Because earlier studies showed the cell surface
heparan sulfate proteoglycan,
syndecan-2, sheds from
colon cancer cells in culture, the functional roles of shed
syndecan-2 were assessed. A non-cleavable mutant of
syndecan-2 in which the Asn148-Leu149 residues were replaced with Asn148-Ile149, had decreased shedding, less
cancer-associated activities of
syndecan-2 in vitro, and less syndecan-2-mediated
metastasis of mouse
melanoma cells in vivo, suggesting the importance of shedding on syndecan-2-mediated pro-tumorigenic functions. Indeed, shed
syndecan-2 from
cancer-
conditioned media and recombinant shed
syndecan-2 enhanced
cancer-associated activities, and depletion of shed
syndecan-2 abolished these effects. Similarly, shed
syndecan-2 was detected from sera of patients from advanced
carcinoma (625.9 ng/ml) and promoted
cancer-associated activities. Furthermore, a series of
syndecan-2 deletion mutants showed that the tumorigenic activity of shed
syndecan-2 resided in the C-terminus of the extracellular domain and a shed
syndecan-2 synthetic
peptide (16 residues) was sufficient to establish subcutaneous primary growth of HT29
colon cancer cells, pulmonary
metastases (B16F10 cells), and primary intrasplenic
tumor growth and liver
metastases (4T1 cells). Taken together, these results demonstrate that shed
syndecan-2 directly enhances
colon cancer progression and may be a promising therapeutic target for controlling
colon cancer development.