Browsing by Subject "Tumor"
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- PublicationOpen AccessAutophagy in the immunosuppressive perivascular microenvironment of glioblastoma(MDPI, 2019-12-31) Molina Gallego, María Luisa; García Bernal, David; Martínez Pérez, Salvador; Valdor Alonso, Rut; Bioquímica y Biología Molecular B e InmunologíaGlioblastoma (GB) has been shown to up-regulate autophagy with anti- or pro-oncogenic effects. Recently, our group has shown how GB cells aberrantly up-regulate chaperone-mediated autophagy (CMA) in pericytes of peritumoral areas to modulate their immune function through cell-cell interaction and in the tumor’s own benefit. Thus, to understand GB progression, the effect that GB cells could have on autophagy of immune cells that surround the tumor needs to be deeply explored. In this review, we summarize all the latest evidence of several molecular and cellular immunosuppressive mechanisms in the perivascular tumor microenvironment. This immunosuppression has been reported to facilitate GB progression and may be differently modulated by several types of autophagy as a critical point to be considered for therapeutic interventions.
- PublicationOpen AccessChaperone-mediated autophagy ablation in pericytes reveals new glioblastoma prognostic markers and efficient treatment against tumor progression(2022-03-18) Molina Gallego, María Luisa; García-Bernal, David; Salinas, María Dolores; Rubio, Gonzalo; Aparicio, Pedro; Moraleda, José M.; Martínez, Salvador; Valdor, Rut; Bioquímica y Biología Molecular B e InmunologíaBackground: The lack of knowledge of the progression mechanisms of glioblastoma (GB), the most aggressive brain tumor, contributes to the absence of successful therapeutic strategies. Our team has recently demonstrated a crucial new role for chaperone-mediated autophagy (CMA) in pericytes (PC)-acquired immunosuppressive function, which prevents anti-tumor immune responses and facilitates GB progression. The possible impact that GB-induced CMA in PC has on other functions that might be useful for future GB prognosis/treatment, has not been explored yet. Thus, we proposed to analyze the contribution of CMA to other GB-induced changes in PC biology and determine if CMA ablation in PC is a key target mechanism for GB treatment. Methods: Studies of RNA-seq and secretome analysis were done in GB-conditioned PC with and without CMA (from knockout mice for LAMP-2A) and compared to control PC. Different therapeutic strategies in a GB mouse model were compared. Results: We found several gene expression pathways enriched in LAMP2A-KO PC and affected by GB-induced CMA in PC that correlate with our previous findings. Phagosome formation, cellular senescence, focal adhesion and the effector function to promote anti-tumor immune responses were the most affected pathways, revealing a transcriptomic profiling of specific target functions useful for future therapies. In addition, several molecules associated with tumor mechanisms and related to tumor immune responses such as gelsolin, periostin, osteopontin, lumican and vitamin D, were identified in the PC secretome dependent on GB-induced CMA. The CMA ablation in PC with GB cells showed an expected immunogenic phenotype able to phagocyte GB cells and a key strategy to develop future therapeutic strategies against GB tumor progression. A novel intravenous therapy using exofucosylated CMA-deficient PC was efficient to make PC reach the tumor niche and facilitate tumor elimination. Conclusion: Our results corroborate previous findings on the impaired immunogenic function of PC with GB-induced CMA, driving to other altered PC functions and the identifications of new target markers related to the tumor immune responses and useful for GB prognosis/therapy. Our work demonstrates CMA ablation in PC as a key target mechanism to develop a successful therapy against GB progression.
- PublicationOpen AccessEditorial: Wnt Signaling in Immune Cell Regulation During Microbial Infection and Cancer(Frontiers, 2020-06-05) Blumenthal, Antje; Martin-Orozco, Elena; Mc Bride, Jere W; Carson, Dennis A; Sen, Malini; Bioquímica y Biología Molecular B e Inmunología
- PublicationOpen AccessExpression of Ccdc85C, a causative protein for murine hydrocephalus, in the mammary gland tumors of dogs(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Tanaka, Natsuki; Izawa, Takeshi; Takenaka, Shigeo; Akiyoshi, Hideo; Yamate, Jyoji; Kuwamura, MitsuruCoiled-coil domain containing 85c (Ccdc85c) is a causative gene for hemorrhagic hydrocephalus mouse which shows hydrocephalus with frequent brain hemorrhage and formation of subcortical band heterotopia. A previous study revealed that Ccdc85C protein is expressed in the systemic simple epithelial cells with proliferative activity in rats and suggested that Ccdc85C expression may be related to the cell proliferation of simple epithelial cells. To reveal the roles of Ccdc85C in the proliferative lesion, we examined the expression patterns of Ccdc85C in the mammary gland tumor of dogs, a common representative tumor derived from simple epithelial cells. In canine mammary gland tumors, Ccdc85C was expressed at the apical junctions of the luminal epithelial cells. Ccdc85C was also distributed throughout the entire cytoplasm of the myoepithelial cells. Ccdc85C expression was observed at the epithelial cells with luminal structures, but was not observed at the epithelial cells forming sheet growth pattern without luminal structure. In carcinomas, Ccdc85C expression in mammary tumor tissue tended to be weaker than that in surrounding normal mammary gland tissue. Ccdc85C is known to cause neurological diseases such as hydrocephalus, and subcortical heterotopia, and the present study is the first to demonstrate Ccdc85C expression in canine mammary tumors and a relationship between Ccdc85C expression and tumor malignancy
- PublicationOpen AccessGlycosylation and lectins-examples of immunesurveillance and immune evasion(Murcia : F. Hernández, 2004) Müller, I.; Jenner, J.; Handgretinger, R.; Riberdy, J.; Kerst, G.Cell surface proteins are posttranslationally modified by tightly regulated enzymes of glycosylation. Typical patterns of glycosylation may signal pathological situations to the immune system. Here, carbohydrate receptors on the surface of cells in the immune system are involved in regulation of effector cells. Moreover, some lectins are circulating in the plasma and take part in host defense. The code of carbohydrate modifications is impaired in malignant cells and yet they are not eliminated. In this review, we focus on recent experimental evidence for regulatory functions of lectins and carbohydrate derivatives in the immune system and tumours.
- PublicationOpen AccessGrading lung neuroendocrine tumors: Controversies in search of a solution(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Pelosi, Giuseppe; Pattini, Linda; Morana, Giovanni; Fabbri, Alessandra; Faccinetto, Alex; Fazio, Nicola; Valeri, Barbara; Sonzogni, AngelicaBackground. Pathological grading of tumors is a way to measure biological aggressiveness. In lung neuroendocrine tumors (NET), grading is tautologically included into the current 2015 WHO histologic classification. Little is known, however, about alternative grading systems in lung NET. Methods. Through an extensive search of the English literature on lung NET (updated to April 2016), the following key questions were addressed: a) current concepts of grading; b) clinicians’ requests for grading; c) functional parameters for grading; d) Ki-67 labeling index (LI) for grading; e) towards an effective pathology grading system. Results. There is some room for inconsistency in the histologic classification of lung NET, likely due to the varying attribution of defining criteria. Innovative diffusion-weighted imaging upon magnetic resonance or molecular analysis could help separate indolent from aggressive lung NET, thus integrating a grading approach other than histology. Troubles in the clinical handling of metastatic or individual tumors when relying on morphology alone support the development of a lungspecific grading system for the more accurate prediction of prognosis and planning therapy in individual patients. To integrate the 2015 WHO classification using innovative grading based on Ki-67 LI, mitotic count and necrosis, a new proposal is emerging where three categories of lung NET are identified, namely Lu-NET G1, Lu-NET G2 and Lu-NET G3, which would allow tumors with similar behavior and therapy to be better handled according to their own biological potential. Conclusion. A new formulation of lung NET grading could have clinical relevance for the individual handling of patients. Key words:
- PublicationOpen AccessHypoxia-inducible factor (HIF) in human tumorigenesis(Murcia : F. Hernández, 2007) Mabjeesh, N.J.; Amir, S.Hypoxia is a major event that occurs in most solid tumors. Intratumoral hypoxia is sufficient to activate the key transcription factor, hypoxia-inducible factor (HIF) that mediates the activation of the “survival machinery” in cancer cells. HIF can also be induced by oxygen-independent genetic alterations that activate a variety of oncogenic signaling pathways or inactivate tumor suppressors. Increased tumor HIF occurs at early stages of carcinogeniesis and is often correlated with increased angiogenesis, malignant progression, poor patient prognosis and chemoradio-resistance. HIF-a subunit, the oxygen-regulated subunit of HIF is overexpressed in a wide range of human solid tumors. Nuclear HIF-a protein immunostaining was restricted to tumor cells compared to normal tissues. Herein, we review and discuss the role of HIF in tumorigenesis and describe the overexpression of HIF-a proteins in human cancers and its association with overall clinical outcomes
- PublicationOpen AccessLymph node lymphangiogenesis, a new concept for modulating tumor metastasis and inflammatory process(Murcia : F. Hernández, 2009) Ji, R.C.The proliferation of lymphatic endothelial cells (LECs) occurs not only in tumor and inflamed tissues, but also in regional draining lymph nodes (LNs). The lymph node lymphangiogenesis (LNLG) has recently emerged as a prominent area in biomedical research, because it is involved in the pathogenesis of several human diseases. The LEC functional features and lymphatic remodeling regulated by lymphangiogenic factors actively promote tumor metastasis and the inflammation process. VEGFA/ VEGFR-2 and VEGF-C/-D/VEGFR-3 have been implicated as the prime mediators in inflammation- or tumor-induced LNLG. This knowledge may provide a foundation for further understanding of specific modification in the gene expression, cell migration, and differentiation of LECs and other cells in lymphaticassociated diseases. Importantly, it should be taken into consideration that inflammation and lymphangiogenesis are strongly linked in the formation and metastasis of cancer when designing therapeutic strategies.
- PublicationOpen AccessMesenchymal stem cell-derived microRNAs: friends or foes of tumor cells?(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Harrell, Carl Randall; Djonov, Valentin; Volarevic, VladislavMesenchymal stem cell (MSC)-dependent biological effects in the tumor microenvironment mainly rely on the activity of MSC-sourced microRNAs (MSCmiRNAs) which modulate protein synthesis in target tumor cells, endothelial cells and tumor-infiltrated immune cells, regulating their phenotype and function. Several MSC-sourced miRNAs (miR-221, miR-23b, miR-21-5p, miR-222/223, miR-15a miR-424, miR-30b, miR-30c) possess tumor-promoting properties and are able to enhance viability, invasiveness and metastatic potential of malignant cells, induce proliferation and sprouting of tumor endothelial cells and suppress effector functions of cytotoxic tumor-infiltrated immune cells, crucially contributing to the rapid growth and progression of tumor tissue. On the contrary, MSCs also produce “anti-tumorigenic” miRNAs (miR-100, miR222-3p, miR-146b miR-302a, miR-338-5p, miR-100-5p and miR-1246) which suppress tumor growth and progression by: up-regulating expression of chemoresistance-related genes in tumor cells, by suppressing neo-angiogenesis and by inducing generation of tumorotoxic phenotypes in tumor-infiltrated lymphocytes. In this review article, we summarize the current knowledge about molecular mechanisms that are responsible for MSC-miRNA-dependent alterations of intracellular signaling in tumor and immune cells and we discuss different insights regarding the therapeutic potential of MSC-derived miRNAs in cancer treatment.
- PublicationOpen AccessPTTG and cancer(Murcia : F. Hernández, 2003) Hamid, T.; Kakar, S.S.Pituitary tumor transforming gene (pttg) is a recently isolated oncogene that is expressed in most of the tumors. Overexpression of pttg results in an increase in cell proliferation, induces cell transformation in vitro, and promotes tumor formation in nude mice. The gene encodes a protein of 202 amino acids with no significant homology with other known proteins. The protein is a multi domain consisting of a transactivation domain, domain required for ubiquitin-mediated proteolysis and a DNA binding domain. pttg protein is bestowed with a multitude of functions and seems to be involved in most of the important mechanisms of cell proliferation, differentiation and signaling. Given the number of processes that are involved in the manifestation of cancer, it thus becomes mandatory to study the role of this potent oncogene in relation to the processes of cell survival, death and functioning.
- PublicationOpen AccessThe role of TET family proteins and 5-hydroxymethylcytosine in human tumors(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2014) Wu, Yi-Chen; Ling, Zhi-QiangTumorigenesis correlates with hypermethylation of tumor suppressors and hypomethylation of oncogenes. DNA methyltransferases (DNMTs) catalyze DNA methylation, and mutations and aberrant expression in DNMT genes are found in multiple human tumors. The discovery of the DNA demethylation function of TET proteins has opened up new avenues for the study of DNA methylation regulation. TET proteins regulate the DNA demethylation pathway through oxidizing 5-mC into 5-hmC, 5-fC, and 5-aC. TET genes have been reported to be frequently mutated in hematopoietic malignancies and are associated with the malignant transformation of cells. Loss-of-function mutations in TET genes have not been reported in human solid tumors. However, 5-hmC has been found to be reduced in various solid tumors, indicating that TET genes may contribute to cellular transformation via regulation of DNA demethylation. As a new epigenetic modification, 5-hmC may be a useful biomarker for the diagnosis of cancers. To better understand the roles of TET and 5-hmC in tumors, the biological functions of TET and 5-hmC should be studied further.
- PublicationOpen AccessTumor glómico de la mano: una localización extradigital poco habitual(Thieme Gruppe, 2014-05) Albaladejo, Francisco; Sánchez Angulo, P.; Hernández Torralba, M.; Martínez Díaz, Francisco; Redondo Carazo, M. V.; Oftalmología, Optometría, Otorrinolaringología y Anatomía PatológicaLos tumores glómicos representan el 2% de los tumores de la mano. Con mayor frecuencia se trata de tumoraciones únicas, situadas a nivel subungueal, a veces periungueal o en el tejido subcutáneo del pulpejo de los dedos. es infrecuente pero pueden afectarse varios dedos en el mismo paciente. la localización extra digital es poco habitual, haciendo aún más difícil su diagnóstico. Se presenta el caso de una paciente de 45 años con una tumoración redondeada de consistencia dura, situada en la base del pulgar a nivel de la eminencia tenar, de 5 años de evolución, que presentaba dolor a la presión e intolerancia al frío. Su extirpación solucionó la clínica y el estudio anatomo-patológico confirmó el diagnóstico.
- PublicationOpen AccessTumor heterogeneity: morphological, molecular and clinical implications(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Lleonart, M. E.; Martin-Duque, P.; Sanchez-Prieto, R.; Moreno, A.; Ramon y Cajal, S.Malignant tumors are characterized by their great heterogeneity and variability. There are hundreds of different types of malignant tumors that harbour many oncogenic alterations. The tumor heterogeneity has important morphological, molecular and clinical implications. Except for some hematopoietic and lymphoproliferative processes and small cell infant tumors, there are not specific molecular alterations for most human tumors. In this review we summarize the most important aspects of carcinogenesis and chemoradiosensitivity of malignant cells. In this regard, some oncogenes such as neu , ras and bcl-2 have been associated with cellular resistance to treatment with anticancer agents. The knowledge of oncogenic alterations involved in each tumor can be important to correlate the morphological features, the genetic background, the prognosis and the clinical response to treatment with anticancer agents. Based on the molecular background of the tumor there are new cancer gene therapy protocols. For example using adenovirus Ela in tumors with overexpression of neu oncogene, inhibitors of tirosine kinase specific for the PDGF receptor in glioma, inhibitors of farnesil transferase to prevent ras activity in tumors with mutations in the ras gene.
- PublicationOpen AccessTumor-associated fibroblasts (Part II): functional impact on tumor tissue(Murcia : F. Hernández, 2002) Kunz-Schughart, L.A.; Knuechel, R.The article focuses on the functional impact of tumor-associated fibroblasts (TAF) on its surrounding cells. It intends to cover the recent knowledge on TAF, the phenotype, and expression profile of which have been described in the first part of the rev i ew series ( Kunz-Schughart and Knuechel, 2002). The present r ev i ew is subdivided into two main chapters: (1) functional impact of TAF on tumor cells and (2) fibroblast-host cell interactions in tumor tissue. In the first paragraph of chapter (1) about the role of fibroblasts in tumor cell growth and differentiation it is reve a l e d , h ow strongly cellular interaction is dependent on fibroblast and tumor cell type as well as the spatial ratio between the cells. The variation of cellular behav i o r depending on quantity of molecules holds also true for the group of ECM molecules, e.g. the balance between MMPs and TIMPs, which provide an interesting therapeutic target in tumor tissue. This is one of the topics addressed in the second paragraph which focuses on tumor cell dissemination. Chapter (2) addresses the relation of TAF to other intra- or peritumoral host cells. The hypoxia-related angiogenesis induction of fibroblasts via growth factor secretion (e.g. VEGF) is considered as important as the immune modulatory properties of fibroblasts on immune cells, such as m o n o cytes/macrophages. These cellular properties can be tested under controlled conditions in threedimensional heterologous cultures of human cells, p r oviding the chance for systematic modification to assess therapeutic effects in an in vivo like environment.
- PublicationOpen AccessUltrastructure and light microscopical study of a Leydig cell tumor of the testis associated with bilateral gynaecomastia(Murcia : F. Hernández, 1989) Muro, M. Moreno; Menchero, S. Coca; Pelegrín, J. A. Martos; Hernández, A. IzquierdoLight and electronmicroscopic study of a Leydig cell testicular tumor in an 18-year-old male is presented. Bilateral gynaecomastia and normal hormonal blood levels were found. Emphasis on the diagnostic value of electronmicroscopy is remarked upon, based on the following ultrastructural characteristics of the cells; 1) Ovoid shaped nuclei with ondulating contours and dispersed and homogeneous chromatin, 2) Rich agranular endoplasmic reticulum with frequent special modifications, such as membranous whorls with a central cytoplasmic mass or lipid droplets, 3) Numerous mitochondria with occasional tubular cristae, 4) Numerous lipid vacuoles. Other structures also identified in this tumor are Reinke crystalloids, cytoplasmic microbodies, myelin figures, gap-type junctional complexes and paracrystalline inclusions of Payer type E, which are less common.