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The complex and continuously evolving features of the tumor microenvironment, varying between tumor histotypes, are characterized by the presence of host cells and tumor cells embedded in a milieu shaped by hypoxia and low pH, resulting from the frequent imbalance between vascularity and tumor cell proliferation. These microenvironmental metabolic stressors play a crucial role in remodeling host cells and tumor cells, contributing to the stimulation of cancer cell heterogeneity, clonal evolution, and multidrug resistance, ultimately leading to progression and metastasis. The extracellular vesicles (EVs), membrane-enclosed structures released into the extracellular milieu by tumor/host cells, are now recognized as critical drivers in the complex intercellular communication between tumor cells and the local cellular components in a hypoxic/acidic microenvironment. Understanding the intricate molecular mechanisms governing the interactions between tumor and host cells within a hypoxic and acidic microenvironment, triggered by the release of EVs, could pave the way for innovative strategies to disrupt the complex interplay of cancer cells with their microenvironment. This approach may contribute to the development of an efficient and safe therapeutic strategy to combat cancer progression. Therefore, we review the major findings on the release of EVs in a hypoxic/acidic tumor microenvironment to appreciate their role in tumor progression toward metastatic disease.
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Ovarian cancer is the deadliest gynaecologic malignancies worldwide. Platinum based chemotherapy is the mainstay treatment for ovarian cancer; however, frequent recurrence and chemoresistance onset in patients with advanced diseases remain a therapeutic challenge. Although mechanisms underlying the development of chemoresistance are still ambiguous, the B-cell lymphoma-2 (Bcl-2) family is closely associated with chemoresistance in ovarian cancer. We previously disclosed that Zeta-Crystallin (CryZ) is a post-transcriptional regulator of Bcl-2 gene expression, by binding to Bcl-2 mRNA and increasing its half-life. Here, we investigated the role of CryZ as a novel therapeutic target in A2780 ovarian carcinoma cells by modulating the protein activity with acetylsalicylic acid (ASA) to restore chemosensitivity. Molecular docking and fragment-mapping based approach revealed potential interaction of ASA within CryZ protein. Inhibition of CryZ binding activity to Bcl-2 and Bcl-xl mRNA targets by ASA was demonstrated in A375 cells. Cytotoxicity assays were conducted in A2780S and A2780R ovarian cancer cells to evaluate if CryZ binding activity inhibition and CryZ silencing were able to reverse cisplatin resistance. ASA-treatment determined a downregulation of Bcl-2 and Bcl-xl mRNA levels in A2780S and A2780R cells. ASA-treatment or CryZ silencing were able to increase and restore the chemosensitivity in both sensitive and resistant A2780 ovarian cancer cells, respectively. In this research article we demonstrated that the pharmacological or genetic inhibition of CryZ restores the sensitivity to cisplatin in a model of sensitive or resistant ovarian cancer cells. These findings suggest a new gene-targeted chemotherapeutic approach to restore the cytotoxicity in drug-resistant ovarian cancers and increase the sensitivity in non-resistant cells.
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BACKGROUND: Human Amniotic Membrane (hAM) is endowed with several biological activities and might be considered an optimal tool in surgical treatment for different ophthalmic pathologies. We pioneered the surgical use of hAM to treat retinal pathologies such as macular holes, tears, and retinal detachments, and to overcome photoreceptor damage in age-related macular degeneration. Although hAM contributed to improved outcomes, the mechanisms of its effects are not yet fully understood. The characterization and explanation of the effects of hAM would allow the adoption of this new natural product in different retinal pathologies, operative contexts, and hAM formulations. At this end, we studied the properties of a hAM extract (hAME) on the ARPE-19 cells. METHODS AND RESULTS: A non-denaturing sonication-based technique was developed to obtain a suitable hAME. Viability, proliferation, apoptosis, oxidative stress, and epithelial-mesenchymal transition (EMT) were studied in hAME-treated ARPE-19 cells. The hAME was able to increase ARPE-19 cell viability even in the presence of oxidative stress (H2O2, TBHP). Moreover, hAME prevented the expression of EMT features, such as EMT-related proteins, fibrotic foci formation, and migration induced by different cytokines. CONCLUSIONS: Our results demonstrate that the hAME retains most of the properties observed in the whole tissue by others. The hAME, other than providing a manageable research tool, could represent a cost-effective and abundant drug to treat retinal pathologies in the future.
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Amnios , Apoptosis , Proliferación Celular , Supervivencia Celular , Estrés Oxidativo , Epitelio Pigmentado de la Retina , Humanos , Amnios/citología , Amnios/efectos de los fármacos , Línea Celular , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/citología , Supervivencia Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Extractos de Tejidos/farmacologíaRESUMEN
Gastric cancer (GC) is the fifth most frequent malignancy and the fourth leading cause of worldwide cancer-related death. Despite the usage of multimodal perioperative chemotherapy (pCT), GC progressively gains chemoresistance, thereby, the identification of suitable targets to overcome drug resistance is fundamental. Amongst the potential biomarkers, carbonic anhydrase IX (CAIX) - associated with a poor prognosis of several solid cancers - has gained the most attention. In a cohort of GC patients who received perioperative FLOT (i.e., Leucovorin, 5-Fluouracil, Docetaxel, and Oxaliplatin) or FOLFOX (i.e., Leucovorin, 5-Fluouracil, and Oxaliplatin), non-responder patients showed an increased expression of tumor CAIX compared to responder group. Moreover, GC cell lines induced to be resistant to 5-Fluouracil, Paclitaxel, Cisplatin, or the combination of 5-Fluorouracil, Oxaliplatin, and Docetaxel, overexpressed CAIX compared to the control. Accordingly, CAIX-high-expressing GC cells showed increased therapy resistance compared to low-expressing cells. Notably, SLC0111 significantly improved the therapy response of both wild-type and resistant GC cells. Overall, these data suggest a correlation between CAIX and GC drug resistance highlighting the potential of SLC-0111 in re-sensitizing GC cells to pCT.
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Antineoplásicos , Inhibidores de Anhidrasa Carbónica , Neoplasias Gástricas , Humanos , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasa Carbónica IX/genética , Anhidrasa Carbónica IX/metabolismo , Línea Celular , Docetaxel/farmacología , Fluorouracilo/farmacología , Leucovorina/farmacología , Oxaliplatino/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Taxoides/farmacología , Taxoides/uso terapéutico , Línea Celular TumoralRESUMEN
Blood vessels are the most important way for cancer cells to survive and diffuse in the body, metastasizing distant organs. During the process of tumor expansion, the neoplastic mass progressively induces modifications in the microenvironment due to its uncontrolled growth, generating a hypoxic and low pH milieu with high fluid pressure and low nutrients concentration. In such a particular condition, reactive oxygen species play a fundamental role, enhancing tumor proliferation and migration, inducing a glycolytic phenotype and promoting angiogenesis. Indeed, to reach new sources of oxygen and metabolites, highly aggressive cancer cells might produce a new abnormal network of vessels independently from endothelial cells, a process called vasculogenic mimicry. Even though many molecular markers and mechanisms, especially in gastric cancer, are still unclear, the formation of such intricate, leaky and abnormal vessel networks is closely associated with patients' poor prognosis, and therefore finding new pharmaceutical solutions to be applied along with canonical chemotherapies in order to control and normalize the formation of such networks is urgent.
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Neoplasias Gástricas , Humanos , Especies Reactivas de Oxígeno , Células Endoteliales/metabolismo , Línea Celular Tumoral , Neovascularización Patológica/metabolismo , Microambiente TumoralRESUMEN
Oleocanthal, a minor polar compound in extra-virgin olive (EVO) oil, contains anticancer properties, which should be encouraged in its use in oncology. Gastric Cancer (GC), a very aggressive human cancer, is often diagnosed at advanced stages, when surgery is substituted or supported by chemotherapy (CT). However, CT frequently fails due to the patient's resistance to the treatment. Thus, the aim of this study is to verify whether an OC-enriched EVO oil extract fraction (OCF) may be useful in order to overcome a resistance to GC. We evaluated the OCF effects on an AGS gastric adenocarcinoma cell line wild type (AGS wt) and on its subpopulations resistant to 5-fluorouracil (5FUr), Paclitaxel (TAXr) or cisplatin (CISr). We found that a 60 µM dose of the OCF acts on the AGS wt, 5FUr and TAXr, leading to the cell cycle inhibition and to a ROS production, but not on CISr cells. Resistance of CISr to the OCF seems to be due to higher levels of antioxidant-enzymes that can counteract the OCF-induced ROS production. Moreover, using the OCF plus 5-fluorouracil, Paclitaxel or cisplatin, we found a potentiating effect compared with a mono-treatment in all resistant GC cells, including CISr. In conclusion, the use of the OCF in the management of GC has shown very interesting advantages, opening-up the possibility to evaluate the efficacy of the OCF in vivo, as a valid adjuvant in the treatment of resistant GC.
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Chemotherapy is still widely used as a coadjutant in gastric cancer when surgery is not possible or in presence of metastasis. During tumor evolution, gatekeeper mutations provide a selective growth advantage to a subpopulation of cancer cells that become resistant to chemotherapy. When this phenomenon happens, patients experience tumor recurrence and treatment failure. Even if many chemoresistance mechanisms are known, such as expression of ATP-binding cassette (ABC) transporters, aldehyde dehydrogenase (ALDH1) activity and activation of peculiar intracellular signaling pathways, a common and universal marker for chemoresistant cancer cells has not been identified yet. In this study we subjected the gastric cancer cell line AGS to chronic exposure of 5-fluorouracil, cisplatin or paclitaxel, thus selecting cell subpopulations showing resistance to the different drugs. Such cells showed biological changes; among them, we observed that the acquired chemoresistance to 5-fluorouracil induced an endothelial-like phenotype and increased the capacity to form vessel-like structures. We identified the upregulation of thymidine phosphorylase (TYMP), which is one of the most commonly reported mutated genes leading to 5-fluorouracil resistance, as the cause of such enhanced vasculogenic ability.
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Resistencia a Antineoplásicos , Fluorouracilo/farmacología , Neovascularización Patológica/inducido químicamente , Neoplasias Gástricas/irrigación sanguínea , Neoplasias Gástricas/tratamiento farmacológico , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Fluorouracilo/metabolismo , Humanos , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Paclitaxel/farmacología , Neoplasias Gástricas/patología , Talidomida/farmacología , Timidina Fosforilasa/genética , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Present study addresses the challenge of incorporating hydrophilic streptomycin sulphate (STRS; log P -6.4) with high dose (1 g/day) into a lipid matrix of SLNs. Cold high-pressure homogenization technique used for SLN preparation achieved 30% drug loading and 51.17 ± 0.95% entrapment efficiency. Polyethylene glycol 600 as a supporting-surfactant assigned small size (218.1 ± 15.46 nm) and mucus-penetrating property. It was conceived to administer STRS-SLNs orally rather than intramuscularly. STRS-SLNs remained stable on incubation for varying times in SGF or SIF. STRS-SLNs were extensively characterised for microscopic (TEM and AFM), thermal (DSC), diffraction (XRD) and spectroscopic (NMR and FTIR) properties and showed zero-order controlled release. Enhanced (60 times) intracellular uptake was observed in THP-1 and Pgp expressing LoVo and DLD-1 cell lines, using fluorescein-SLNs. Presence of SLNs in LoVo cells was also revealed by TEM studies. STRS-SLNs showed 3 times reduction in MIC against Mycobacterium tuberculosis H37RV (256182) in comparison to free STRS. It also showed better activity against both M. bovis BCG and Mycobacterium tuberculosis H37RV (272994) in comparison to free STRS. Cytotoxicity and acute toxicity studies (OECD 425 guidelines) confirmed in vitro and in vivo safety of STRS-SLNs. Single-dose oral pharmacokinetic studies in rat plasma using validated LCMS/MS technique or the microbioassay showed significant oral absorption and bioavailability (160% - 710% increase than free drug).
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Antituberculosos/administración & dosificación , Portadores de Fármacos/química , Mycobacterium bovis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Estreptomicina/administración & dosificación , Administración Oral , Animales , Antituberculosos/química , Antituberculosos/farmacocinética , Antituberculosos/toxicidad , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Composición de Medicamentos/métodos , Liberación de Fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Lípidos/química , Macrófagos/metabolismo , Masculino , Pruebas de Sensibilidad Microbiana , Nanopartículas/química , Tamaño de la Partícula , Ratas , Solubilidad , Estreptomicina/química , Estreptomicina/farmacocinética , Estreptomicina/toxicidad , Células THP-1 , Pruebas de Toxicidad AgudaRESUMEN
The present study describes a special lipid-polyethylene glycol matrix solid lipid nanoparticles (SLNs; 138 nm; -2.07 mV) for ocular delivery. Success of this matrix to encapsulate (entrapment efficiency - 62.09%) a hydrophilic drug, fluconazole (FCZ-SLNs), with no burst release (67% release in 24 h) usually observed with most water-soluble drugs, is described presently. The system showed 164.64% higher flux than the marketed drops (Zocon®) through porcine cornea. Encapsulation within SLNs and slow release did not compromise efficacy of FCZ-SLNs. Latter showed in vitro and in vivo antifungal effects, including antibiofilm effects comparable to free FCZ solution. Developed system was safe and stable (even to sterilisation by autoclaving); and showed optimal viscosity, refractive index and osmotic pressure. These SLNs could reach up to retina following application as drops. The mechanism of transport via corneal and non-corneal transcellular pathways is described by fluorescent and TEM images of mice eye cross sections. Particles streamed through the vitreous, crossed inner limiting membrane and reached the outer retinal layers.
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Antifúngicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Fluconazol/administración & dosificación , Liposomas , Nanopartículas , Animales , Antifúngicos/farmacocinética , Antifúngicos/farmacología , Biopelículas/efectos de los fármacos , Línea Celular , Química Farmacéutica/métodos , Córnea/metabolismo , Portadores de Fármacos/química , Liberación de Fármacos , Femenino , Fluconazol/farmacocinética , Fluconazol/farmacología , Ratones , Ratones Endogámicos C57BL , Polietilenglicoles/química , Segmento Posterior del Ojo/metabolismo , Conejos , Ratas , Porcinos , Distribución TisularRESUMEN
To date, 5-Fluorouracil (5FU) is a major component of several chemotherapy regimens, thus its study is of fundamental importance to better understand all the causes that may lead to chemoresistance and treatment failure. Given the evident differences between prognosis in Asian and Caucasian populations, triggered by clear genetic discordances and given the extreme genetic heterogeneity of gastric cancer (GC), the evaluation of the most frequent mutations in every single member of the 5FU conversion and activation pathway might reveal several important results. Here, we exploited the cBioPortal analysis software to query a large databank of clinical and wide-genome studies to evaluate the components of the three major 5FU transformation pathways. We demonstrated that mutations in such ways were associated with a poor prognosis and reduced overall survival, often caused by a deletion in the TYMP gene and amplification in TYMS. The use of prodrugs and dihydropyrimidine dehydrogenase (DPD) inhibitors, which normally catabolizes 5FU into inactive metabolites, improved such chemotherapies, but several steps forward still need to be taken to select better therapies to target the chemoresistant pools of cells with high anaplastic features and genomic instability.
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Acidosis characterizes the microenvironment of most solid tumors and is considered a new hallmark of cancer. It is mainly caused by both "aerobic" and "anaerobic" glycolysis of differently adapted cancer cells, with the final product lactic acid being responsible of the extracellular acidification. Many evidences underline the role of extracellular acidosis in tumor progression. Among the different findings, we demonstrated that acidosis-exposed cancer cells are characterized by an epithelial-to-mesenchymal transition phenotype with high invasive ability, high resistance to apoptosis, anchorage-independent growth, and drug therapy. Acidic melanoma cells over-express SOX2, which is crucial for the maintenance of their oxidative metabolism, and carbonic anhydrase IX, that correlates with poor prognosis of cancer patients. Considering these evidences, we realized that the profile outlined for acid cancer cells inevitably remind us the stemness profile. Therefore, we wondered whether extracellular acidosis might induce in cancer cells the acquisition of stem-like properties and contribute to the expansion of the cancer stem cell sub-population. We found that a chronic adaptation to acidosis stimulates in cancer cells the expression of stem-related markers, also providing a high in vitro/in vivo clonogenic and trans-differentiating ability. Moreover, we observed that the acidosis-induced stem-like phenotype of melanoma cells was reversible and related to the EMT induction. These findings help to characterize a further aspect of stem cell niche, contributing to the sustainment and expansion of cancer stem cell subpopulation. Thus, the usage of agents controlling tumor extracellular acidosis might acquire great importance in the clinic for the treatment of aggressive solid tumor. KEY MESSAGES: ⢠Extracellular acidosis up-regulates EMT and stem-related markers in melanoma cells ⢠Acidic medium up-regulates in vitro self-renewal capacity of melanoma cells ⢠Chronic acidosis adaptation induces trans-differentiation ability in melanoma cells ⢠Melanoma cells adapted to acidosis show higher tumor-initiating potential than control cells ⢠Extracellular acidosis promotes a stem-like phenotype in prostate and colorectal carcinoma cells.
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Melanoma/metabolismo , Melanoma/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Microambiente Tumoral , Acidosis/metabolismo , Animales , Apoptosis , Biomarcadores , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Espacio Extracelular , Femenino , Glucólisis , Humanos , Concentración de Iones de Hidrógeno , Melanoma/etiología , Ratones , FenotipoRESUMEN
In the original version of this article Ana Guzman-Aranguez's name appeared incorrect.
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Gastric cancer (GC) is turning out today to be one of the most important welfare issues for both Asian and European countries. Indeed, while the vast majority of the disease burden is located in China and in Pacific and East Asia, GC in European countries still account for about 100,000 deaths per year. With this review article, we aim to focus the attention on one of the most complex cellular pathways involved in GC proliferation, invasion, migration, and metastasis: the MAP kinases. Such large kinases family is to date constantly studied, since their discovery more than 30 years ago, due to the important role that it plays in the regulation of physiological and pathological processes. Interactions with other cellular proteins as well as miRNAs and lncRNAs may modulate their expression influencing the cellular biological features. Here, we summarize the most important and recent studies involving MAPK in GC. At the same time, we need to underly that, differently from cancers arising from other tissues, where MAPK pathways seems to be a gold target for anticancer therapies, GC seems to be unique in any aspect. Our aim is to review the current knowledge in MAPK pathways alterations leading to GC, including H. pylori MAPK-triggering to derail from gastric normal epithelium to GC and to encourage researches involved in MAPK signal transduction, that seems to definitely sustain GC development.
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Sistema de Señalización de MAP Quinasas , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neoplasias Gástricas/metabolismo , Animales , Biomarcadores , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Susceptibilidad a Enfermedades , Epigénesis Genética , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/microbiología , Helicobacter pylori , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , MicroARNs/genética , Metástasis de la Neoplasia , Estadificación de Neoplasias , ARN Largo no Codificante/genética , Neoplasias Gástricas/etiología , Neoplasias Gástricas/patologíaRESUMEN
Statins, widely prescribed for cardiovascular diseases, are also being eyed for management of age-related macular degeneration (AMD). Poor bioavailability and blood-aqueous barrier may however limit significant ocular concentration of statins following oral administration. We for the first time propose and investigate local application of atorvastatin (ATS; representative statin) loaded into solid lipid nanoparticles (SLNs), as self-administrable eye drops. Insolubility, instability, and high molecular weight > 500 of ATS, and ensuring that SLNs reach posterior eye were the challenges to be met. ATS-SLNs, developed (2339/DEL/2014) using suitable components, quality-by-design (QBD) approach, and scalable hot high-pressure homogenization, were characterized and evaluated comprehensively for ocular suitability. ATS-SLNs were 8 and 12 times more bioavailable (AUC) in aqueous and vitreous humor, respectively, than free ATS. Three-tier (in vitro, ex vivo, and in vivo) ocular safety, higher corneal flux (2.5-fold), and improved stability (13.62 times) including photostability of ATS on incorporation in ATS-SLNs were established. Autoclavability and aqueous nature are the other highlights of ATS-SLNs. Presence of intact fluorescein-labeled SLNs (F-SLNs) in internal eye tissues post-in vivo application as eye drops provides direct evidence of successful delivery. Perinuclear fluorescence in ARPE-19 cells confirms the effective uptake of F-SLNs. Prolonged residence, up to 7 h, was attributed to the mucus-penetrating nature of ATS-SLNs. Graphical abstract.
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Atorvastatina/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Lípidos/administración & dosificación , Nanopartículas/administración & dosificación , Soluciones Oftálmicas/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Atorvastatina/química , Atorvastatina/farmacocinética , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Córnea/metabolismo , Liberación de Fármacos , Células Epiteliales/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Lípidos/química , Lípidos/farmacocinética , Degeneración Macular/tratamiento farmacológico , Masculino , Nanopartículas/química , Soluciones Oftálmicas/química , Soluciones Oftálmicas/farmacocinética , Permeabilidad , Conejos , Ratas , PorcinosRESUMEN
Crystallins were firstly found as structural proteins of the eye lens. To this family belong proteins, such as ζ-crystallin, expressed ubiquitously, and endowed with enzyme activity. ζ-crystallin is a moonlighting protein endowed with two main different functions: (1) mRNA binding with stabilizing activity; (2) NADPH:quinone oxidoreductase. ζ-crystallin has been clearly demonstrated to stabilize mRNAs encoding proteins involved in renal glutamine catabolism during metabolic acidosis resulting in ammoniagenesis and bicarbonate ion production that concur to compensate such condition. ζ-crystallin binds also mRNAs encoding for antiapoptotic proteins, such as Bcl-2 in leukemia cells. On the other hand, the physiological role of its enzymatic activity is still elusive. Gathering research evidences and data mined from public databases, we provide a framework where all the known ζ-crystallin properties are called into question, making it a hypothetical pivotal player in cancer, allowing cells to hijack or subjugate the acidity response mechanism to increase their ability to resist oxidative stress and apoptosis, while fueling their glutamine addicted metabolism.
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Neoplasias/metabolismo , zeta-Cristalinas/metabolismo , Acidosis/metabolismo , Amoníaco/metabolismo , Animales , Apoptosis , Glutamina/metabolismo , Humanos , Estrés Oxidativo , Unión Proteica , ARN Mensajero/metabolismoRESUMEN
Gastric cancer is an active topic of clinical and basic research due to high morbidity and mortality. To date, gastrectomy and chemotherapy are the only therapeutic options for gastric cancer patients, but drug resistance, either acquired or primary, is the main cause for treatment failure. Differences in development and response to cancer treatments have been observed among ethnically diverse GC patient populations. In spite of major incidence, GC Asian patients have a significantly better prognosis and response to treatments than Caucasian ones due to genetic discordances between the two populations. Gene therapy could be an alternative strategy to overcome such issues and especially CRISPR/Cas9 represents one of the most intriguing gene-editing system. Thus, in this review article, we want to provide an update on the currently used therapies for the treatment of advanced GC. Graphical abstract.
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Terapia Genética/métodos , Neoplasias Gástricas/terapia , Terapia Genética/tendencias , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Gástricas/genéticaRESUMEN
Carbonic anhydrase (CA, EC 4.2.1.1) IX is regarded as a tumour hypoxia marker and CA inhibitors have been proposed as a new class of antitumor agents, with one such agent in Phase II clinical trials. The expression of some CAs, in particular the isoforms CA IX and CA XII, has been correlated with tumour aggressiveness and progression in several cancers. The aim of this study was to evaluate the possibility that CA IX could represent a marker related to clear cell Renal Cell Carcinoma (ccRCC). Bcl-2 and Bax, and the activity of caspase-3, evaluated in tissue biopsies from patients, were congruent with resistance to apoptosis in ccRCCs with respect to healthy controls, respectively. In the same samples, the CA IX and pro-angiogenic factor VEGF expressions revealed that both these hypoxia responsive proteins were strongly increased in ccRCC with respect to controls. CA IX plasma concentration and CA activity were assessed in healthy volunteers and patients with benign kidney tumours and ccRCCs. CA IX expression levels were found strongly increased only in plasma from ccRCC subjects, whereas, CA activity was found similarly increased both in plasma from ccRCC and benign tumour patients, compared to healthy volunteers. These results show that the plasmatic level of CA IX, but not the CA total activity, can be considered a diagnostic marker of ccRCCs. Furthermore, as many reports exist relating CA IX inhibition to a better outcome to anticancer therapy in ccRCC, plasma levels of CA IX could be also predictive for response to therapy.
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Biomarcadores de Tumor , Anhidrasa Carbónica IX/sangre , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/diagnóstico , Anciano , Western Blotting , Anhidrasa Carbónica IX/genética , Anhidrasa Carbónica IX/metabolismo , Carcinoma de Células Renales/enzimología , Caspasa 3/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia ArribaRESUMEN
Fibroblast growth factor 2 (FGF2) is involved in many physiological and pathological processes. Fgf2 deregulation contributes to the acquisition of malignant features of melanoma and other cancers. FGF2 is an alternative translation product expressed as five isoforms, a low-molecular-weight (18 KDa) and four high-molecular-weight (22, 22.5, 24, 34 KDa) isoforms, with different subcellular distributions. An internal ribosomal entry site (IRES) in its mRNA controls the translation of all the isoforms with the exception for the cap-dependent 34 KDa. The 18-KDa isoform has been extensively studied, while very few is known about the roles of high molecular weight isoforms. FGF2 is known to promote melanoma development and progression. To disclose the differential contribution of FGF2 isoforms in melanoma, we forced the expression of IRES-dependent low-molecular-weight (LMW, 18 KDa) and high-molecular-weight (HMW, 22, 22.5, 24 KDa) isoforms in a human metastatic melanoma cell line. This comparative study highlights that, while LMW isoform confers stem-like features to melanoma cells and promotes angiogenesis, HMW isoforms induce higher migratory ability and contribute to tumor perfusion by promoting vasculogenic mimicry (VM) when endothelial cell-driven angiogenesis is lacking. To conclude, FGF2 isoforms mainly behave in specific, antithetical manners, but can cooperate in different steps of tumor progression, providing melanoma cells with major malignant features. KEY MESSAGE: FGF2 is an alternative translation product expressed as different isoforms termed LMW and HMW. FGF2 is involved in melanoma development and progression. HMW FGF2 isoforms enhance in vitro motility of melanoma cells. LMW FGF2 confers stem-like features and increases in vivo metastasization. LMW FGF2 promotes angiogenesis while HMW FGF2 induces vasculogenic mimicry.
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Factor 2 de Crecimiento de Fibroblastos/genética , Sitios Internos de Entrada al Ribosoma , Melanoma/genética , Melanoma/patología , Isoformas de ARN , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Melanoma/metabolismo , Ratones , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Receptores CXCR4/metabolismo , Migración Transendotelial y Transepitelial/genéticaRESUMEN
Ophthalmic mycoses including corneal keratitis or endophthalmitis affects 6-million persons/year and can cause blindness. Its management requires antifungals to penetrate the ocular tissue. Oral use of Ketoconazole (KTZ), the first broad-spectrum antifungal to be marketed, is now restricted to life-threatening infections due to severe adverse effects and drug-interactions. Local use of KTZ loaded nanocarrier system can address its toxicity, poor solubility, photodegradation, permeation and bioavailability issues. Solid lipid nanoparticles (SLNs) comprising Compritol(®) 888 ATO and PEG 600 matrix, were presently prepared using hot high-pressure homogenization. Employing extensive characterization: TEM, NMR, DSC, XRD and FTIR, it is proposed that SLNs comprise of a polyethylene glycol (PEG) core into which KTZ is dissolved. PEG endows the lipid matrix with amorphousness and imperfections; rigidity; and, stability to aggregation, on storage and autoclaving. PEG is a simple, cost-effective and safe polymer with superior solubilizing and surfactant-supporting properties. Without its inclusion KTZ could not be loaded into SLNs. It ensured high incorporation efficiency (70%) of KTZ; small size (126 nm); and, better permeation into the eye. Pharmacokinetic studies indicated 2.5 and 1.6 fold higher bioavailability (AUC) in aqueous and vitreous humor, respectively. Biocompatibility and in vitro (both in corneal and retinal cell lines) and in vivo (in rabbits) ocular safety is the other highlight of developed formulation.