Heparan Sulfate Proteoglycans in Human Colorectal Cancer

Abstract

Colorectal cancer is the third most common cancer worldwide, accounting for more than 610,000 mortalities every year. Prognosis of patients is highly dependent on the disease stage at diagnosis. Therefore, it is crucial to investigate molecules involved in colorectal cancer tumorigenesis, with possible use as tumor markers. Heparan sulfate proteoglycans are complex molecules present in the cell membrane and extracellular matrix, which play vital roles in cell adhesion, migration, proliferation, and signaling pathways. In colorectal cancer, the cell surface proteoglycan syndecan-2 is upregulated and increases cell migration. Moreover, expression of syndecan-1 and syndecan-4, generally antitumor molecules, is reduced. Levels of glypicans and perlecan are also altered in colorectal cancer; however, their role in tumor progression is not fully understood. In addition, studies have reported increased heparan sulfate remodeling enzymes, as the endosulfatases. Therefore, heparan sulfate proteoglycans are candidate molecules to clarify colorectal cancer tumorigenesis, as well as important targets to therapy and diagnosis.

Figure 1

Putative model of the functions of HSPGs in CRC cells. The cell surface HSPG syndecan-2 (Syn-2) is upregulated and promotes cancer cell adhesion, proliferation, migration, and metastasis. Syndecan-1 and syndecan-4 (Syn-1; Syn-4), generally antitumor molecules, are reduced in colon carcinoma cells. The cell surface HSPG glypican-1 (Gly-1) is increased in CRC and is involved in tumor progression. The augmentation of matrix HSPG perlecan favors angiogenesis and tumor growth. The SULF enzymes are upregulated, and the edition of HS chains promotes proliferation and invasion of CRC cells. In addition, SULFs release growth factors that were bound to HS, stimulating the Wnt signaling pathway and the activation of β-catenin.

Figure 2

Expression of syndecan-2 (Syn-2) in normal colorectal cell line (CCD 841 CoN), in nonmetastatic CRC cell line CACO-2, and in high metastatic CRC cell line HCT-116. Immunostaining (red) was detected using an antibody specific for syndecan-2 (Santa Cruz) and an Alexa Fluor 594-labeled secondary antibody. Cell nuclei were stained with DAPI (blue). Images were obtained using a confocal a microscope Leica Microsystems TCS SP8 and analyzed by software LAS-AF.

Figure 3

Expression of SULF1 and SULF2 in CRC tissue sample. Immunostaining was detected using an antibody specific for SULF1 or SULF2 (Santa Cruz) and HRP peroxidase/DAB reaction. Tissue samples were stained after with hematoxylin. Images were obtained using a Nikon Eclipse microscope.