Proteoglycans control numerous normal and pathological processes, among which are morphogenesis, tissue repair, inflammation, vascularization and cancer metastasis. During tumor development and growth, proteoglycan expression is markedly modified in the tumor microenvironment. Altered expression of proteoglycans on tumor and stromal cell membranes affects cancer cell signaling, growth and survival, cell adhesion, migration and angiogenesis. Despite the high complexity and heterogeneity of breast cancer, the rapid evolution in our knowledge that proteoglycans are among the key players in the breast tumor microenvironment suggests their potential as pharmacological targets in this type of cancer. It has been recently suggested that pharmacological treatment may target proteoglycan metabolism, their utilization as targets for immunotherapy or their direct use as therapeutic agents. The diversity inherent in the proteoglycans that will be presented herein provides the potential for multiple layers of regulation of breast tumor behavior. This review summarizes recent developments concerning the biology of selected proteoglycans in breast cancer, and presents potential targeted therapeutic approaches based on their novel key roles in breast cancer.

Galectin-3, the only chimera galectin found in vertebrates, is one of the best-studied galectins. It is expressed in several cell types and is involved in a broad range of physiological and pathological processes, such as cell adhesion, cell activation and chemoattraction, cell cycle, apoptosis, and cell growth and differentiation. However, this molecule raises special interest due to its role in regulating cancer cell activities. Galectin-3 has high affinity for β-1,6-N-acetylglucosamine branched glycans, which are formed by the action of the β1,6-N-acetylglucosaminyltransferase V (Mgat5). Mgat5-related changes in protein/lipid glycosylation on cell surface lead to alterations in the clustering of membrane proteins through lattice formation, resulting in functional advantages for tumor cells. Galectin-3 presence enhances migration and/or invasion of many tumors. Galectin-3-dependent clustering of integrins promotes ligand-induced integrin activation, leading to cell motility. Galectin-3 binding to mucin-1 increases transendothelial invasion, decreasing metastasis-free survival in an experimental metastasis model. Galectin-3 also affects endothelial cell behavior by regulating capillary tube formation. This lectin is found in the tumor stroma, suggesting a role for microenvironmental galectin-3 in tumor progression. Galectin-3 also seems to be involved in the recruitment of tumor-associated macrophages, possibly contributing to angiogenesis and tumor growth. This lectin can be a relevant factor in turning bone marrow in a sanctuary for leukemia cells, favoring resistance to therapy. Finally, galectin-3 seems to play a relevant role in orchestrating distinct cell events in tumor microenvironment and for this reason, it can be considered a target in tumor therapies. In conclusion, this review aims to describe the processes of tumor progression and metastasis involving extracellular galectin-3 and its expression and regulation.

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Inflammation and cancer are related pathologies acting synergistically to promote tumor progression. In both, hematogenous metastasis and inflammation, P-selectin participates in interactions involving tumor cells, platelets, leukocytes and endothelium. Heparin has been shown to inhibit P-selectin and as a consequence it blunts metastasis and inflammation. Some heparin analogs obtained from marine invertebrates are P-selectin inhibitors and do not induce bleeding effects. The present work focuses on the P-selectin blocking activity of a unique heparan sulfate (HS) from the bivalve mollusk Nodipecten nodosus. Initially, we showed that the mollusk HS inhibited LS180 colon carcinoma cell adhesion to immobilized P-selectin in a dose-dependent manner. In addition, we demonstrated that this glycan attenuates leukocyte rolling on activated endothelium and inflammatory cell recruitment in thioglycollate-induced peritonitis in mice. Biochemical analysis indicated that the invertebrate glycan also inhibits heparanase, a key player in cell invasion and metastasis. Experimental metastasis of Lewis lung carcinoma cells was drastically attenuated by the mollusk HS through a mechanism involving inhibition of platelet-tumor-cell complex formation in blood vessels. These data suggest that the mollusk HS is a potential alternative to heparin for inhibiting P-selectin-mediated events such as metastasis and inflammatory cell recruitment.

The functionality of the tumor suppressor p53 is altered in more than 50% of human cancers, and many individuals with cancer exhibit amyloid-like buildups of aggregated p53. An understanding of what triggers the pathogenic amyloid conversion of p53 is required for the further development of cancer therapies. Here, perturbation of the p53 core domain (p53C) with subdenaturing concentrations of guanidine hydrochloride and high hydrostatic pressure revealed native-like molten globule (MG) states, a subset of which were highly prone to amyloidogenic aggregation. We found that MG conformers of p53C, probably representing population-weighted averages of multiple states, have different volumetric properties, as determined by pressure perturbation and size-exclusion chromatography. We also found that they bind the fluorescent dye 4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid (bis-ANS) and have a native-like tertiary structure that occludes the single Trp residue in p53. Fluorescence experiments revealed conformational changes of the single Trp and Tyr residues before p53 unfolding and the presence of MG conformers, some of which were highly prone to aggregation. p53C exhibited marginal unfolding cooperativity, which could be modulated from unfolding to aggregation pathways with chemical or physical forces. We conclude that trapping amyloid precursor states in solution is a promising approach for understanding p53 aggregation in cancer. Our findings support the use of single-Trp fluorescence as a probe for evaluating p53 stability, effects of mutations, and the efficacy of therapeutics designed to stabilize p53.

Tumor progression is regulated by a complex interplay between neoplastic cells and the tumor microenvironment. Tumor associated macrophages have been shown to promote breast cancer progression in advanced disease and more recently, in early stage cancers. However, little is known about the macrophage-derived factors that promote tumor progression in early stage lesions. Using a p53-null model of early stage mammary tumor progression, we found that Gas6 is highly expressed in pre-invasive lesions associated with increased infiltrating macrophages, as compared to those with few recruited macrophages. We show that F4/80 + CD11b + macrophages produce Gas6 in premalignant lesions in vivo , and that macrophage-derived Gas6 induces a tumor-like phenotype ex vivo . Using a 3-D co-culture system, we show that macrophage-derived Gas6 activates its receptor Axl and downstream survival signals including Akt and STAT3, which was accompanied by altered E-cadherin expression to induce a malignant morphology. In vivo studies demonstrated that deletion of stromal Gas6 delays early stage progression and decreases tumor formation, while tumor growth in established tumors remains unaffected. These studies suggest that macrophage-derived Gas6 is a critical regulator of the transition from premalignant to invasive cancer, and may lead to the development of unique biomarkers of neoplastic progression for patients with early stage breast cancer, including ductal carcinoma in situ .

Mayaro virus (MAYV) is an emergent sylvatic alphavirus in South America, related to sporadic outbreaks of a chikungunya-like human febrile illness accompanied by severe arthralgia. Despite its high potential for urban emergence, MAYV is still an obscure virus with scarce information about its infection cycle, including the corresponding early events. Even for prototypical alphaviruses, the cell entry mechanism still has some rough edges to trim: although clathrin-mediated endocytosis is quoted as the putative route, alternative paths as distinct as direct virus genome injection through the cell plasma membrane seems to be possible. Our aim was to clarify crucial details on the entry route exploited by MAYV to gain access into the host cell. Tracking the virus since its first contact with the surface of Vero cells by fluorescence microscopy, we show that its entry occurs by a fast endocytic process and relies on fusion with acidic endosomal compartments. Moreover, blocking clathrin-mediated endocytosis or depleting cholesterol from the cell membrane leads to a strong inhibition of viral infection, as assessed by plaque assays. Following this clue, we found that early endosomes and caveolae-derived vesicles are both implicated as target membranes for MAYV fusion. Our findings unravel the very first events that culminate in a productive infection by MAYV and shed light on potential targets for a rational antiviral therapy, besides providing a better comprehension of the entry routes exploited by alphaviruses to get into the cell.

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