Minbiziaren aurkako CAR-T zelulen bidezko immunoterapia

The last years immunotherapy has become a useful strategy in the fight against cancer. One of the most popular therapies is called CAR-T. In this treatment, the patient’s T lymphocytes are removed and modified in the laboratory to enhance the action against the tumour by placing a type of “sensor” on its surface (CAR receptor). Thus, the patient is re- introduced with the transformed lymphocytes, which search for, recognize, and attack tumour cells. In this review, we will explain the structure, mode of generation, and adverse effects of CAR receptors on therapy. Finally, CAR-T immunotherapy has been shown to be effective in several blood tumours, as well as in certain types of solid tumors.; Azkenengo urteotan immunoterapia minbiziari aurre egiteko estrategia baliagarria bihurtu da. Terapia ezagunenetako bati CAR-T deritzo. Tratamendu honetan, gaixoaren T linfozitoak atera eta laborategian aldatu egiten dira tumorearen aurkako ekintza hobetzeko, "sentsore" mota bat jarrita haren gainazalean (CAR errezeptorea). Horrela, pazienteari berriro linfozito eraldatuak sartzen zaizkio, hauek tumore-zelulak bilatu, ezagutu eta erasotzeko. Berrikuspen honetan, CAR errezeptoreen egitura, sortzeko era eta terapiaren efektu desiragaitzak azalduko ditugu. Azkenik, CAR-T immunoterapia odoleko hainbat tumoretan eraginkorra dela frogatu da, bai eta tumore solido mota batzuetan ere

Vascular endothelial growth factor regulates melanoma cell adhesion and growth in the bone marrow microenvironment via tumor cyclooxygenase-2

Background: Human melanoma frequently colonizes bone marrow (BM) since its earliest stage of systemic dissemination, prior to clinical metastasis occurrence. However, how melanoma cell adhesion and proliferation mechanisms are regulated within bone marrow stromal cell (BMSC) microenvironment remain unclear. Consistent with the prometastatic role of inflammatory and angiogenic factors, several studies have reported elevated levels of cyclooxygenase-2 (COX-2) in melanoma although its pathogenic role in bone marrow melanoma metastasis is unknown. Methods: Herein we analyzed the effect of cyclooxygenase-2 (COX-2) inhibitor celecoxib in a model of generalized BM dissemination of left cardiac ventricle-injected B16 melanoma (B16M) cells into healthy and bacterial endotoxin lipopolysaccharide (LPS)-pretreated mice to induce inflammation. In addition, B16M and human A375 melanoma (A375M) cells were exposed to conditioned media from basal and LPS-treated primary cultured murine and human BMSCs, and the contribution of COX-2 to the adhesion and proliferation of melanoma cells was also studied. Results: Mice given one single intravenous injection of LPS 6 hour prior to cancer cells significantly increased B16M metastasis in BM compared to untreated mice; however, administration of oral celecoxib reduced BM metastasis incidence and volume in healthy mice, and almost completely abrogated LPS-dependent melanoma metastases. In vitro, untreated and LPS-treated murine and human BMSC-conditioned medium (CM) increased VCAM-1-dependent BMSC adherence and proliferation of B16M and A375M cells, respectively, as compared to basal medium-treated melanoma cells. Addition of celecoxib to both B16M and A375M cells abolished adhesion and proliferation increments induced by BMSC-CM. TNF alpha and VEGF secretion increased in the supernatant of LPS-treated BMSCs; however, anti-VEGF neutralizing antibodies added to B16M and A375M cells prior to LPS-treated BMSC-CM resulted in a complete abrogation of both adhesion-and proliferation-stimulating effect of BMSC on melanoma cells. Conversely, recombinant VEGF increased adherence to BMSC and proliferation of both B16M and A375M cells, compared to basal medium-treated cells, while addition of celecoxib neutralized VEGF effects on melanoma. Recombinant TNFa induced B16M production of VEGF via COX-2-dependent mechanism. Moreover, exogenous PGE2 also increased B16M cell adhesion to immobilized recombinant VCAM-1. Conclusions: We demonstrate the contribution of VEGF-induced tumor COX-2 to the regulation of adhesion-and proliferation-stimulating effects of TNFa, from endotoxin-activated bone marrow stromal cells, on VLA-4-expressingThis work was supported in part by grants from the Basque Country Government (IT-487-07), the ISCIII (ADE09/90041), and the Burdinola Professorship on Molecular Medicin

Identification of sugar moieties in chief cells of the rat fundic gastric glands

Many studies have been conducted to determine the composition of the glyconjugates of the mucus-secreting cells of the fundic glands of the stomach. However, the chief cells of these glands have been largely ignored because they secrete mainly zymogens with a lower glycosylation. The aim of this work was to analyze the glycoconjugates of the gastric chief cells by a battery of 17 different lectins, recognizing Fucose, N-AcetylGalactosamine, Galactose, N-Acetylneuramiinic acid, N-AcetylGlucosamine and Mannose containing oligosaccharides. Histochemical techniques were performed with several lectins and also combined with two pre-treatments; β-elimination, which removes O-linked oligosaccharides, and incubation with Peptide-N-Gycosidase F, which removes N-linked oligosaccharides. In addition, acid hydrolysis was performed before WGA histochemistry, and incubation with glucose oxidase before Con A labeling. Many lectins did not stain the chief cells. In addition, the presence of O-glycans in the apical cell membrane was demonstrated with the lectins AAL, HPA, MPA/MPL, PNA, RCA-I, and WGA. Some of these O-glycans were resistant to short-term β-elimination pre-treatments. Mannose-binding lectins stained the basal cytoplasm of the chief cells. The level of glycosylation of the chief cells was lower than that of the mucous cells. The presence of O-glycans in the apical cell membrane is consistent with the presence of mucins such as MUC1 in the apical membrane of chief cells. Moreover, Mannose-binding lectins revealed N-glycosylation in the basal cytoplasm. The knowledge of gastric chief cell glycoconjugates is relevant because of their potential involvement not only in in physiological but also in pathological processes, such as cancer.This work was supported by the University of the Basque Country UPV/EHU (Grant numbers: EHUA13/15, EHUA15/26); and Fundación Séneca, Comunidad Autónoma de la Región de Murcia (Grant number 04542/GERM/06)

GeromiRs Are Downregulated in the Tumor Microenvironment during Colon Cancer Colonization of the Liver in a Murine Metastasis Model

Cancer is a phenomenon broadly related to ageing in various ways such as cell cycle deregulation, metabolic defects or telomerases dysfunction as principal processes. Although the tumor cell is the main actor in cancer progression, it is not the only element of the disease. Cells and the matrix surrounding the tumor, called the tumor microenvironment (TME), play key roles in cancer progression. Phenotypic changes of the TME are indispensable for disease progression and a few of these transformations are produced by epigenetic changes including miRNA dysregulation. In this study, we found that a specific group of miRNAs in the liver TME produced by colon cancer called geromiRs, which are miRNAs related to the ageing process, are significantly downregulated. The three principal cell types involved in the liver TME, namely, liver sinusoidal endothelial cells, hepatic stellate (Ito) cells and Kupffer cells, were isolated from a murine hepatic metastasis model, and the miRNA and gene expression profiles were studied. From the 115 geromiRs and their associated hallmarks of aging, which we compiled from the literature, 75 were represented in the used microarrays, 26 out of them were downregulated in the TME cells during colon cancer colonization of the liver, and none of them were upregulated. The histone modification hallmark of the downregulated geromiRs is significantly enriched with the geromiRs miR-15a, miR-16, miR-26a, miR-29a, miR-29b and miR-29c. We built a network of all of the geromiRs downregulated in the TME cells and their gene targets from the MirTarBase database, and we analyzed the expression of these geromiR gene targets in the TME. We found that Cercam and Spsb4, identified as prognostic markers in a few cancer types, are associated with downregulated geromiRs and are upregulated in the TME cells.This work was supported by grants from Instituto de Salud Carlos III (AC17/00012), cofounded by the European Union projects (European Regional Development Fund/European Science Foundation, Investing in your future), (ERA-Net program EracoSysMed, JTC-2 2017) and (H2020-FETOPEN, Circular Vision, Project 899417); Diputación Foral de Gipuzkoa and the Department of Economic Development and Infrastructures of the Basque Government (DFG109/20) and the Department of Economic Development and Infrastructures of the Basque Government (DFG109/Grants Health Department of the Basque Government (Spain), RIS3 call, Exp. No. 2020333039 and 2020333001. 20)

Proprotein convertases blockage up-regulates specifically metallothioneins coding genes in human colon cancer stem cells

ABSTRACT: Despite continuous exertion made, colon cancer still represents a major health problem and its incidence continues being high worldwide. There is growing evidence in support of the cancer stem cells (CSCs) being central in the initiation of this cancer, and CSCs have been the focus of various studies for the identification of new ways of treatment. Lately, the proprotein convertases (PCs) were reported to regulate the maturation and expression of various molecules involved in the malignant phenotype of colon cancer cells, however, the identity of the molecules regulated by these serine proteases in CSCs is unknown. In this study, we used the general PCs inhibitor, the Decanoyl-RVKR-chloromethylketone (Decanoyl-RVKR-CMK) that inhibits all the PCs found in the secretory pathway, and analyzed its effect on CSCs using RNA-seq analysis. Remarkably, from the only 9 upregulated genes in the human SW620-derived sphere-forming cells, we identified 7 of the 11 human metallothioneins, all of them localized on chromosome 16, and zinc related proteins as downstream effectors of the PCs. The importance of these molecules in the regulation of cell proliferation, differentiation and chemoresistance, and their reported potential tumor suppressor role and loss in colon cancer patients associated with worse prognosis, suggests that targeting PCs in the control of the malignant phenotype of CSCs is a new potential therapeutic strategy in colon cancer

Is There Such a Thing as a Genuine Cancer Stem Cell Marker? Perspectives from the Gut, the Brain and the Dental Pulp

The conversion of healthy stem cells into cancer stem cells (CSCs) is believed to underlie tumor relapse after surgical removal and fuel tumor growth and invasiveness. CSCs often arise from the malignant transformation of resident multipotent stem cells, which are present in most human tissues. Some organs, such as the gut and the brain, can give rise to very aggressive types of cancers, contrary to the dental pulp, which is a tissue with a very remarkable resistance to oncogenesis. In this review, we focus on the similarities and differences between gut, brain and dental pulp stem cells and their related CSCs, placing a particular emphasis on both their shared and distinctive cell markers, including the expression of pluripotency core factors. We discuss some of their similarities and differences with regard to oncogenic signaling, telomerase activity and their intrinsic propensity to degenerate to CSCs. We also explore the characteristics of the events and mutations leading to malignant transformation in each case. Importantly, healthy dental pulp stem cells (DPSCs) share a great deal of features with many of the so far reported CSC phenotypes found in malignant neoplasms. However, there exist literally no reports about the contribution of DPSCs to malignant tumors. This raises the question about the particularities of the dental pulp and what specific barriers to malignancy might be present in the case of this tissue. These notable differences warrant further research to decipher the singular properties of DPSCs that make them resistant to transformation, and to unravel new therapeutic targets to treat deadly tumors.This work has been financed by The University of The Basque Country (UPV/EHU): Grant number GIU16/66, UFI 11/44, COLAB19/03 and IKERTU-2020.0155 (to F.U), the Basque Government/Eusko Jaurkaritza: ELKARTEK KK-2019/00093 (to U.F.), and MINECO “Ramón y Cajal” program RYC-2013-13450 and MINECO PID2019-104766RB-C21 (to P.J.R.). L.J. was funded by a UPV/EHU postdoctoral fellowship DOKBERRI 2019 (DOCREC19/49) program

Listu-guruinaren enbriogenesia eta seinalizazio-bideak.

Mammalian salivary gland is an epithelial structure that is highly branched during development and is designed to produce and secrete saliva in the body. There are three main types of salivary glands; however, the most commonly studied is submandibular salivary gland. This review describes the different stages of the mouse embryo salivary gland development. At the same time, it summarizes the basic signaling pathways and mechanisms that guide this development process; FGF, Shh, Notch, Wnt, Eda, ECMs and the nervous system. Understanding the mechanisms that operate during development is essential for the design of effective therapies for affected gland and regeneration.; Ugaztunen listu-guruina egitura epitelial bat da, oso adarkatuta garatzen dena eta listua ekoizteko eta jariatzeko diseinatuta dagoena. Gizakietan hiru listu-guruin nagusi daude. Hala ere, barailapeko listu-guruina da aztertuena. Berrikuspen honetan, saguaren barailapeko listu-guruinaren enbrioi-garapeneko garaiak azaltzen dira. Aldi berean, garapeneko prozesu honek gidatzen dituen oinarrizko seinalizazio-bideak eta mekanismoak laburbiltzen dira: FGF, Shh, Notch, Wnt, Eda, ECMak eta nerbio-sistema. Garapenean zehar agertzen diren mekanismoak hobeto ulertzea funtsezkoa da kaltetutako guruinaren birsorkuntza-terapia eraginkorrak diseinatzeko

What Are the Roles of Proprotein Convertases in the Immune Escape of Tumors?

Protein convertases (PCs) play a significant role in post-translational procedures by transforming inactive precursor proteins into their active forms. The role of PCs is crucial for cellular homeostasis because they are involved in cell signaling. They have also been described in many diseases such as Alzheimer’s and cancer. Cancer cells are secretory cells that send signals to the tumor microenvironment (TME), remodeling the surrounding space for their own benefits. One of the most important components of the TME is the immune system of the tumor. In this review, we describe recent discoveries that link PCs to the immune escape of tumors. Among PCs, many findings have determined the role of Furin (PC3) as a paramount enzyme causing the TME to induce tumor immune evasion. The overexpression of various cytokines and proteins, for instance, IL10 and TGF-B, moves the TME towards the presence of Tregs and, consequently, immune tolerance. Furthermore, Furin is implicated in the regulation of macrophage activity that contributes to the increased impairment of DCs (dendritic cells) and T effector cells. Moreover, Furin interferes in the MHC Class_1 proteolytic cleavage in the trans-Golgi network. In tumors, the T cytotoxic lymphocytes (CTLs) response is impeded by the PD1 receptor (PD1-R) located on CTLs and its ligand, PDL1, located on cancer cells. The inhibition of Furin is a subtle means of enhancing the antitumor response by repressing PD-1 expression in tumors or macrophage cells. The impacts of other PCs in tumor immune escape have not yet been clarified to the extent that Furin has. Accordingly, the influence of other types of PCs in tumor immune escape is a promising topic for further consideration

Neural Crest Stem Cells from Dental Tissues: A New Hope for Dental and Neural Regeneration

Several stem cell sources persist in the adult human body, which opens the doors to both allogeneic and autologous cell therapies. Tooth tissues have proven to be a surprisingly rich and accessible source of neural crest-derived ectomesenchymal stem cells (EMSCs), which may be employed to repair disease-affected oral tissues in advanced regenerative dentistry. Additionally, one area of medicine that demands intensive research on new sources of stem cells is nervous system regeneration, since this constitutes a therapeutic hope for patients affected by highly invalidating conditions such as spinal cord injury, stroke, or neurodegenerative diseases. However, endogenous adult sources of neural stem cells present major drawbacks, such as their scarcity and complicated obtention. In this context, EMSCs from dental tissues emerge as good alternative candidates, since they are preserved in adult human individuals, and retain both high proliferation ability and a neural-like phenotype in vitro. In this paper, we discuss some important aspects of tissue regeneration by cell therapy and point out some advantages that EMSCs provide for dental and neural regeneration. We will finally review some of the latest research featuring experimental approaches and benefits of dental stem cell therapy