**5. Conclusion**

442 Breast Cancer – Focusing Tumor Microenvironment, Stem Cells and Metastasis

Therefore, relative expression of certain PGs or modification in their GAG chains may affect tumor aggressive phenotype through promoting survival, growth, and the metastatic capability of tumor cells. P-selectin can bind to CS-GAGs of these PGs and binding to each PG can have different functional consequences. These molecules has been linked to motility, invasion, angiogenesis, and cancer stem cell properties. Therefore, depending on the setting and expression of other molecules, P-selectin interaction may lead to various tumor

In studying the role of P-selectin in tumor growth and metastasis in a P-selectin-deficient Rag2-/- background, it was demonstrated that growth of subcutaneously challenged tumor cells were reduced significantly in the absence of P-selectin (Kim et al., 1998). This significantly slower growth rate in P-selectin deficient mice was unexpected because Pselectin is assumed to play a role in leukocytic infiltrates within tumors, which are generally inversely associated with tumor growth (Kreider et al., 1984). These findings, consistent with our hypothesis, demonstrate that the presence of P-selectin ligands on tumor cells and P-selectin-mediated interactions with stroma leads to tumorigenesis and tumor growth

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

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

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

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

suppressed metastatic spread of the murine osteosarcoma cells to the liver.

promoting outcomes.

promotion.

**4. Diagnostic and therapeutic values** 

initiation and outcome of the disease in clinical setting.

therapeutic strategy for aggressive breast cancer.

Breast cancer cell surface CS-GAGs and their interaction with P-selectin should be considered as viable targets for the development of novel diagnostic or therapeutic strategies. Our studies suggest that CS-GAGs, their biosynthetic pathway, or the core protein carrying them, can be potential targets in dealing with aggressive breast tumors. However, in order to efficiently block tumor cell dissemination by interrupting Pselectin/CS interaction, targeting any single PG does not seem to be enough, as other PGs can probably compensate and support metastatic processes. In this regard, global targeting of specific CS isomers, or combined targeting of the glycan and the PG, may be effective approaches.
