RESUMEN
Functional roles for the cancer cell-associated membrane type I matrix metalloproteinase (MT1-MMP) during early steps of the metastatic cascade in primary tumors remain unresolved. In an effort to determine its significance, we determined the in vivo effects of RNAi-mediated downregulation in mammary cancer cells on the migration, blood and lymphatic vessel invasion (LVI), and lymph node and lung metastasis. We also correlated the expression of cancer cell MT1-MMP with blood vessel invasion (BVI) in 102 breast cancer biopsies. MT1-MMP downregulation in cancer cells decreased lung metastasis without affecting primary tumor growth. The inhibition of lung metastasis correlated with reduced cancer cell migration and BVI. Furthermore, cancer cell-expressed MT1-MMP upregulated the expression of MT1-MMP in vascular endothelial cells, but did not affect MT1-MMP expression in lymphatic endothelial cells, LVI, or lymph node metastasis. Of clinical importance, we observed that elevated MT1-MMP expression correlated with BVI in biopsies from triple-negative breast cancers (TNBC), which have a poor prognosis and high incidence of distant metastasis, relative to other breast cancer subtypes. Together, our findings established that MT1-MMP activity in breast tumors is essential for BVI, but not LVI, and that MT1-MMP should be further explored as a predictor and therapeutic target of hematogenous metastasis in TNBC patients.
Asunto(s)
Neoplasias de la Mama/irrigación sanguínea , Metaloproteinasa 14 de la Matriz/biosíntesis , Animales , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/fisiología , Regulación hacia Abajo , Células Endoteliales/enzimología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Metástasis Linfática , Metaloproteinasa 14 de la Matriz/metabolismo , Ratones , Ratones SCID , Metástasis de la Neoplasia , Neovascularización Patológica/enzimología , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Ratas , Receptor ErbB-2/biosíntesis , Receptor ErbB-2/deficiencia , Receptores de Estrógenos/biosíntesis , Receptores de Estrógenos/deficiencia , Receptores de Progesterona/biosíntesis , Receptores de Progesterona/deficienciaRESUMEN
The purpose of the present study was to determine whether the presence of a biphasic activated partial thromboplastin time (aPTT) waveform (BPW) is associated with adverse clinical outcomes among patients not in an intensive care unit (ICU). Consecutive patients from the emergency department or non-ICU inpatient floors with a BPW (n = 24) were enrolled prospectively, along with 24 matched control subjects with a normal aPTT waveform. Patients with a BPW had a significantly longer hospital stay (mean [median], 16.9 [11] vs 4.9 [2.5] days; P = .011), were more likely to have a positive microbial culture (16/24 [67%] vs 3/24 [13%]; P < .001), were transferred more often to an ICU (6/24 [25%] vs 0/24 [0%]; P = .010), and were more likely to receive an RBC transfusion (11/24 [46%] vs 5/24 [21%]; P = .047) or a fresh frozen plasma transfusion (5/24 [21%] vs 0/24 [0%]; P = .025). Emergency department patients with a BPW were more likely to be admitted (11/11 vs 5/11; P = .018). These results suggest that the BPW is associated with an increased rate of adverse events among non-ICU patients. Further study in this population is warranted.
Asunto(s)
Coagulación Sanguínea , Coagulación Intravascular Diseminada/sangre , Evaluación de Procesos y Resultados en Atención de Salud , Tiempo de Tromboplastina Parcial , Adulto , Anciano , Anciano de 80 o más Años , Coagulación Sanguínea/fisiología , Transfusión Sanguínea , Servicio de Urgencia en Hospital , Humanos , Procesamiento de Imagen Asistido por Computador , Unidades de Cuidados Intensivos , Tiempo de Internación , Persona de Mediana Edad , Sistemas en Línea , Óptica y Fotónica , Fotometría/instrumentaciónRESUMEN
The effects of elevated fibrinogen on thrombin and reptilase times have not been well documented. High fibrinogen levels are common (38% of specimens submitted to our coagulation laboratory). Among 102 patients in the present study, an endogenously elevated fibrinogen level was significantly associated, as follows, with prolonged reptilase times: 1 (4%) of 28 with normal fibrinogen levels, 6 (20%) of 30 with levels in the 400 to 700 mg/dL (4.0-7.0 g/L) range, 10 (34%) of 29 with levels in the 700 to 1,000 mg/dL (7.0-10.0 g/L) range, and 7 (47%) of 15 with fibrinogen levels greater than 1,000 mg/dL (10.0 g/L). This association was independent of patient age and fibrin degradation product titer. In contrast, thrombin time was not altered notably by elevated fibrinogen levels. In 4 patients studied further, the prolonged clotting times could be corrected or nearly corrected by adding calcium chloride or albumin, whereas no such corrections were demonstrable in samples from several hereditary dysfibrinogenemia control subjects. An elevated fibrinogen level is common and is associated with reptilase time prolongations. For patients with prolonged reptilase times, a fibrinogen assay is suggested before establishing a diagnosis of dysfibrinogenemia.