Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions. Aberrant glycosylation can lead to... Show moreGlycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions. Aberrant glycosylation can lead to uncontrolled cell proliferation, cell-matrix interactions, migration and differentiation, and has been shown to be involved in cancer and other diseases. The epithelial-to-mesenchymal transition is a key step in the metastatic process by which cancer cells gain the ability to invade tissues and extravasate into the bloodstream. This cellular transformation process, which is associated by morphological change, loss of epithelial traits and gain of mesenchymal markers, is triggered by the secreted cytokine transforming growth factor-beta (TGF-beta). TGF-beta bioactivity is carefully regulated, and its effects on cells are mediated by its receptors on the cell surface. In this review, we first provide a brief overview of major types of glycans, namely,N-glycans,O-glycans, glycosphingolipids and glycosaminoglycans that are involved in cancer progression. Thereafter, we summarize studies on how the glycosylation of TGF-beta signaling components regulates TGF-beta secretion, bioavailability and TGF-beta receptor function. Then, we review glycosylation changes associated with TGF-beta-induced epithelial-to-mesenchymal transition in cancer. Identifying and understanding the mechanisms by which glycosylation affects TGF-beta signaling and downstream biological responses will facilitate the identification of glycans as biomarkers and enable novel therapeutic approaches. Show less
Transforming growth factor (TGF)-beta is a secreted multifunctional cytokine that signals via plasma membrane TGF-beta type I and type II receptors and intercellular SMAD transcriptional effectors.... Show moreTransforming growth factor (TGF)-beta is a secreted multifunctional cytokine that signals via plasma membrane TGF-beta type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-beta signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-beta can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-beta in cancer cells are blocked, TGF-beta signaling can act as tumor promoter by its ability to stimulate epithelial-to-mesenchymal transition of cancer cells, by stimulating angiogenesis, and by promoting evasion of immune responses. In this review, we will discuss the rationale and challenges of targeting TGF-beta signaling in cancer and summarize the clinical status of TGF-beta signaling inhibitors that interfere with TGF-beta bioavailability, TGF-beta/receptor interaction, or TGF-beta receptor kinase function. Moreover, we will discuss targeting of TGF-beta signaling modulators and downstream effectors as well as alternative approaches by using promising technologies that may lead to entirely new classes of drugs. Show less
