Cancer is an important cause of morbidity and mortality worldwide. Advances in research on the biology of cancer revealed alterations in several key pathways underlying tumorigenesis and provided molecular targets for developing new and improved existing therapies. Syndecan-4, a transmembrane heparan sulfate proteoglycan, is a central mediator of cell adhesion, migration and proliferation. Although several studies have demonstrated important roles of syndecan-4 in cell behavior and its interactions with growth factors, extracellular matrix (ECM) molecules and cytoskeletal signaling proteins, less is known about its role and expression in multiple cancer. The data summarized in this review demonstrate that high expression of syndecan-4 is an unfavorable biomarker for estrogen receptor-negative breast cancer, glioma, liver cancer, melanoma, osteosarcoma, papillary thyroid carcinoma and testicular, kidney and bladder cancer. In contrast, in neuroblastoma and colorectal cancer, syndecan-4 is downregulated. Interestingly, syndecan-4 expression is modulated by anticancer drugs. It is upregulated upon treatment with zoledronate and this effect reduces invasion of breast cancer cells. In our recent work, we demonstrated that the syndecan-4 level was reduced after trastuzumab treatment. Similarly, syndecan-4 levels are also reduced after panitumumab treatment. Together, the data found suggest that syndecan-4 level is crucial for understanding the changes involving in malignant transformation, and also demonstrate that syndecan-4 emerges as an important target for cancer therapy and diagnosis.

Heparan sulfate proteoglycans (HSPGs) play important roles in cancer initiation and progression, by interacting with the signaling pathways that affect proliferation, adhesion, invasion and angiogenesis. These roles suggest the possibility of various strategies of regulation of these molecules. In this review, we demonstrated that the anticancer drugs can regulate the heparan sulfate proteoglycans activity in different ways: some act directly in core protein, and can bind to a specific type of HSPG. Others drugs interact with glycosaminoglycans chains, and others can act directly in enzymes that regulate HSPGs levels. We also demonstrated that the HSPGs drug targets can be divided into four groups: monoclonal antibodies, antitumor antibiotic, natural products, and mimetics peptide. Interestingly, many drugs demonstrated in this review are approved by FDA and is used in cancer therapy (Food and Drug Administration) like trastuzumab, panitumumab, bleomycin and bisphosphonate zoledronic acid (ASCO) or are in clinical trials like codrituzumab and genistein. This review should help researchers to understand the mechanism of action of anticancer drugs existing and also may inspire the discovery of new drugs that regulate the heparan sulfate proteoglycans activity.

Anoikis is a form of programmed cell death induced by loss of contact from neighboring cells or from their extracellular matrix (ECM). Many tumorigenic cells are anoikis resistant, facilitating cancer progression and metastasis. Trastuzumab is a monoclonal antibody used for the treatment of breast and gastric cell cancer, but its mechanism of action is not well elucidated and its target molecules not well defined. Heparan sulfate proteoglycans (HSPGs) and glycosaminoglycans (GAGs) play important roles in tumor development and in response of cancer cells to drugs. This study investigates the effect of trastuzumab on the expression of HSPGs and sulfated glycosaminoglycans (SGAGs) in anoikis-resistant endothelial cells. After trastuzumab treatment, endothelial cells resistant to anoikis show an increase in adhesion to fibronectin followed by a decrease in invasion, proliferation, and angiogenic capacity. In addition, a significant increase in the number of cells in the S phase of the cell cycle was also observed. In relation to HSPGs and SGAGs expression, we observed a decrease in syndecan-4 and perlecan expression, as well as in the heparan sulfate biosynthesis in anoikis-resistant endothelial cells after exposure to trastuzumab. Our results suggest that trastuzumab interacts with GAGs and proteoglycans of the cell surface and ECM and through this interaction controls cellular events in anoikis-resistant endothelial cells. K E Y W O R D Sanoikis, cancer, heparan sulfate proteoglycans, sulfated glycosaminoglycans, trastuzumab

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