Resistance to cisplatin in human lung adenocarcinoma cells: effects on the glycophenotype and epithelial to mesenchymal transition markers.

The characteristics that grant the most malignancy to cancer cells are the ability to evade apoptotic mechanisms and the capacity to migrate beyond the boundaries of the original tissue. Studies by our own group and others show that changes in glycosylation are now considered hallmarks of cancer cells and are also able to impact tumor malignancy. This study aims to evaluate changes in the glycosylation profile of the A549 lung cancer cells brought about by the induction of a MDR phenotype as well as investigate the relationship between drug resistance, the cell glycophenotype and EMT. We induced resistance by employing a continuous treatment with cisplatin. Our results demonstrate overexpression of ABC transporters as well as anti-apoptotic members of the Bcl-2 family, leading to a MDR phenotype. The cells also undergo a classic EMT process, displaying the iconic cadherin switch and increased of both total and oncofetal fibronectin, coupled with increased cell motility. We also managed to show changes in the expression of both glycosyltransferases and the glycan epitopes they are responsible for building. We also suggest that perhaps not only changes in cell sialylation are common during resistance induction but are essential to it.

Non-self glycan structures as possible modulators of cancer progression: would polysaccharides from Cryptococcus spp. impact this phenomenon?

Invasive fungal infections (IFI) are responsible for a large number of annual deaths. Most cases are closely related to patients in a state of immunosuppression, as is the case of patients undergoing chemotherapy. Cancer patients are severely affected by the worrisome proportions that an IFI can take during cancer progression, especially in an already immunologically and metabolically impaired patient. There is scarce knowledge about strategies to mitigate cancer progression in these cases, beyond conventional treatment with antifungal drugs with a narrow therapeutic range. However, in recent years, ample evidence has surfaced describing the possible interferences that IFI may have both on the progression of pre-existing cancers and in the induction of newly transformed cells. The leading gambit for modulation of tumor progression comes from the ability of fungal virulence factors to modulate the host's immune system, since they are found in considerable concentrations in the tumor microenvironment during infection. In this context, cryptococcosis is of particular concern, since the main virulence factor of the pathogenic yeast is its polysaccharide capsule, which carries constituents with high immunomodulatory properties and cytotoxic potential. Therefore, we open a discussion on what has already been described regarding the progression of cryptococcosis in the context of cancer progression, and the possible implications that fungal glycan structures may take in both cancer development and progression.

Bittersweet Sugars: How Unusual Glycan Structures May Connect Epithelial-to-Mesenchymal Transition and Multidrug Resistance in Cancer.

Cancer cells are characterized by metabolic reprogramming, which enables their survival in of-ten inhospitable conditions. A very well-documented example that has gained attraction in re-cent years and is already considered a hallmark of transformed cells is the reprogramming of carbohydrate metabolism. Such a feature, in association with the differential expression of en-zymes involved in the biosynthesis of glycoconjugates, generically known as glycosyltransfer-ases, contributes to the expression of structurally atypical glycans when compared to those ex-pressed in healthy tissues. The latest studies have demonstrated that glycophenotypic alterations are capable of modulating multifactorial events essential for the development and/or progres-sion of the disease. Herein, we will address the importance of glycobiology in modern medi-cine, focusing on the ability of unusual/truncated O-linked glycans to modulate two complex and essential phenomena for cancer progression: the acquisition of the multidrug resistance (MDR) phenotype and the activation of molecular pathways associated with the epithelial-mesenchymal transition (EMT) process, an event deeply linked with cancer metastasis.

The Blessed Union of Glycobiology and Immunology: A Marriage That Worked.

In this article, we discuss the main aspects regarding the recognition of cell surface glycoconjugates and the immunomodulation of responses against the progression of certain pathologies, such as cancer and infectious diseases. In the first part, we talk about different aspects of glycoconjugates and delve deeper into the importance of N-glycans in cancer immunotherapy. Then, we describe two important lectin families that have been very well studied in the last 20 years. Examples include the sialic acid-binding immunoglobulin (Ig)-like lectins (siglecs), and galectins. Finally, we discuss a topic that needs to be better addressed in the field of glycoimmunology: the impact of oncofetal antigens on the cells of the immune system. New findings in this area are of great importance for advancement, especially in the field of oncology, since it is already known that cellular interactions mediated by carbohydrate-carbohydrate and/or carbohydrate proteins are able to modulate the progression of different types of cancer in events that compromise the functionality of the immune responses.

Expression of O-glycosylated oncofetal fibronectin in alternatively activated human macrophages.

Macrophage (Mϕ) polarization is an essential phenomenon for the maintenance of homeostasis and tissue repair, and represents the event by which Mϕ reach divergent functional phenotypes as a result to specific stimuli and/or microenvironmental signals. Mϕ can be polarized into two main phenotypes, M1 or classically activated and M2 or alternatively activated. These two categories diverge in many aspects, such as secreted cytokines, markers of cell surface, and biological functions. Over the last 10 years, many potential markers have been proposed for both M1 and M2 human Mϕ. However, there is scarce information regarding the glycophenotype adopted by these cells. Here, we show that M2- but not M1-polarized Mϕ expresses high levels of an unusual glycoform of fibronectin (FN), named O-glycosylated oncofetal FN (onf-FN), found in fetal/cancer cells, but not in healthy tissues. The onf-FN expression was confirmed in vitro by Western blot and real-time RT-qPCR in primary and cell line monocyte-derived Mϕ. onf-FN was induced by IL-4 and IL-13, but not by pro-inflammatory stimuli (LPS and INF-γ). RNA and protein analysis clearly demonstrated that it is specifically associated with the M2 polarization. In conclusion, we show by the first time that O-glycosylated onf-FN is expressed by M2-polarized Mϕ.

Glycobiology of Cancer: Sugar Drives the Show.

Cancer development and progression is associated with aberrant changes in cellular glycosylation. Cells expressing altered glycan-structures are recognized by cells of the immune system, favoring the induction of inhibitory immune processes which subsequently promote tumor growth and spreading. Here, we discuss about the importance of glycobiology in modern medicine, taking into account the impact of altered glycan structures expressed in cancer cells as potential glycobiomarkers of disease, as well as on cancer development and progression.

The Sweet Side of Fungal Infections: Structural Glycan Diversity and Its Importance for Pathogenic Adaptation.

Fungal infections are the most common secondary infections in debilitated individuals in a state of chronic disease or immunosuppression. Despite this, most fungal infections are neglected, mainly due to the lower frequency of their more severe clinical forms in immunocompetent individuals with a healthy background. However, over the past few years, several cases of severe fungal infections in healthy individuals have provoked a change in the epidemiological dynamics of fungal infections around the world, both due to recurrent outbreaks in previously infrequent regions and the greater emergence of more pathogenic fungal variants affecting healthy individuals, such as in the Cryptococcus genus. Therefore, before the arrival of a scenario of prevalent severe fungal infections, it is necessary to assess more carefully what are the real reasons for the increased incidence of fungal infection globally. What are the factors that are currently contributing to this new possible epidemiological dynamic? Could these be of a structural nature? Herein, we propose a discussion based on the importance of the virulence factors of glycoconjugate composition in the adaptation of pathogenic fungal species into the current scenario of increasing severity of these infections.

Trypanosoma cruzi trans-Sialidase as a Potential Vaccine Target Against Chagas Disease.

Chagas' disease is caused by the protozoan Trypanosoma cruzi, described in the early 20th century by the Brazilian physician Dr. Carlos Chagas. There was a great amount of research devoted to diagnosis, treatment and prevention of the disease. One of the most important discoveries made since then, impacting the understanding of how the parasite interacts with the host's immune system, was the description of trans-sialidase. It is an unique enzyme, capable of masking the parasite's presence from the host, while at the same time dampening the activation of CD8+ T cells, the most important components of the immune response. Since the description of Chagas' disease in 1909, extensive research has identified important events in the disease in order to understand the biochemical mechanism that modulates T. cruzi-host cell interactions and the ability of the parasite to ensure its survival. The importance of the trans-sialidase enzyme brought life to many studies for the design of diagnostic tests, drugs and vaccines. While many groups have been prolific, such efforts have encountered problems, among them: the fact that while T. cruzi have many genes that are unique to the parasite, it relies on multiple copies of them and the difficulty in providing epitopes that result in effective and robust immune responses. In this review, we aim to convey the importance of trans-sialidase as well as to provide a history, including the initial failures and the most promising successes in the chasing of a working vaccine for a disease that is endemic in many tropical countries, including Brazil.

COVID-19 Infection and Neuropathological Features.

The pathology associated with COVID-19 infection is progressively being revealed. Recent postmortem assessments have revealed acute airway inflammation as well as diffuse alveolar damage, which bears resemblance to severe acute respiratory syndromes induced by both SARS-CoV and MERS-CoV infections. Although recent papers have highlighted some neuropathologies associated with COVID-19 infection, little is known about this topic of great importance in the area of public health. Here, we discuss how neuroinflammation related to COVID-19 could be triggered by direct viral neuroinvasion and/or cytokine release over the course of the infection.