Insights into the role of sulfated glycans in cancer cell adhesion and migration through use of branched peptide probe

Santos

et al. 2019

Journal of Oncology

Galectin-3 (Gal-3) is a multifunctional β-galactoside-binding lectin that once synthesized is expressed in the nucleus, cytoplasm, cell surface, and extracellular environment. Gal-3 plays an important role in breast cancer tumors due to its ability to promote interactions between cell-cell and cell-extracellular matrix (ECM) elements, increasing tumor survival and metastatic dissemination. Still, the mechanism by which Gal-3 interferes with tumor cell migration and metastasis formation is complex and not fully understood. Here, we showed that Gal-3 knockdown increased the migration ability of 4T1 murine breast cancer cells in vitro. Using the 4T1 orthotopic breast cancer spontaneous metastasis mouse model, we demonstrated that 4T1-derived tumors were significantly larger in the presence of Gal-3 (scramble) in comparison with Gal-3 knockdown 4T1-derived tumors. Nevertheless, Gal-3 knockdown 4T1 cells were outnumbered in the bone marrow in comparison with scramble 4T1 cells. Finally, we reported here a decrease in the content of cell-surface syndecan-1 and an increase in the levels of chondroitin sulfate proteoglycans such as versican in Gal-3 knockdown 4T1 cells both in vitro and in vivo. Overall, our findings establish that Gal-3 downregulation during breast cancer progression regulates cell-associated and tumor microenvironment glycosaminoglycans (GAGs)/proteoglycans (PG), thus enhancing the metastatic potential of tumor cells.

Section: Discussionmentioning

confidence: 99%

Galectin-3 Regulates the Expression of Tumor Glycosaminoglycans and Increases the Metastatic Potential of Breast Cancer

Santos

et al. 2019

Journal of Oncology

“…NT4 bound specifically with high affinity to membrane‐sulfated glycosaminoglycans (GAG) and to different membrane endocytic receptors belonging to the low‐density lipoprotein receptor family, including LRP1 and LRP6, all already known as potential druggable tumor markers involved in cancer biology . NT4 was much more selective than native monomeric analogues for binding to different human cancer cells and tissues .…”

Section: Branched Peptide Applicationsmentioning

confidence: 99%

“…Considering the role of sulfated GAGs in cancer cell interaction with the extracellular matrix, the effect of NT4 in cancer cell adhesion and migration was analyzed on different supports. NT4 inhibited adhesion and migration of different human cancer cell lines, strongly affecting the directionality of cell movement …”

Section: Branched Peptide Applicationsmentioning

confidence: 99%

Branched peptides as bioactive molecules for drug design

et al. 2018

Self Cite

Peptides are regarded as good candidates for new biotherapeutics in medicine. Several peptides have already completed clinical development, with more than 60 peptide‐based drugs already on the market, and a further 500 derivatives currently in developmental stages. Branched peptides are an emerging class of synthetic molecules being assessed for drug development. Here, we review possible clinical uses of branched peptides, considering major features such as stability, half‐life, toxicity, and efficacy compared to monomeric peptides, biodistribution, as well as modifications, encapsulation, and conjugation to improve delivery or bypass drug resistance. We focus in particular on the use of branched peptides in oncology and infectious diseases.

“…The cancer selectivity of NT4 peptides is much higher than that of native monomeric neurotensin, which unlike NT4 does not discriminate between healthy human tissues and cancer [ 10 , 12 , 14 ]. We demonstrated that the branched structure gives NT4 the ability to bind sulfated glycosaminoglycan (GAG) chains of membrane heparan sulfate proteoglycans (HSPG), as well as different endocytic receptors of the low density lipoprotein receptor (LDLR) family, like LRP1 and LRP6 [ 16 , 17 ]. LDLR are already known to share many heparin-binding ligands with HSPG and both families include potential druggable tumor markers involved in cancer biology [ 18 – 21 ].…”

Section: Introductionmentioning

confidence: 99%

Coupling to a cancer-selective heparan-sulfate-targeted branched peptide can by-pass breast cancer cell resistance to methotrexate

et al. 2017

Self Cite

Cancer-selective tetra-branched peptides, named NT4, can be coupled to different functional units for cancer cell imaging or therapy. NT4 peptides specifically bind to lipoprotein receptor-related proteins (LRP) receptors and to heparan sulfate chains on membrane proteoglycans and can be efficiently internalized by cancer cells expressing these membrane targets. Since binding and internalization of NT4 peptides is mediated by specific NT4 receptors on cancer cell membranes and this may allow drug resistance produced by drug membrane transporters to be by-passed, we tested the ability of drug-armed NT4 to by-pass drug resistance in cancer cell lines.We found that MTX-conjugated NT4 allows drug resistance to be by-passed in MTX-resistant human breast cancer cells lacking expression of folate reduced carrier. NT4 peptides appear to be extremely promising cancer-selective targeting agents that can be exploited as theranostics in personalized oncological applications.