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Aberrant activation of hedgehog (Hh) signaling has been observed in a wide variety of tumors and accounts for more than 25% of human cancer deaths. Inhibitors targeting the Hh signal transducer Smoothened (SMO) are widely used and display a good initial efficacy in patients suffering from basal cell carcinoma (BCC); however, a large number of patients relapse. Though SMO mutations may explain acquired therapy resistance, a growing body of evidence suggests that the non-canonical, SMO-independent activation of the Hh pathway in BCC patients can also account for this adverse effect. In this review, we highlight the importance of glioma-associated oncogene (GLI) transcription factors (the main downstream effectors of the canonical and the non-canonical Hh cascade) and their putative role in the regulation of multiple oncogenic signaling pathways. Moreover, we discuss the contribution of the Hh signaling to malignant transformation and propose GLIs as central hubs in tumor signaling networks and thus attractive molecular targets in anti-cancer therapies.
The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has uncovered the pivotal functions exerted by the small leucine-rich proteoglycans, decorin and biglycan, in affecting tumor growth and progression. In their soluble forms, decorin and biglycan act as powerful signaling molecules. By receptor-mediated signal transduction, both proteoglycans modulate key processes vital for tumor initiation and progression, such as autophagy, inflammation, cell-cycle, apoptosis, and angiogenesis. Despite of their structural homology, these two proteoglycans interact with distinct cell surface receptors and thus modulate distinct signaling pathways that ultimately affect cancer development. In this review, we summarize growing evidence for the complex roles of decorin and biglycan signaling in tumor biology and address potential novel therapeutic implications.
In this comprehensive review, we will dissect the impact of research on proteoglycans focusing on recent developments involved in their synthesis, degradation, and interactions, while critically assessing their usefulness in various biological processes. The emerging roles of proteoglycans in global infections, specifically the SARS-CoV-2 pandemic, and their rising functions in regenerative medicine and biomaterial science have significantly affected our current view of proteoglycans and related compounds. The roles of proteoglycans in cancer biology and their potential use as a next-generation protein-based adjuvant therapy to combat cancer is also emerging as a constructive and potentially beneficial therapeutic strategy. We will discuss the role of proteoglycans in selected and emerging areas of proteoglycan science, such as neurodegenerative diseases, autophagy, angiogenesis, cancer, infections and their impact on mammalian diseases.