chondroitin-sulfates and Carcinogenesis

Considering the high mortality of ovarian cancer, novel approaches for diagnostics and therapy are urgently needed. Cancer initiation, progression, and invasion occur in a complex and dynamic microenvironment which depends on the interplay between host cell responses and tumor activity. Chondroitin sulfate (CS), a special highly sulfated sugar, forms an important intermediate player in this respect. Depending on the (micro)structural diversity of chondroitin sulfate chains, various ligands interact with this special group of glycosaminoglycans, making it a key molecule for many physiological and pathological processes, including cancer development. This review focuses on the various functions of chondroitin sulfate in tumor growth, angiogenesis, dissemination and immunosilencing of ovarian cancer. We also shed light on possible future diagnostic and therapeutic modalities for ovarian cancer based on the large variety in chondroitin sulfate microstructure and function. It is concluded that the class of chondroitin sulfate represents an attractive target to interfere with the process of ovarian tumorigenesis.

Topics: Carcinogenesis; Cell Adhesion; Cell Movement; Chondroitin Sulfates; Extracellular Matrix; Female; Glycosaminoglycans; Humans; Neoplasm Invasiveness; Neovascularization, Pathologic; Ovarian Neoplasms; Tumor Escape

Expression of the glycosaminoglycan chondroitin sulfate-E (CS-E) is misregulated in many human cancers, including breast cancer. Cell-surface associated CS-E has been shown to have pro-tumorigenic functions, and pharmacological treatment with exogenous CS-E has been proposed to interfere with tumor progression mediated by endogenous CS-E. However, the effects of exogenous CS-E on breast cancer cell behavior, and the molecular mechanisms deployed by CS-E are not well understood. We show here that treatment with CS-E, but not other chondroitin forms, could interfere with the invasive protrusion formation and migration of breast cancer cells in three-dimensional organotypic cultures. Microarray analysis identified transcriptional programs controlled by CS-E in these cells. Importantly, negative regulation of the pro-metastatic extracellular matrix gene Col1a1 was required for the anti-migratory effects of exogenous CS-E. Knock-down of Col1a1 gene expression mimics the effects of CS-E treatment, while exposing cells to a preformed collagen I matrix interfered with the anti-migratory effects of CS-E. In addition, CS-E specifically interfered with Wnt/beta-catenin signaling, a known pro-tumorigenic pathway. Lastly, we demonstrate that Col1a1 is a positively regulated target gene of the Wnt/beta-catenin pathway in breast cancer cells. Together, our data identify treatment with exogenous CS-E as negative regulatory mechanism of breast cancer cell motility through interference with a pro-tumorigenic Wnt/beta-catenin-Collagen I axis.

Topics: Animals; beta Catenin; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chondroitin Sulfates; Collagen Type I; Collagen Type I, alpha 1 Chain; Down-Regulation; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Mammary Neoplasms, Animal; Mice; Neoplasm Invasiveness; Oligonucleotide Array Sequence Analysis; Reproducibility of Results; RNA, Messenger; Signal Transduction; Wnt Proteins