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Introduction: Esophageal cancer (EC) seems to display increased glycolytic activity, but clinical studies on the expression/prognostic significance of glycometabolism-related proteins, as well as functional assays, are missing. Methods: Expression of 10 glycolytic biomarkers was evaluated by immunohistochemistry in tissue sections from 95 patients. Two esophageal squamous cell carcinoma (ESCC) cell lines were used to assess the effect of monocarboxylate transporter (MCT) downregulation on cell viability and extracellular lactate/glucose accumulation. Results: Expression of MCT1, MCT4, CD147, and GLUT1 was significantly associated with an ESCC histopathology, while a poor clinicopathological profile was seen in GLUT1- and LDHA-positive EC cases. In the ESCC group, MCT1 immunoreactivity is associated with high TNM stage and metastasis. The 3-year overall survival (OS) rate was significantly influenced by MCT4 and CAIX positivity and HKII negativity. Those biomarkers were considered independent prognostic factors of OS in multivariate analysis. Dual inhibition of MCT1/4 expression decreased cell viability and extracellular lactate accumulation in ESCC cells. Conclusion: Elevated glycolytic rates correlate with a poor clinicopathological profile in EC patients. MCT4 and CAIX positivity independently predict a worse prognosis. Due to the lack of information on treatment modalities, we could not further infer the role of these biomarkers in predicting response to therapy, which needs to be assessed in future studies. In addition, MCT1/4 targeting should be performed both “in vitro” and “in vivo” to further explore its impact on tumor growth and response to classical therapies. HKII expression and function, particularly in the tumor stroma, should be investigated.

Purpose: Successful therapy of patients with prostate cancer is highly dependent on reliable diagnostic and prognostic biomarkers. Brachyury is considered a negative prognostic factor in colon and lung cancer; however, there are no reports on Brachyury's expression in prostate cancer.Experimental Design: In this study, we aimed to assess the impact of Brachyury expression in prostate tumorigenesis using a large series of human prostate samples comprising benign tissue, prostate intraepithelial neoplasia (PIN) lesions, localized tumor, and metastatic tissues. The results obtained were compared with what can be inferred from the Oncomine database. In addition, multiple in vitro models of prostate cancer were used to dissect the biologic role of Brachyury in prostate cancer progression.Results: We found that Brachyury is significantly overexpressed in prostate cancer and metastatic tumors when compared with normal tissues, both at protein and at mRNA levels. Brachyury expression in the cytoplasm correlates with highly aggressive tumors, whereas the presence of Brachyury in the nucleus is correlated with tumor invasion. We found that Brachyury-positive cells present higher viability, proliferation, migration, and invasion rates than Brachyury-negative cells. Microarray analysis further showed that genes co-expressed with Brachyury are clustered in oncogenic-related pathways, namely cell motility, cell-cycle regulation, and cell metabolism.Conclusions: Collectively, the present study suggests that Brachyury plays an important role in prostate cancer aggressiveness and points, for the first time, to Brachyury as a significant predictor of poor prostate cancer prognosis. Our work paves the way for future studies assessing Brachyury as a possible prostate cancer therapeutic target. Clin Cancer Res; 20(18); 4949–61. ©2014 AACR.

Supplementary Figure S5. Brachyury overexpression modulates expression of EMT and stem cell markers in prostate cancer cell lines.

An unbalanced diet is one of the well-known risk factors for the development of colorectal cancer (CRC). This type of cancer is currently the main cause of cancer-related deaths worldwide, urging the need for new and more effective preventive and therapeutic approaches. It is already known that CRC patients have alterations in the microbial community and metabolism. In this regard, a concept that has been recently attracting the attention of the scientific community is the development of functional food or nutraceuticals, as a new and more effective strategy to overcome CRC patient-associated dysbiosis. Particularly, dairy product enriched diets are the major dairy source of dietary calcium, vitamin D and folate intake, which are well-known to have a protective effect against CRC development. In addition, these products are rich in both pre- and probiotics, constituting a double strategy to modulate both the intestinal microbiota composition and the production of microbial metabolites. Short-chain fatty acids (SCFA), namely, acetate, butyrate, and propionate, are major contributors to colonic homeostasis since they regulate several biological and metabolic processes. In this review, we performed a state of art study concerning the use of dietary patterns, specifically the dairy-derived diet, in the modulation of the human microbiota and their potential use as pre-, pro- or synbiotics for the development of new preventive and therapeutic strategies for CRC., This article is a result of the project EcoAgriFood NORTE-01-0145-FEDER-00009, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Sara Gomes thanks FCT for her PhD grant SFRH/BD/140965/2018. This work was financed by the Portuguese Foundation for Science and Technology (Fundação para a Ciência e a Tecnologia, FCT) within the scope of project PTDC/QUIQIN/28662/2017. This work was also supported by the strategic programme UID/BIA/04050/2019 funded by national funds through the FCT I.P.

Introduction: Hepatocellular carcinoma (HCC) has been associated to non-alcoholic fatty liver disease (NAFLD). We sought to investigate the immunoexpression of several glycolytic metabolism-associated markers in patients with HCC associated to NAFLD and associate these factors to their clinical-pathological characteristics. Methods: We evaluated 35 HCC specimens from 21 patients diagnosed with non-alcoholic steatohepatitis (NASH) undergoing liver resection (12 patients), liver transplantation (8 patients), or both (1 patient). Histological features, clinical aspects, demographic and biochemical data, as well as the immunohistochemical reactivity for monocarboxylate transporters 1, 2, and 4; their chaperone CD147; carbonic anhydrase IX; and glucose transporter-1 (GLUT1) were assessed. Results: Metabolic-associated cirrhosis was present in 12 of the 21 patients (8 child A and 4 child B scores). From 9 patients without cirrhosis, 3 presented NASH F3 and 6 NASH F2. Sixteen (76%) had diabetes mellitus, 17 (81%) arterial hypertension, and 19 (90%) body mass index above 25 kg/m2; 8 (38%) had dyslipidemia. From 35 nodules, steatosis was found in 26, ballooning in 31 nodules, 25 of them diagnosed as steatohepatitic subtype of HCC. MCT4 immunoexpression was associated with extensive intratumoral fibrosis, advanced clinical stages, and shorter overall survival. GLUT1 was noticeable in nodules with extensive intratumoral steatosis, higher intratumoral fibrosis, and advanced clinical stages. Immunohistochemical expression of the metabolic biomarkers MCT4 and GLUT1 was higher in patients with Barcelona-clinic liver cancer B or C. GLUT1 correlated with higher degree of steatosis, marked ballooning, intratumoral fibrosis, and higher parenchymal necroinflammatory activity. Conclusion: Our data indicate that the expression of the glycolytic phenotype of metabolic markers, especially GLUT1 and MCT4, correlates with a more severe course of HCC occurring in NASH patients.

Proliferating cancer cells have high energy demands, which is mainly obtained through glycolysis. The transmembrane trafficking of lactate, a major metabolite produced by glycolytic cancer cells, relies on monocarboxylate transporters (MCTs). MCT1 optimally imports lactate, although it can work bidirectionally, and its activity has been linked to cancer aggressiveness and poor outcomes. AZD3965, a specific MCT1 inhibitor, was tested both in vitro and in vivo, with encouraging results; a phase I clinical trial has already been undertaken. Thus, analysis of the experimental evidence using AZD3965 in different cancer types could give valuable information for its clinical use. This systematic review aimed to assess the in vivo anticancer activity of AZD3965 either alone (monotherapy) or with other interventions (combination therapy). Study search was performed in nine different databases using the keywords “AZD3965 in vivo” as search terms. The results show that AZD3965 successfully decreased tumor growth and promoted intracellular lactate accumulation, which confirmed its effectiveness, especially in combined therapy. These results support the setup of clinical trials, but other important findings, namely AZD3965 enhanced activity when given in combination with other therapies, or MCT4-induced treatment resistance, should be further considered in the clinical trial design to improve therapy response., This work has been funded by National funds, through the Foundation for Science and Technology (FCT)-project UIDB/50026/2020 and UIDP/50026/2020 and by the project NORTE-01- 0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). J.A. received a fellowship from FCT, ref. SFRH/BPD/116784/2016.

Colorectal cancer (CRC) has been ranked as one of the cancer types with a higher incidence and one of the most mortal. There are limited therapies available for CRC, which urges the finding of intracellular targets and the discovery of new drugs for innovative therapeutic approaches. In addition to the limited number of effective anticancer agents approved for use in humans, CRC resistance and secondary effects stemming from classical chemotherapy remain a major clinical problem, reinforcing the need for the development of novel drugs. In the recent years, the phenoxazines derivatives, Nile Blue analogues, have been shown to possess anticancer activity, which has created interest in exploring the potential of these compounds as anticancer drugs. In this context, we have synthetized and evaluated the anticancer activity of different benzo[

Tumor blood vessels create optimal conditions for glioblastoma (GBM) growth and therapy resistance. Therefore, tissue engineering techniques evolved towards allowing its inclusion in preclinical in vitro GBM models. In comparison with conventional ones, less representative of tumor biology, these new tools might significantly improve GBM treatment, contributing to a higher throughput screening in drug research and to the clinical translation of these therapies.

Deregulation of cell metabolism is an established cancer hallmark that contributes to tumor initiation and progression, as well as tumor heterogeneity. In solid tumors, alterations in different metabolic pathways, including glycolysis, pentose phosphate pathway, glutaminolysis and fatty acid metabolism, support the high proliferative rates and macromolecule biosynthesis of cancer cells. Despite advances in therapy, urothelial tumors still exhibit high recurrence and mortality rates, especially in advanced stages of disease. These tumors harbor gene mutations and expression patterns which play an important role in metabolic reprogramming. Taking into account the unique metabolic features underlying carcinogenesis in these cancers, new and promising therapeutic targets based on metabolic alterations must be considered. Furthermore, the combination of metabolic inhibitors with conventional targeted therapies may improve effectiveness of treatments. This review will summarize the metabolic alterations present in urological tumors and the results with metabolic inhibitors currently available.

Previously, inflammation has been found to be associated with the development of lung cancer. Despite their well-characterized pro-inflammatory functions, the putative roles of interleukin-17 (IL-17) cytokine family members in tumorigenesis have remained controversial. While IL-17A exhibits both pro- and anti-tumor effects, IL-17F has been suggested to serve as a candidate for cancer therapy. Thus, we aimed at clarifying the involvement of IL-17A/F in lung cancer. IL-17 receptor expression in human and murine lung cancer cells was assessed using immunofluorescence. The effect of IL-17A/F stimulation on lung cancer cell viability (SRB assay) and metabolism (glucose consumption and lactate production) was evaluated under normoxic and hypoxic conditions. Characterization of IL-17A/F-stimulated macrophages was performed by flow cytometry and ELISA. The effect of conditioned media (CM) from IL-17A/F-stimulated macrophages was evaluated on lung cancer cell migration. The effect of CM-stimulated macrophages on lung tumor growth, proliferation and angiogenesis was evaluated in vivo using a chicken chorioallantoic membrane (CAM) assay. No alterations in lung cancer cell viability or metabolism were observed upon direct stimulation with IL-17A/F. We found, however, that CM from IL-17A/F-stimulated macrophages promoted both murine and human lung cancer cell progression through an increased migration capacity in vitro and enhanced in vivo tumor growth, proliferation and angiogenesis. These findings were supported by an increased polarization of human macrophages towards a M2-like phenotype. Our data indicate that IL-17A/F act through immune cell orchestration, i.e., of macrophages, to promote lung cancer cell growth and progression. In addition, our data provide a link between IL-17A/F activity and lung cancer cell-macrophage crosstalk.

Energy production by cancer is driven by accelerated glycolysis, independently of oxygen levels, which results in increased lactate production. Lactate is shuttled to and from cancer cells via monocarboxylate transporters (MCTs). MCT1 works both as an importer and an extruder of lactate, being widely studied in recent years and generally associated with a cancer aggressiveness phenotype. The aim of this systematic review was to assess the prognostic value of MCT1 immunoexpression in different malignancies. Study collection was performed by searching nine different databases (PubMed, EMBASE, ScienceDirect, Scopus, Cochrane Library, Web of Science, OVID, TRIP and PsycINFO), using the keywords “cancer”, “Monocarboxylate transporter 1”, “SLC16A1” and “prognosis”. Results showed that MCT1 is an indicator of poor prognosis and decreased survival for cancer patients in sixteen types of malignancies; associations between the transporter’s overexpression and larger tumour sizes, higher disease stage/grade and metastasis occurrence were also frequently observed. Yet, MCT1 overexpression correlated with better outcomes in colorectal cancer, pancreatic ductal adenocarcinoma and non-small cell lung cancer patients. These results support the applicability of MCT1 as a biomarker of prognosis, although larger cohorts would be necessary to validate the overall role of MCT1 as an outcome predictor.

(1) BRAF mutations are associated with high mortality and are a substantial factor in therapeutic decisions. Therapies targeting BRAF-mutated tumors, such as vemurafenib (PLX), have significantly improved the overall survival of melanoma patients. However, patient relapse and low response rates remain challenging, even with contemporary therapeutic alternatives. Highly proliferative tumors often rely on glycolysis to sustain their aggressive phenotype. 3-bromopyruvate (3BP) is a promising glycolysis inhibitor reported to mitigate resistance in tumors. This study aimed to evaluate the potential of 3BP as an antineoplastic agent for PLX-resistant melanoma treatment. (2) The effect of 3BP alone or in combination with PLX on viability, proliferation, colony formation, cell death, migration, invasion, epithelial-mesenchymal marker and metabolic protein expression, extracellular glucose and lactate, and reactive species were evaluated in two PLX-resistant melanoma cell lines. (3) 3BP treatment, which was more effective as monotherapy than combined with PLX, disturbed the metabolic and epithelial-mesenchymal profile of PLX-resistant cells, impairing their proliferation, migration, and invasion and triggering cell death. (4) 3BP monotherapy is a potent metabolic-disrupting agent against PLX-resistant melanomas, supporting the suppression of the malignant phenotype in this type of neoplasia., This study was supported by FAPESP, Fundação de Amparo à Pesquisa do Estado de São Paulo, Brasil (2015/25351-6; 2016/10821-0; 2016/13021-4; 2017/12620-4; 2019/14189-4), and CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasil (309998/2019-0). São Paulo Research Foundation (2019/07502-8).

Triple-negative breast cancer (TNBC) represents 15-25% of the new breast cancer cases diagnosed worldwide every year. TNBC is among the most aggressive and worst prognosis breast cancer, mainly because targeted therapies are not available. Herein, we developed a magnetic theranostic hybrid nanovehicle for targeted treatment of TNBC through pH-triggered tumour associated macrophages (TAMs) targeting. The lipid core of the nanovehicle was composed of a Carnaúba wax matrix that simultaneously incorporated iron oxide nanoparticles and doxorubicin (DOX) - a chemotherapeutic drug. These drug-loaded wax nanovehicles were modified with a combination of two functional and complementary molecules: (i) a mannose ligand (macrophage targeting) and (ii) an acid-sensitive sheddable polyethylene glycol (PEG) moiety (specificity). The TAMs targeting strategy relied on the mannose-mannose receptor recognition exclusively after acid-sensitive "shedding" of the PEG in the relatively low tumour microenvironment pH. The pH-induced targeting capability towards TAMs was confirmed in vitro in a J774A.1 macrophage cell line at different pH (7.4 and 6.5). Biocompatibility and efficacy of the final targeted formulations were demonstrated in vitro in the TNBC MDA-MB-231 cell line and in vivo in an M-Wnt tumour-bearing (TNBC) mouse model. A preferential accumulation of the DOX-loaded lipid nanovehicles in the tumours of M-Wnt-tumour bearing mice was observed, which resulted both on an efficient tumour growth inhibition and a significantly reduced off-target toxicity compared to free DOX. Additionally, the developed magnetic hybrid nanovehicles showed outstanding performances as T

Facing recent threats of coronavirus disease (COVID-19), an educational strategy was designed and applied to middle school students in order to reinforce related knowledge and behaviors. A group of 65 middle school students (14-18 years old) developed several designed online curricular activities. After the intervention, students answered a questionnaire to assess if they: (a) were familiar with the terms COVID 19 and SARS-CoV-2; (b) were conscious about the importance of preventive measures to stop the spread of this disease; (c) were engaged in these activities; (d) were motivated to research on health-related issues. This study was a first to attempt to evaluate student's perceptions about SARS-CoV-2 infection and support education regarding COVID-19, mainly on the reinforcement of preventive measures.

Bladder cancer - the tenth most frequent cancer worldwide - has a heterogeneous natural history and clinical behaviour. The predominant histological subtype, urothelial bladder carcinoma, is characterized by high recurrence rates, progression and both primary and acquired resistance to platinum-based therapy, which impose a considerable economic burden on health-care systems and have substantial effects on the quality of life and the overall outcomes of patients with bladder cancer. The incidence of urothelial tumours is increasing owing to population growth and ageing, so novel therapeutic options are vital. Based on work by The Cancer Genome Atlas project, which has identified targetable vulnerabilities in bladder cancer, immune checkpoint inhibitors (ICIs) have arisen as an effective alternative for managing advanced disease. However, although ICIs have shown durable responses in a subset of patients with bladder cancer, the overall response rate is only ~15-25%, which increases the demand for biomarkers of response and therapeutic strategies that can overcome resistance to ICIs. In ICI non-responders, cancer cells use effective mechanisms to evade immune cell antitumour activity; the overlapping Warburg effect machinery of cancer and immune cells is a putative determinant of the immunosuppressive phenotype in bladder cancer. This energetic interplay between tumour and immune cells leads to metabolic competition in the tumour ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function. Thus, molecular hallmarks of cancer cell metabolism are potential therapeutic targets, not only to eliminate malignant cells but also to boost the efficacy of immunotherapy. In this sense, integrating the targeting of tumour metabolism into immunotherapy design seems a rational approach to improve the therapeutic efficacy of ICIs.

It is generally accepted that metabolism is able to shape the immune response. Only recently we are gaining awareness that the metabolic crosstalk between different tumor compartments strongly contributes to the harsh tumor microenvironment (TME) and ultimately impairs immune cell fitness and effector functions. The major aims of this review are to provide an overview on the immune system in cancer; to position oxygen shortage and metabolic competition as the ground of a restrictive TME and as important players in the anti-tumor immune response; to define how immunotherapies affect hypoxia/oxygen delivery and the metabolic landscape of the tumor; and vice versa, how oxygen and metabolites within the TME impinge on the success of immunotherapies. By analyzing preclinical and clinical endeavors, we will discuss how a metabolic characterization of the TME can identify novel targets and signatures that could be exploited in combination with standard immunotherapies and can help to predict the benefit of new and traditional immunotherapeutic drugs., M. Mazzone was supported by European Research Council (ERC) Consolidator Grant 773208, Fonds Wetenschappelijk Onderzoek (Flemish Research Foundation) Grants G0D1717N and G066515N, and Stichting Tegen Kanker (Fondation Contre le Cancer) Grant 2014197. C. Riera-Domingo was supported by Fonds Wetenschappelijk Onderzoek (Flemish Research Foundation) Grant 1108919N. S. Granja received a fellowship from the Foundation for Science and Technology (FCT) Ref. No. SFRH/BPD/117858/2016. F. Baltazar worked under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020) under the Portugal Partnership Agreement, through the European Regional Development Fund (FEDER), and through the Competitiveness Factors Operational Programme (COMPETE) and by National funds, through the FCT, under the scope of the project POCI-01-0145-FEDER-007038. F. Baltazar also acknowledges financial support from the projects Ref. No. NORTE-01-0145-FEDER-031142 and UTAP-EXPL/NTec/0038/2017. C. Stockmann was supported by Swiss National Fund (179235), the Swiss Cancer Research (KFS-4397-02-2018), and the National Center of Compentence in Research (NCCR): Kidney Control of Homeostasis (183774). P.-C. Ho was supported in part by the SNSF Project Grant 31003A_182470 and ERC Staring Grant 802773-Mito-Guide.

Background: Glioblastomas (GBMs) present remarkable metabolism reprograming, in which many cells display the “Warburg effect”, with the production of high levels of lactate that are extruded to the tumour microenvironment by monocarboxylate transporters (MCTs). We described previously that MCT1 is up-regulated in human GBM samples, and MCT1 inhibition decreases glioma cell viability and aggressiveness. In the present study, we aimed to unveil the role of MCT1 in GBM prognosis and to explore it as a target for GBM therapy in vivo. Methods: MCT1 activity and protein expression were inhibited by AR-C155858 and CHC compounds or stable knockdown with shRNA, respectively, to assess in vitro and in vivo the effects of MCT1 inhibition and on response of GBM to temozolomide. Survival analyses on GBM patient cohorts were performed using Cox regression and Log-rank tests. Results: High levels of MCT1 expression were revealed to be a predictor of poor prognosis in multiple cohorts of GBM patients. Functionally, in U251 GBM cells, MCT1 stable knockdown decreased glucose consumption and lactate efflux, compromising the response to the MCT1 inhibitors CHC and AR-C155858. MCT1 knockdown significantly increased the survival of orthotopic GBM intracranial mice models when compared to their control counterparts. Furthermore, MCT1 downregulation increased the sensitivity to temozolomide in vitro and in vivo, resulting in significantly longer mice survival. Conclusions: This work provides first evidence for MCT1 as a new prognostic biomarker of GBM survival and further supports MCT1 targeting, alone or in combination with classical chemotherapy, for the treatment of GBM., This work has been funded by ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI–Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122; by National funds, through the Foundation for Science and Technology (FCT)–project UIDB/50026/2020 and UIDP/50026/2020 and by the projects NORTE-01-0145-FEDER-000039 and NORTE-01-0247- FEDER-045914, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by project PTDC/BTM-SAL/31142/2017 (funded by FCT) and Brazilian MCTI/CNPq No73/2013. VMG was recipient of a fellowship and BC recipient of a contract from Fundação para a Ciência e Tecnologia (FCT), Portugal, refs. SFRH/BD/51997/2012 and CEECIND/00072/2018, respectively

Made available in DSpace on 2021-06-25T10:31:38Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-06-15 Mutations on the epidermal growth factor receptor (EGFR), induction of angiogenesis, and reprogramming cellular energetics are all biological features acquired by tumor cells during tumor development, and also known as the hallmarks of cancer. Targeted therapies that combine drugs that are capable of acting against such concepts are of great interest, since they can potentially improve the therapeutic efficacy of treatments of complex pathologies, such as glioblastoma (GBM). However, the anatomical location and biological behavior of this neoplasm imposes great challenges for targeted therapies. A novel strategy that combines alpha-cyano-4-hydroxycinnamic acid (CHC) with the monoclonal antibody cetuximab (CTX), both carried onto a nanotechnology-based delivery system, is herein proposed for GBM treatment via nose-to-brain delivery. The biological performance of Poly (D,L-lactic-co-glycolic acid)/chitosan nanoparticles (NP), loaded with CHC, and conjugated with CTX by covalent bonds (conjugated NP) were extensively investigated. The NP platforms were able to control CHC release, indicating that drug release was driven by the Weibull model. An ex vivo study with nasal porcine mucosa demonstrated the capability of these systems to promote CHC and CTX permeation. Blot analysis confirmed that CTX, covalently associated to NP, impairs EGRF activation. The chicken chorioallantoic membrane assay demonstrated a trend of tumor reduction when conjugated NP were employed. Finally, images acquired by fluorescence tomography evidenced that the developed nanoplatform was effective in enabling nose-to-brain transport upon nasal administration. In conclusion, the developed delivery system exhibited suitability as an effective novel co-delivery approaches for GBM treatment upon intranasal administration. School of Pharmaceutical Science São Paulo State University UNESP, Rodovia Araraquara/Jaú Km 01 Laboratório de Nanotecnologia Farmacêutica e Sistemas de Liberação de Fármacos FarmaTec Faculdade de Farmácia Universidade Federal de Goiás - UFG, 5ª Avenida c/Rua 240 s/n, Praça Universitária Life and Health Sciences Research Institute (ICVS) School of Medicine University of Minho ICVS/3B's-PT Government Associate Laboratory Molecular Oncology Research Center Barretos Cancer Hospital School of Pharmaceutical Science São Paulo State University UNESP, Rodovia Araraquara/Jaú Km 01

The cancer cells’ metabolism is altered due to deregulation of key proteins, including glucose transporter 1 (GLUT-1), whose mRNA levels are influenced by microRNAs (miRNAs). Renal cell carcinoma (RCC) is the most common and lethal neoplasia in the adult kidney, mostly due to the lack of accurate diagnosis and follow-up biomarkers. Being a metabolic associated cancer, this study aimed to understand the hsa-miR-144-5p and hsa-miR-186-3p’s potential as biomarkers of clear cell RCC (ccRCC), establishing their role in its glycolysis status. Using three ccRCC lines, the intra- and extracellular levels of both miRNAs, GLUT-1’s mRNA expression and protein levels were assessed. Glucose consumption and lactate production were evaluated as glycolysis markers. A decrease of intracellular levels of these miRNAs and increase of their excretion was observed, associated with an increase of GLUT-1’s levels and glycolysis’ markers. Through a liquid biopsy approach, we found that RCC patients present higher plasmatic levels of hsa-miR-186-3p than healthy individuals. The Hsa-miR144-5p’s higher levels were associated with early clinical stages. When patients were stratified according to miRNAs plasmatic levels, low plasmatic levels of hsa-miR-144-5p and high plasmatic levels of hsa-miR-186-3p (high-risk group) showed the worst overall survival. Thus, circulating levels of these miRNAs may be potential biomarkers of ccRCC prognosis., M.M. and I.N. are recipients of a research scholarship awarded by LPCC-NRN (Portuguese League Against Cancer—Northern Branch). F.D. is a Ph.D. fellow from the project NORTE-01-0145- FEDER-000027, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This project was also funded by the research Center of the Portuguese Oncology Institute of Porto [CI-IPOP-21-2015].

Background: The aim was to investigate the clinical significance of nestin immunohistochemical expression in head and neck area lesions and to study its role in patient survival and recurrence. Methods: 39 (44.3%) nasosinus, 37 (42%) major salivary gland (6 submandibular and 31 parotid) and 12 (13.6%) oral cavity lesions of paraffin-embedded samples were retrospectively included. Results: The expression was categorized into grades, negative for 55 (62.5%) cases, grade 1 in 10 cases (11.4%), grade 2 in 12 cases (13.6%), and grade 3 in 11 cases (12.5%), 100% of pleomorphic adenomas were positive for nestin with grade 3 intensity, 100% of polyps and inverted papillomas were negative (p &lt, 0.001). The lowest estimate of disease-free-survival (DFS) was for grade 1 expression, with 50 months, confidence interval (CI): 95% 13.3–23.9 months and the highest for grade 3 expression, 167.9 months (CI: 95% 32.1–105 months, Log-Rank = 14.846, p = 0.002). ROC (receiver operating characteristic) curves revealed that the positivity for nestin (+/−) in relation to malignancy, presented a sensitivity of 50.98%, a specificity of 81.08%, with an area under the curve of 0.667 (p = 0.009). Conclusions: Nestin could be a useful marker to detect the presence of stem cells in head and neck tumors that have a role in tumor initiation and progression.

Renal cell carcinoma (RCC) is the most common and lethal tumor of the urological system. Curative treatment of localized RCC includes nephrectomy, radio-ablation, and active surveillance, whereas metastatic RCC (mRCC) requires a combination of surgery and systemic therapy. Response to conventional therapy is limited but, recently, many novel therapies for mRCC have emerged, including targeted therapies and new immunotherapeutic agents. Nevertheless, development of resistance and limited durable responses demand new anticancer candidates with improved selectivity and efficacy. In this review, we summarize recent preclinical studies of novel natural and synthetic compounds to treat RCC, detailing their mechanisms of action and anticancer activities.

Made available in DSpace on 2021-06-25T12:42:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-02-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Programa de Apoio ao Desenvolvimento Cientifico (PADC) Current researches report an actual benefit of a treatment for oral cancer via inhibition of proteolytic matrix metalloproteinases (MPP) with a peptide drug, called CTT1. However, peptides present poor oral bioavailability. Topical administration on oral mucosa avoids its passage through the gastrointestinal tract and the first-pass liver metabolism, but the barrier function of the oral mucosa can impair the permeation and retention of CTT1. The objective of this study is to incorporate CTT1 into a mucoadhesive precursor of liquid crystalline system (PLCS) as an interesting strategy for the topical treatment of oral cancer. PLCS consisting of oleic acid, ethoxylated 20 and propoxylated cetyl alcohol 5, polyethyleneimine (P)-associated chitosan (C) dispersion and CTT1 (FPC-CTT1) was developed and characterized by polarized light microscopy (PLM) and small-angle X-ray scattering (SAXS). In vitro permeation and retention across esophageal mucosa, in vitro cytotoxicity towards tongue squamous cell carcinoma cells, and in vivo evaluation of vascular changes using the chick embryo chorioallantoic membrane (CAM) model were performed. PLM and SAXS showed that FPC-CTT1acted as PLCS, because it formed a lamellar liquid crystalline system after the addition of artificial saliva. FPC-CTT1increased approximately 2-fold the flux of permeation and 3- fold the retention of CTT1 on the porcine esophageal mucosa. CTT1 does not affect cell viability. CAM tests showed that FPC preserved the blood vessels and it can be a safe formulation. These findings encourage the use of the FPC-CTT1 for topical treatment of oral cancer. Univ Estadual Campinas, UNICAMP, Piracicaba Dent Sch Dept Biosci, BR-13414903 Piracicaba, SP, Brazil Sao Paulo State Univ, Sch Pharmaceut Sci, Dept Drugs & Med, UNESP, BR-14800903 Araraquara, SP, Brazil Univ Minho, Life & Hlth Sci Res Inst ICVS, Sch Hlth Sci, P-4710057 Braga, Portugal ICVS 3Bs PT Govt Associate Lab, P-4710057 Braga, Portugal Sao Paulo State Univ, Sch Pharmaceut Sci, Dept Drugs & Med, UNESP, BR-14800903 Araraquara, SP, Brazil FAPESP: 13/015651 FAPESP: 16/06337-5 FAPESP: 19/07245-5 FAPESP: 2014/50928-2 CNPq: 465687/2014-8