Cancer is a leading cause of mortality within the aging European population. Therapeutic targeting is hampered by the complexity of the disease, which includes not only molecular changes within the tumor cell itself, but also within its microenvironment. Tumor angiogenesis, tumor-stroma interactions, interactions with immune cells, with the extracellular matrix and cancer stem cell niches allow for malignant cell survival and promote metastasis, the leading cause for cancer-associated mortality. Proteoglycans (PGs) and glycosaminoglycans (GAGs) – structurally diverse carbohydrates of the extracellular matrix and cell surfaces - have emerged as novel biomarkers and molecular players both within tumor cells and their microenvironment, as they integrate signals from growth factors, chemokines and integrins, and cell-cell as well as matrix adhesion. Importantly, their expression is dysregulated in numerous tumor entities, and has been shown to modulate each of the hallmarks of cancer as defined by Hanahan and Weinberg (Cell 2011). We hypothesize that dysregulated function of PGs and GAGs simultaneously affects all molecular steps towards cancer metastasis as a general principle applicable to multiple tumor entities. Pharmacological modulation of their function thus emerges as an attractive multitargeted antitumoral approach which simultaneously acts at multiple levels of disease progression. Besides providing extensive knowledge transfer and training for researchers, the combined expertise of the GLYCANC consortium aims at performing a detailed structural analysis of PG and GAG glycans in disease using state-of-the art methodology, analysing their regulation via epigenetic mechanisms and microRNAs, and elucidating molecular mechanisms underlying aberrant PG and GAG function. GLYCANC will lead to a deeper understanding of glycan structures and glycan-dependent mechanisms promoting cancer progression, providing the basis for rational multitargeted anticancer approaches.
Pathogenetic involvement of PGs in the hallmarks of cancer (see Ibrahim SA et al. FEBS J 2014 for detailed information). Dysregulated expression of PGs modulates several key events in tumor progression, the so-called hallmarks of cancer. (1) As classical co-receptors for receptor tyrosine kinases, they can sustain and enhance proliferative signaling. (2) Proteoglycans are capable of modulating TGFbeta signaling, thus influencing the process of evading growth suppression. (3) Decorin, syndecan-1 and additional PGs modulate signaling pathways that lead to a resistance to cell death. (4) The HSPG syndecan-1 has been implicated in modulating a cancer stem cell phenotype, which is linked to its role in wnt-signaling. Enhanced stemness contributes to replicative immortality. (5) Several PG families and the HS-degrading enzyme heparanase are capable of regulating tumor angiogenesis, by sequestering angiogenic factors, by promoting their release and receptor interactions. (6) PGs modulate tumor cell invasion and metastasis by regulating the activity of ECM degrading enzymes such as MMPs and heparanase, by promoting integrin-associated signaling pathways, which enhance cell motility, by enhancing the activity of chemokines as coreceptors, by influencing tumor cell-endothelial cell interactions, and by modulating the proinvasive process of EMT. These functions are closely linked to the tumor microenvironment and to a regulatory role of PGs in inflammation.