RESUMEN
Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.
Asunto(s)
Neoplasias de la Mama/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Metástasis de la Neoplasia/genética , Recurrencia Local de Neoplasia/genética , Animales , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Ratones , Metástasis de la Neoplasia/patología , Recurrencia Local de Neoplasia/patología , Células Madre Neoplásicas , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Allergic rhinoconjunctivitis is a clinical condition that impairs quality of life. The use of traditional drugs in many cases is not enough to improve quality of life in these patients. METHODS: In this pilot study we used the Sanispira Nasal filters in 15 patients (mean age 34,7 years) affected by allergic rhinoconjunctivitis for 18 days. At each follow-up visit, patients were assessed with a specific quality of life questionnaire, a symptoms form and a drugs form that evaluates the use of antiallergic drugs in the last week. Patients sensitive to environmental allergens wore Sanispira nasal filters during the day, while patients sensitive to domestic allergens wore the device during the night. RESULTS: Thirteen patients completed the study. We found an improvement significative (p=0,0241) of the total score of RQLQ of 23,10 points between baseline and 18 days ( total score at baseline prior to nasal filter insertion= 60,60, at 1 week = 42, 28, at 18 days= 34, 10). A significative improvement in the nasal symptoms domain between baseline and 18 days (in particular stuffy nose p=0,047; runny nose p=0,012; sneezing p=0,0021; ) and one item of practical problems domain, the need to repeatedly blow the nose(p=0,082). The total score of symptoms evaluated with the symptoms form improved significantly from baseline to 18 days. Total symptoms score at baseline was 9,7; at 1 week it was 8,1 and at 18 days it was 4,7. The improvement was statistically significant (p=0,0092). Three of the thirteen patients that completed the study eliminated completely the use of drugs during of the study. CONCLUSIONS: The use of SANISPIRA ®, has shown encouraging results, with an improvement in the quality of life in Rhinoconjunctivitis patients specially an improvement in nasal and ocular symptoms.
Asunto(s)
Conjuntivitis Alérgica/psicología , Calidad de Vida , Rinitis Alérgica Perenne/psicología , Adulto , Conjuntivitis Alérgica/terapia , Femenino , Filtración , Humanos , Masculino , Proyectos Piloto , Rinitis Alérgica , Rinitis Alérgica Perenne/terapia , Encuestas y CuestionariosRESUMEN
We have previously shown that estrogens binding to estrogen receptor (ER) α increase proliferation of Leydig tumor cells. Estrogens can also bind to G protein-coupled ER (GPER) and activation of this receptor can either increase or decrease cell proliferation of several tumor types. The aim of this study was to investigate GPER expression in R2C rat tumor Leydig cells, evaluate effects of its activation on Leydig tumor cell proliferation and define the molecular mechanisms triggered in response to its activation. R2C cells express GPER and its activation, using the specific ligand G-1, is associated with decreased cell proliferation and initiation of apoptosis. Apoptosis after G-1 treatment was asserted by appearance of DNA condensation and fragmentation, decrease in Bcl-2 and increase in Bax expression, cytochrome c release, caspase and poly (ADP-ribose) polymerase-1 (PARP-1) activation. These effects were dependent on GPER activation because after silencing of the gene, using a specific small interfering RNA, cyt c release, PARP-1 activation and decrease in cell proliferation were abrogated. These events required a rapid, however, sustained extracellular regulated kinase 1/2 activation. G-1 was able to decrease the growth of R2C xenograft tumors in CD1 nude mice while increasing the number of apoptotic cells. In addition, in vivo administration of G-1 to male CD1 mice did not cause any alteration in testicular morphology, while cisplatin, the cytotoxic drug currently used for the therapy of Leydig tumors, severely damaged testicular structure, an event associated with infertility in cisplatin-treated patients. These observations indicate that GPER targeting for the therapy of Leydig cell tumor may represent a good alternative to cisplatin to preserve fertility in Leydig tumor patients.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Tumor de Células de Leydig/tratamiento farmacológico , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Testiculares/tratamiento farmacológico , Animales , Antineoplásicos Hormonales/farmacología , Línea Celular Tumoral , Forma del Núcleo Celular/efectos de los fármacos , Ciclopentanos/farmacología , Daño del ADN , Estradiol/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Expresión Génica , Tumor de Células de Leydig/patología , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Desnudos , Quinolinas/farmacología , Ratas , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Neoplasias Testiculares/patología , Testículo/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cancer stem cell (SC) chemoresistance may be responsible for the poor clinical outcome of non-small-cell lung cancer (NSCLC) patients. In order to identify the molecular events that contribute to NSCLC chemoresistance, we investigated the DNA damage response in SCs derived from NSCLC patients. We found that after exposure to chemotherapeutic drugs NSCLC-SCs undergo cell cycle arrest, thus allowing DNA damage repair and subsequent cell survival. Activation of the DNA damage checkpoint protein kinase (Chk) 1 was the earliest and most significant event detected in NSCLC-SCs treated with chemotherapy, independently of their p53 status. In contrast, a weak Chk1 activation was found in differentiated NSCLC cells, corresponding to an increased sensitivity to chemotherapeutic drugs as compared with their undifferentiated counterparts. The use of Chk1 inhibitors in combination with chemotherapy dramatically reduced NSCLC-SC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe. Consistently, the co-administration of the Chk1 inhibitor AZD7762 and chemotherapy abrogated tumor growth in vivo, whereas chemotherapy alone was scarcely effective. Such increased efficacy in the combined use of Chk1 inhibitors and chemotherapy was associated with a significant reduction of NSCLC-SCs in mouse xenografts. Taken together, these observations support the clinical evaluation of Chk1 inhibitors in combination with chemotherapy for a more effective treatment of NSCLC.