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OBJECTIVES: To assess the efficacy of hydroxychloroquine in combination with azithromycin in terms of clinical and biochemical outcomes in adult patients with COVID-19 hospitalized for acute respiratory distress syndrome (ARDS), and to describe the occurrence of adverse events. METHOD: Retrospective comparative study, based in a quaternary private hospital in Rio de Janeiro, Brazil, involving 193 adult patients hospitalized for mild and moderate COVID-19 related ARSD, analyzing treatment efficacy based on clinical and biochemical outcomes. RESULTS: The active group comprised 101 (52.3%) patients using hydroxychloroquine associated with azithromycin and the control group 92 (47.7%) patients who did not take these medications. Median age was 59 (47-70) in the active group and 65 (47-77) in the control group (pâ¯<â¯0.05). Patients in the control group had greater extent of pulmonary involvement on baseline chest CT scans (pâ¯<â¯0.05). All other baseline variables (BMI, comorbidities, previous use of medications and biochemical assessments) were similar between groups. In the medication group, 25% (25 out of 101) were admitted to the ICU, compared to 21% (19 out of 92) in the control group (pâ¯>â¯0.05). No difference in mortality, duration of non-invasive oxygen use or duration of hospitalization was seen between groups. The therapeutic regimen was well tolerated, with only eight (7.9%) patients presenting gastrointestinal symptoms and eight (7.9%) patients withdrawn treatment due to QTc prolongation. CONCLUSIONS: Patients treated with hydroxychloroquine combined with azithromycin and the control group had similar clinical outcomes. This therapeutic regimen was considered ineffective in hospitalized patients with mild to moderate COVID-19 related ARDS and was associated with few non-severe adverse events.
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Tratamiento Farmacológico de COVID-19 , Hidroxicloroquina , Adulto , Azitromicina/efectos adversos , Brasil , Quimioterapia Combinada , Humanos , Hidroxicloroquina/efectos adversos , Persona de Mediana Edad , Estudios Retrospectivos , SARS-CoV-2RESUMEN
ABSTRACT Objectives: To assess the efficacy of hydroxychloroquine in combination with azithromycin in terms of clinical and biochemical outcomes in adult patients with COVID-19 hospitalized for acute respiratory distress syndrome (ARDS), and to describe the occurrence of adverse events. Method: Retrospective comparative study, based in a quaternary private hospital in Rio de Janeiro, Brazil, involving 193 adult patients hospitalized for mild and moderate COVID-19 related ARSD, analyzing treatment efficacy based on clinical and biochemical outcomes. Results: The active group comprised 101 (52.3%) patients using hydroxychloroquine associated with azithromycin and the control group 92 (47.7%) patients who did not take these medications. Median age was 59 (47-70) in the active group and 65 (47−77) in the control group (p < 0.05). Patients in the control group had greater extent of pulmonary involvement on baseline chest CT scans (p < 0.05). All other baseline variables (BMI, comorbidities, previous use of medications and biochemical assessments) were similar between groups. In the medication group, 25% (25 out of 101) were admitted to the ICU, compared to 21% (19 out of 92) in the control group (p > 0.05). No difference in mortality, duration of non-invasive oxygen use or duration of hospitalization was seen between groups. The therapeutic regimen was well tolerated, with only eight (7.9%) patients presenting gastrointestinal symptoms and eight (7.9%) patients withdrawn treatment due to QTc prolongation. Conclusions: Patients treated with hydroxychloroquine combined with azithromycin and the control group had similar clinical outcomes. This therapeutic regimen was considered ineffective in hospitalized patients with mild to moderate COVID-19 related ARDS and was associated with few non-severe adverse events.
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Humanos , Adulto , COVID-19/tratamiento farmacológico , Hidroxicloroquina/efectos adversos , Brasil , Estudios Retrospectivos , Azitromicina/efectos adversos , Quimioterapia Combinada , SARS-CoV-2 , Persona de Mediana EdadRESUMEN
BACKGROUND: Gastric cancer is the fifth most common cancer and the third cause of global cancer mortality. CDX2 is an intestinal differentiation marker with prognostic value in gastric cancer and transcriptionally regulates the expression of glycoprotein A33 (GPA33) and liver intestine cadherin (LI-cadherin). METHODS: This study evaluated the clinical significance of the combined expression of CDX2 and its targets GPA33 and LI-cadherin in gastric cancer by fluorescence-based multiplex immunohistochemistry together with digital image analysis and chromogenic immunohistochemistry in 329 gastric cancer samples arranged in tissue microarrays. Additionally, publicly available RNA-seq expression data from 354 gastric cancer samples from the TCGA database were used to validate the immunohistochemistry results. RESULTS: Expression of the three markers (CDX2, GPA33, and LI-cadherin) was strongly correlated, defining an intestinal differentiation panel. Low or negative protein expression of the intestinal differentiation panel identified patients with particularly poor overall survival, irrespective of the methodology used, and was validated in the independent series at the RNA-seq level. CONCLUSIONS: Expression of the intestinal differentiation panel (CDX2, GPA33, and LI-cadherin) defines a set of biomarkers with a strong biological rationale and favourable impact for prognostication of gastric cancer patients.
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Antígenos de Diferenciación/metabolismo , Biomarcadores de Tumor/metabolismo , Factor de Transcripción CDX2/metabolismo , Cadherinas/metabolismo , Intestinos/citología , Glicoproteínas de Membrana/metabolismo , Neoplasias Gástricas/patología , Anciano , Diferenciación Celular , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/cirugía , Tasa de SupervivenciaRESUMEN
BACKGROUND: Basal-like breast cancer (BLBC) is a poor prognosis subgroup of triple-negative carcinomas that still lack specific target therapies and accurate biomarkers for treatment selection. P-cadherin is frequently overexpressed in these tumors, promoting cell invasion, stem cell activity and tumorigenesis by the activation of Src-Family kinase (SRC) signaling. Therefore, our aim was to evaluate if the treatment of BLBC cells with dasatinib, the FDA approved SRC inhibitor, would impact on P-cadherin induced tumor aggressive behavior. METHODS: P-cadherin and SRC expression was evaluated in a series of invasive Breast Cancer and contingency tables and chi-square tests were performed. Cell-cell adhesion measurements were performed by Atomic Force Microscopy, where frequency histograms and Gaussian curves were applied. 2D and 3D cell migration and invasion, proteases secretion and self-renew potential were evaluated in vitro. Student's t-tests were used to determine statistically significant differences. The cadherin/catenin complex interactions were evaluated by in situ proximity-ligation assay, and statistically significant results were determined by using Mann-Whitney test with a Bonferroni correction. In vivo xenograft mouse models were used to evaluate the impact of dasatinib on tumor growth and survival. ANOVA test was used to evaluate the differences in tumor size, considering a confidence interval of 95%. Survival curves were estimated by the Kaplan-Meier's method, using the log-rank test to assess significant differences for mice overall survival. RESULTS: Our data demonstrated that P-cadherin overexpression is significantly associated with SRC activation in breast cancer cells, which was also validated in a large series of primary tumor samples. SRC activity suppression with dasatinib significantly prevented the in vitro functional effects of P-cadherin overexpressing cells, as well as their in vivo tumorigenic and metastatic ability, by increasing mice overall survival. Mechanistically, SRC inhibition affects P-cadherin downstream signaling, rescues the E-cadherin/p120-catenin complex to the cell membrane, recovering cell-cell adhesion function. CONCLUSIONS: In conclusion our findings show that targeting P-cadherin/SRC signaling and functional activity may open novel therapeutic opportunities for highly aggressive and poor prognostic basal-like breast cancer.
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Neoplasias de la Mama/patología , Cadherinas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Familia-src Quinasas/antagonistas & inhibidores , Animales , Carcinogénesis/efectos de los fármacos , Cateninas/metabolismo , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Dasatinib/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Metástasis de la Neoplasia , Catenina deltaRESUMEN
Multigene signatures generate crucial prognostic information particularly useful for cancer patients where clinical parameters and traditional immunohistochemical markers alone lead to equivocal prognosis. Clinicians are now provided with molecular tools that assist in the outline of adjuvant therapies, namely helping decide on the extension of adjuvant endocrine therapy or on suppressing adjuvant chemotherapy in patients were toxic effects are particularly deleterious or when this treatment is fundamentally not needed. The importance of cancer multigene prognostic signatures is well elucidated in the guidelines for adjuvant systemic therapy in early-stage breast cancer and the guidelines on disease staging that are progressively integrating gene expression assays as classification biomarkers. In addition to the predictive and prognostic value, some genetic tests provide intrinsic subtyping classification. Herewith, we compare the molecular tests OncotypeDX, MammaPrint, Prosigna, EndoPredict, Breast Cancer Index, Mammostrat, and IHC4 and report the eligibility of each one in the suitable setting. Through to now, there is not a commercially available multigene test that makes recommendations regarding adjuvant treatment for HER-2 and triple negative breast cancers. Thus, these patients still receive adjuvant chemotherapy. Importantly, triple negative carcinomas are very heterogeneous regarding prognosis and new molecular signatures that decipher this very heterogeneous subgroup of breast cancer may improve the clinical management of the disease.
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Studies of the role of actin in tumour progression have highlighted its key contribution in cell softening associated with cell invasion. Here, using a human breast cell line with conditional Src induction, we demonstrate that cells undergo a stiffening state prior to acquiring malignant features. This state is characterized by the transient accumulation of stress fibres and upregulation of Ena/VASP-like (EVL). EVL, in turn, organizes stress fibres leading to transient cell stiffening, ERK-dependent cell proliferation, as well as enhancement of Src activation and progression towards a fully transformed state. Accordingly, EVL accumulates predominantly in premalignant breast lesions and is required for Src-induced epithelial overgrowth in Drosophila. While cell softening allows for cancer cell invasion, our work reveals that stress fibre-mediated cell stiffening could drive tumour growth during premalignant stages. A careful consideration of the mechanical properties of tumour cells could therefore offer new avenues of exploration when designing cancer-targeting therapies.
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Actinas/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Transformación Celular Neoplásica/patología , Fibras de Estrés/patología , Animales , Mama/patología , Neoplasias de la Mama/genética , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Línea Celular , Movimiento Celular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Conjuntos de Datos como Asunto , Drosophila , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Fosforilación , ARN Interferente Pequeño/metabolismo , Imagen de Lapso de Tiempo , Análisis de Matrices Tisulares , Regulación hacia Arriba , Familia-src Quinasas/metabolismoRESUMEN
Axillary lymph node metastases represent the most powerful breast cancer prognostic factor, dictating disease staging and clinical therapeutic decisions. Nonetheless, breast cancer patients with positive lymph nodes still exhibit a heterogeneous behavior regarding disease progression. Stem-like subpopulations of cancer cells show high migratory and metastatic capacity, thus we hypothesize that breast cancer stem cell markers evaluation in metastasized lymph nodes could provide a more accurate prediction of patient's prognosis. Therefore, the expression profile of P-cadherin, CD44, and CD49f, which have been already associated to stem cell properties in breast cancer, has been evaluated by immunohistochemistry in a series of 135 primary tumors and matched axillary lymph node metastases from 135 breast cancer patients. Taking in consideration the expression of the stem cell markers only in axillary nodes, P-cadherin was the only biomarker significantly associated with poor disease-free and overall patient's survival. Moreover, although a concordant expression between primary tumors and matched lymph nodes has been found in the majority of the cases, a small but significant percentage displayed divergent expression (18.2-26.2%). Remarkably, although CD44 and CD49f changes between primary tumors and lymph node metastasis did not impact survival, the cases that were positive for P-cadherin in lymph node metastases being negative in the primary tumor, presented the worst disease-free and overall survival of the whole series. Accordingly, negative cases for this marker in the lymph nodes with positive expression in the matched breast carcinoma demonstrated a better prognosis, which overlapped with tumors that were negative in both sites. P-cadherin and CD49f gain of expression was mainly found in triple-negative carcinomas. Our results indicate for the first time that the evaluation of P-cadherin expression in lymph node metastases is an important predictor of disease outcome, being a putative valuable marker for axillary-based breast cancer decisions in the clinical practice.
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Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Cadherinas/biosíntesis , Metástasis Linfática/patología , Adulto , Anciano , Axila , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Cadherinas/análisis , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , PronósticoRESUMEN
P-cadherin is a classical cell-to-cell adhesion molecule with a homeostatic function in several normal tissues. However, its behaviour in the malignant setting is notably dependent on the cellular context. In some tumour models, such as melanoma and oral squamous cell carcinoma, P-cadherin acts as a tumour suppressor, since its absence is associated with a more aggressive cancer cell phenotype; nevertheless, the overexpression of this molecule is linked to significant tumour promoting effects in the breast, ovarian, prostate, endometrial, skin, gastric, pancreas and colon neoplasms. Herein, we review the role of P-cadherin in cancer cell invasion, as well as in loco-regional and distant metastatic dissemination. We focus in P-cadherin signalling pathways that are activated to induce invasion and metastasis, as well as cancer stem cell properties. The signalling network downstream of P-cadherin is notably dependent on the cellular and tissue context and includes the activation of integrin molecules, receptor tyrosine kinases, small molecule GTPases, EMT transcription factors, and crosstalk with other cadherin family members. As new oncogenic molecular pathways mediated by P-cadherin are uncovered, putative therapeutic options can be tested, which will allow for the targeting of invasion or metastatic disease, depending on the tumour model.
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Cadherinas/metabolismo , Invasividad Neoplásica/patología , Cadherinas/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Humanos , Invasividad Neoplásica/genética , Células Madre Neoplásicas/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: Cancer stem cells are hypoxia-resistant and present a preponderant glycolytic metabolism. These characteristics are also found in basal-like breast carcinomas (BLBC), which show increased expression of cancer stem cell markers.Recently, we demonstrated that P-cadherin, a biomarker of BLBC and a poor prognostic factor in this disease, mediates stem-like properties and resistance to radiation therapy. Thus, the aim of the present study was to evaluate if P-cadherin expression was associated to breast cancer cell populations with an adapted phenotype to hypoxia. METHODS: Immunohistochemistry was performed to address the expression of P-cadherin, hypoxic, glycolytic and acid-resistance biomarkers in primary human breast carcinomas. In vitro studies were performed using basal-like breast cancer cell lines. qRT-PCR, FACS analysis, western blotting and confocal microscopy were used to assess the expression of P-cadherin after HIF-1α stabilization, achieved by CoCl2 treatment. siRNA-mediated knockdown was used to silence the expression of several targets and qRT-PCR was employed to evaluate the effects of P-cadherin on HIF-1α signaling. P-cadherin high and low breast cancer cell populations were sorted by FACS and levels of GLUT1 and CAIX were assessed by FACS and western blotting. Mammosphere forming efficiency was used to determine the stem cell activity after specific siRNA-mediated knockdown, further confirmed by western blotting. RESULTS: We demonstrated that P-cadherin overexpression was significantly associated with the expression of HIF-1α, GLUT1, CAIX, MCT1 and CD147 in human breast carcinomas. In vitro, we showed that HIF-1α stabilization was accompanied by increased membrane expression of P-cadherin and that P-cadherin silencing led to a decrease of the mRNA levels of GLUT1 and CAIX. We also found that the cell fractions harboring high levels of P-cadherin were the same exhibiting more GLUT1 and CAIX expression. Finally, we showed that P-cadherin silencing significantly decreases the mammosphere forming efficiency in the same range as the silencing of HIF-1α, CAIX or GLUT1, validating that all these markers are being expressed by the same breast cancer stem cell population. CONCLUSIONS: Our results establish a link between aberrant P-cadherin expression and hypoxic, glycolytic and acid-resistant breast cancer cells, suggesting a possible role for this marker in cancer cell metabolism.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Cadherinas/metabolismo , Carcinoma Ductal de Mama/metabolismo , Glucólisis , Desequilibrio Ácido-Base/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Anhidrasa Carbónica IX , Anhidrasas Carbónicas/genética , Anhidrasas Carbónicas/metabolismo , Línea Celular Tumoral , Femenino , Expresión Génica , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Fenotipo , Esferoides Celulares/metabolismo , Análisis de Matrices TisularesRESUMEN
P-cadherin is a classical cell-cell adhesion molecule that, in contrast to E-cadherin, has a positive role in breast cancer progression, being considered a poor prognostic factor in this disease. In previous reports, we have shown that this protein induces cancer stem cell and invasive properties to basal-like breast cancer cells. Here, we clarify the downstream signaling pathways that are triggered by P-cadherin to mediate these effects. We demonstrated that P-cadherin inhibition led to a significant decreased adhesion of cancer cells to the basement membrane substrate laminin, as well as to a major reduction in the expression of the laminin receptor α6ß4 integrin. Remarkably, the expression of this heterodimer was required for the invasive capacity and increased mammosphere forming efficiency induced by P-cadherin expression. Moreover, we showed that P-cadherin transcriptionally up-regulates the α6 integrin subunit expression and directly interacts with the ß4 integrin subunit. We still showed that P-cadherin downstream signaling, in response to laminin, involves the activation of focal adhesion (FAK), Src and AKT kinases. The association between the expression of P-cadherin, α6ß4 heterodimer and the active FAK and Src phosphorylated forms was validated in vivo. Our data establish that there is a crosstalk between P-cadherin and the laminin receptor α6ß4 integrin signaling pathway, which link has never been previously described. The activation of this heterodimer explains the stem cell and invasive properties induced by P-cadherin to breast cancer cells, pointing to a new molecular mechanism that may be targeted to counteract the effects induced by this adhesion molecule.
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Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Cadherinas/metabolismo , Integrina alfa6beta4/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Animales , Neoplasias de la Mama/genética , Adhesión Celular/fisiología , Línea Celular Tumoral , Femenino , Xenoinjertos , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Invasividad Neoplásica , Fosforilación , Transducción de Señal , Regulación hacia ArribaRESUMEN
The identification and characterization of cancer stem cells might lead to more effective control of neoplastic disease, by directing therapies to the most aggressive cells. For that reason, the identification of cancer stem cells (CSCs) in breast tumours is one of the priorities in breast cancer research, which has resulted in many studies attempting to identify their presence based on the expression of specific molecular markers. In this review, we describe the main molecular markers that have been identified as being able to recognise CSCs in breast carcinomas, the major molecular pathways that regulate CSCs and their association with the different molecular subtypes.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Células Madre Neoplásicas/patología , Antígeno AC133 , Familia de Aldehído Deshidrogenasa 1 , Animales , Antígenos CD/análisis , Mama/patología , Femenino , Glicoproteínas/análisis , Humanos , Receptores de Hialuranos/análisis , Isoenzimas/análisis , Péptidos/análisis , Retinal-Deshidrogenasa/análisis , Transducción de Señal/fisiología , Vía de Señalización Wnt/fisiologíaRESUMEN
Although the luminal progenitor cell of the normal mammary gland hierarchy has been proposed as the cell-of-origin for basal-like breast cancers, finding the cancer stem cell (CSC) phenotype for this malignancy has proven a difficult task, mostly due to the lack of specific markers. Recently, basal-like sporadic and familial cases of breast cancer have been linked to BRCA1 gene inactivation, which enables the upregulation of the target-repressed CDH3/P-cadherin gene, an important biomarker of basal-like breast carcinomas. Previously, we demonstrated that P-cadherin overexpression can mediate aggressive behavior in these tumors. Thus, our aim was to test whether P-cadherin mediates stem cell properties in basal-like breast carcinomas. Using a series of breast cancer cell lines and primary tumors, we showed that P-cadherin was directly associated with the expression of the breast stem markers CD44, CD49f, and aldehyde dehydrogenase 1 in the basal subtype. Moreover, cell population enriched for P-cadherin expression comprised increased in vitro mammosphere-forming efficiency and capacity to grow colonies in three-dimensional cultures as well as greater tumorigenicity. Importantly, an association was found with stem-/progenitor-like phenotypes of the breast, including the luminal progenitor population, CD49f(+) CD24(+). Additionally, P-cadherin expression conferred resistance to x-ray-induced cell death, sustaining a role for this molecule in another stem cell property. In summary, we demonstrated, for the first time, that P-cadherin mediates stem cell properties, which could be explored in order to better define the CSC phenotype of basal-like breast tumors and the cell-of-origin of this malignancy.
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Neoplasias de la Mama/metabolismo , Cadherinas/biosíntesis , Regulación Neoplásica de la Expresión Génica , Receptores de Hialuranos/biosíntesis , Integrina alfa6/biosíntesis , Proteínas de Neoplasias/biosíntesis , Neoplasias Basocelulares/metabolismo , Células Madre Neoplásicas/metabolismo , Familia de Aldehído Deshidrogenasa 1 , Neoplasias de la Mama/patología , Muerte Celular/efectos de la radiación , Línea Celular Tumoral , Femenino , Humanos , Isoenzimas/biosíntesis , Neoplasias Basocelulares/patología , Células Madre Neoplásicas/patología , Retinal-Deshidrogenasa/biosíntesis , Rayos XRESUMEN
P-cadherin is a cell-cell adhesion molecule, whose expression is highly associated with undifferentiated cells in normal adult epithelial tissues, as well as with poorly differentiated carcinomas. Its expression has been already reported in human embryonic stem cells and it is presumed to be a marker of stem or progenitor cells of some epithelial tissues. In normal breast, P-cadherin has an essential role during ductal mammary branching, being expressed by the monolayer of epithelial cap cells at the end buds. In mature mammary tissue, its expression is restricted to the myoepithelium; it has been postulated that it may also be present in early luminal progenitor cells. In breast cancer, P-cadherin is frequently overexpressed in high-grade tumours, being a well-established indicator of poor patient prognosis. It has been reported as an important inducer of cancer cell migration and invasion, with underlying molecular mechanisms involving the signalling mediated by its juxtamembrane domain, the secretion of matrix metalloproteases to the extracellular media, and the cleavage of a P-cadherin soluble form with pro-invasive activity. Intracellularly, this protein interferes with the endogenous cadherin/catenin complex, inducing p120-catenin delocalization to the cytoplasm, and the consequent activation of Rac1/Cdc42 and associated alterations in the actin cytoskeleton. Considering P-cadherin's role in cancer cell invasion and metastasis formation, a humanized monoclonal antibody was recently produced to antagonize P-cadherin-associated signalling pathways, which is currently under Phase I clinical trials. In this review, the most important findings about the role of P-cadherin in normal breast development and cancer will be illustrated and discussed, with emphasis on the most recent data.
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Neoplasias de la Mama/etiología , Mama/crecimiento & desarrollo , Cadherinas/fisiología , Animales , Biomarcadores de Tumor/fisiología , Mama/embriología , Mama/fisiología , Neoplasias de la Mama/patología , Neoplasias de la Mama/fisiopatología , Cadherinas/genética , Adhesión Celular , Diferenciación Celular , Movimiento Celular , Epigénesis Genética , Transición Epitelial-Mesenquimal , Femenino , Humanos , Glándulas Mamarias Animales/embriología , Glándulas Mamarias Animales/crecimiento & desarrollo , Glándulas Mamarias Animales/fisiología , Neoplasias Mamarias Experimentales/etiología , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/fisiopatología , Ratones , Modelos Biológicos , Invasividad Neoplásica , Células Madre Neoplásicas/fisiología , Pronóstico , Transducción de SeñalRESUMEN
BACKGROUND AND AIM: The study of CD44/CD24 and ALDH1 expression is the most accurate method to identify cancer stem cells (CSC) from breast cancer populations. However, the overlap between CD44(+)CD24(-/low) and ALDH1(high) CSC phenotypes in breast cancer seems to be very small, as well as their distribution among intrinsic breast cancer subtypes. Due to this discrepancy, it is imperative to improve the understanding of breast CSC marker distribution. METHODS: 466 invasive breast carcinomas and eight breast cancer cell lines were analysed for the expression of CD44, CD24 and ALDH1, to evaluate their distribution among the distinct molecular subtypes. RESULTS: Basal-like tumours (76.5%) contained the higher percentage of cells with the CSC phenotype CD44(+)CD24(-/low) (p<0.0001). From ALDH1-positive cases, 39.4% were also basal-like tumours (p<0.0001). The analysis of breast cancer cell lines indicated that luminal cell lines are mainly enriched in a CD44(-/low)CD24(+) cell population, basal/mesenchymal breast cancer cell lines are enriched in the CD44(+)CD24(-/low) phenotype, whereas the remaining basal/epithelial cell lines are mainly positive for both markers. ALDH1 activity was mainly found in HER-OE and basal/epithelial breast cancer cell. CONCLUSIONS: CD44(+)CD24(-/low) and ALDH1(+) phenotypes seem to identify CSC with distinct levels of differentiation. It seems that the paramount method and biomarkers that identify breast CSC within the distinct molecular subtypes need to be better explored, because it is pivotal to translate the CSC concept to clinical practice. In the future, the recognition of reliable markers to distinguish the CSC pool in each molecular subtype will be decisive for the development of specific target therapies.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Antígeno CD24/metabolismo , Receptores de Hialuranos/metabolismo , Isoenzimas/metabolismo , Células Madre Neoplásicas/metabolismo , Retinal-Deshidrogenasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Familia de Aldehído Deshidrogenasa 1 , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Células Madre Neoplásicas/patología , FenotipoRESUMEN
Fetus-in-fetu (FIF) is a rare pathological condition, which presents as a congenital tumor, usually in the abdomen or retroperitoneum. A few cases have been reported in the cranial cavity, cervical spine, ovarium, scrotum and liver. We presently report a case of intrapulmonary FIF in a 12-year-old girl who was on treatment for pulmonary tuberculosis and had no symptoms related to the tumor. To our knowledge this is the first reported case of FIF with pulmonary presentation.