lee et al., 2002). The cisplatin loaded CS-reactive liposomes suppressed metastatic spread of the murine osteosarcoma cells to the liver.

We have shown CS interactions with P-selectin and the significance of P-selectin binding in metastasis of a murine mammary cell line (Monzavi-Karbassi et al., 2007). Our findings support the concept that CS chains promote survival in the circulation, and tumor cell extravasation via P-selectin-mediated binding to platelets and endothelial cells. Using heparin to block P-selectin binding to tumor cells as anti-metastatic therapy has been the subject of many studies (Borsig et al., 2001; Stevenson et al., 2005). However, blocking Pselectin action through the inhibition of binding to its many ligands may affect cellular immunity that could be a tumor friendly side effect of a potential treatment. To avoid unfavorable impact of such a treatment on lymphocyte trafficking and infiltration, targeting relevant tumor-specific P-selectin ligands should be prioritized as an alternative long-term therapeutic strategy for aggressive breast cancer.

To develop therapeutics targeting CS entity we envision three major strategies. 1) Targeting particular CS types through blocking the expression of particular CS structures or the usage of small molecules, is supposed to attenuate metastasis efficiency. In this category, blocking the expression of a key sulfotransferase with siRNA may be considered a potential therapeutic approach at this point. Development of small molecules with fine specificity can also be proposed for blocking particular isomers of CS with reactive molecules. 2) Specific targeting of a prominent CS-carrying PG with definite impact on tumor progression and metastasis. CSPG4 is considered a prominent CSPG with a tumor promoting role. MAb targeting CSPG4 have been developed in melanoma and testing them for treatment of patients with aggressive breast cancer falls in line with our data (Wang et al., 2010a; Wang et al., 2010b). However, targeting a core protein may bring in specificity issues as these PGs are also expressed in stroma. Additionally, tumor cells can escape treatment by immune editing and replacing a PG with another one. 3) Targeting a combination of sugar and PG that can be accomplished by simultaneous targeting of the core protein and the polysaccharide, or by developing reagents like mAb specific for the whole entity (polysaccharide and the core protein).
