The Role of Proteoglycans in Cancer Metastasis and Circulating Tumor Cell Analysis.

Theresa D Ahrens,Mette Ø Agerbæk,Charlotte B Spliid,Caroline Løppke,Nicolai T Sand,Thomas M Clausen,Sara R Bang-Christensen,Amalie M Jørgensen,Ali Salanti

doi:10.3389/fcell.2020.00749

Abstract

Circulating tumor cells (CTCs) are accessible by liquid biopsies via an easy blood draw. They represent not only the primary tumor site, but also potential metastatic lesions, and could thus be an attractive supplement for cancer diagnostics. However, the analysis of rare CTCs in billions of normal blood cells is still technically challenging and novel specific CTC markers are needed. The formation of metastasis is a complex process supported by numerous molecular alterations, and thus novel CTC markers might be found by focusing on this process. One example of this is specific changes in the cancer cell glycocalyx, which is a network on the cell surface composed of carbohydrate structures. Proteoglycans are important glycocalyx components and consist of a protein core and covalently attached long glycosaminoglycan chains. A few CTC assays have already utilized proteoglycans for both enrichment and analysis of CTCs. Nonetheless, the biological function of proteoglycans on clinical CTCs has not been studied in detail so far. Therefore, the present review describes proteoglycan functions during the metastatic cascade to highlight their importance to CTCs. We also outline current approaches for CTC assays based on targeting proteoglycans by their protein cores or their glycosaminoglycan chains. Lastly, we briefly discuss important technical aspects, which should be considered for studying proteoglycans.

Highlights

During cancer progression, metastatic spread occurs when cancer cells disseminate from the primary tumor and travel to a distant site to form a metastasis (Micalizzi et al, 2017)
Another study reported a correlation between the expression of glypican-1 on the exosomal surface and the tumor burden in pancreatic cancer patients (Melo et al, 2015), supporting a prognostic value of proteoglycans associated with exosomes in carcinogenesis
To our knowledge, none of the major studies on chondroitin sulfate proteoglycan 4 (CSPG4)-positive circulating tumor cells (CTCs) in cutaneous melanoma have yet found any correlation between CTC levels and BRAF-mutational status or adjuvant therapy. Another recent study revealed that the transcriptomic profile of CSPG4-enriched CTC populations from six patients was dominated by up-regulation of tumor necrosis factor alpha (TNFα)/nuclear factor kappa B (NF-κB) as well as signal transducer and activator of transcription (STAT) pathways

Summary

Introduction

Metastatic spread occurs when cancer cells disseminate from the primary tumor and travel to a distant site to form a metastasis (Micalizzi et al, 2017). We will discuss how proteoglycans play active roles in cancer cell proliferation, migration, survival, plasticity, and invasion with a dedicated focus on the function of both the protein core and the GAG chains.

Results

Conclusion