Theranostic Applications of Glycosaminoglycans in Metastatic Renal Cell Carcinoma

Abstract

Renal cell carcinoma (RCC) makes up the majority of kidney cancers, with a poor prognosis for metastatic RCC (mRCC). Challenges faced in the management of mRCC, include a lack of reliable prognostic markers and biomarkers for precise monitoring of disease treatment, together with the potential risk of toxicity associated with more recent therapeutic options. Glycosaminoglycans (GAGs) are a class of carbohydrates that can be categorized into four main subclasses, viz., chondroitin sulfate, hyaluronic acid, heparan sulfate and keratan sulfate. GAGs are known to be closely associated with cancer progression and modulation of metastasis by modification of the tumor microenvironment. Alterations of expression, composition and spatiotemporal distribution of GAGs in the extracellular matrix (ECM), dysregulate ECM functions and drive cancer invasion. In this review, we focus on the clinical utility of GAGs as biomarkers for mRCC (which is important for risk stratification and strategizing effective treatment protocols), as well as potential therapeutic targets that could benefit patients afflicted with advanced RCC. Besides GAG-targeted therapies that holds promise in mRCC, other potential strategies include utilizing GAGs as drug carriers and their mimetics to counter cancer progression, and enhance immunotherapy through binding and transducing signals for immune mediators.

Identification of Molecular Mechanisms of Ameloblastoma and Drug Repositioning by Integration of Bioinformatics Analysis and Molecular Docking Simulation

“…Various investigations of PG/GAG in the oral cavity reported either expression or potential involvement of these factors in the progression of oral squamous cell carcinoma and salivary tumors. 21 As for odontogenic tumors, CS PG is widely observed but variably expressed in epithelial nests and stroma of both AM and keratocystic odontogenic tumor, and the keratocystic odontogenic tumors have been renamed odontogenic keratocyst in the 2017 World Health Organization (WHO) classification of head and neck tumors. 22 In our present study, the alterations of PG, heparin sulfate, and glycosaminoglycan were enriched in both GO and KEGG pathway analyses and may be associated with the molecular pathogenesis of AM.…”

Revisiting the Syndecans: Master Signaling Regulators with Prognostic and Targetable Therapeutic Values in Breast Carcinoma

“…However, due to the adverse effects caused by heparin, such as bleeding and thrombocytopenia [ 168 ], intense research studies have been performed to develop heparin analogs or HS mimetics with no anticoagulant activities and fewer side effects. In this regard, and based on the impressive data of their anticancer effects in preclinical models, the HS mimetics muparfostat (PI-88), pixatimod (PG545), and necuparanib (M402) entered clinical trial phases I, II, and III alone or in combined therapy to evaluate their safety and beneficial effects on the survival of a patient with different advanced solid cancers and multiple myeloma (reviewed in [ 165 , 169 ]). The mechanism of action of these HS-mimetics is primarily mediated via inhibition of heparanase-mediated angiogenesis and metastasis, competitive binding with growth factors, and/or activation of tumor-suppressing immune cells (e.g., natural killer and dendritic cells) [ 165 , 169 ].…”

“…In this regard, and based on the impressive data of their anticancer effects in preclinical models, the HS mimetics muparfostat (PI-88), pixatimod (PG545), and necuparanib (M402) entered clinical trial phases I, II, and III alone or in combined therapy to evaluate their safety and beneficial effects on the survival of a patient with different advanced solid cancers and multiple myeloma (reviewed in [ 165 , 169 ]). The mechanism of action of these HS-mimetics is primarily mediated via inhibition of heparanase-mediated angiogenesis and metastasis, competitive binding with growth factors, and/or activation of tumor-suppressing immune cells (e.g., natural killer and dendritic cells) [ 165 , 169 ]. An interesting study showed that in an ex vivo explant model of normal human female mammary tissue, heparanase upregulates the expression and cleavage of SDC1 rather than SDC4, resulting in high mammographic density (a strong and independent risk factor for breast cancer) with a fibrous stroma rich in SDC1.…”

Teaching an Old Drug a New Trick: Targeting Treatment Resistance in Genitourinary Cancers

“…Moreover, while each drug alone is ineffective at its pharmacological dose, the combination effectively eliminates metastasis, thus making an old, failed drug like Sorafenib effective again. Previous works by this group and others showed that HAS3 and related molecules are highly elevated in genitourinary tumors and promote tumor growth, angiogenesis, metastasis, and treatment-induced resistance [ 6 - 22 ]. Therefore, the mechanisms and the targets identified in the studies by Jordan et al and Wang et al should likely have a broad clinical implication.…”