RESUMEN
UNLABELLED: Glioblastoma (GBM) is a highly aggressive brain cancer characterized by local invasion and angiogenic recruitment, yet metastatic dissemination is extremely rare. Here, we adapted a microfluidic device to deplete hematopoietic cells from blood specimens of patients with GBM, uncovering evidence of circulating brain tumor cells (CTC). Staining and scoring criteria for GBM CTCs were first established using orthotopic patient-derived xenografts (PDX), and then applied clinically: CTCs were identified in at least one blood specimen from 13 of 33 patients (39%; 26 of 87 samples). Single GBM CTCs isolated from both patients and mouse PDX models demonstrated enrichment for mesenchymal over neural differentiation markers compared with primary GBMs. Within primary GBMs, RNA in situ hybridization identified a subpopulation of highly migratory mesenchymal tumor cells, and in a rare patient with disseminated GBM, systemic lesions were exclusively mesenchymal. Thus, a mesenchymal subset of GBM cells invades the vasculature and may proliferate outside the brain. SIGNIFICANCE: GBMs are locally invasive within the brain but rarely metastasize to distant organs, exemplifying the debate over "seed" versus "soil." We demonstrate that GBMs shed CTCs with invasive mesenchymal characteristics into the circulation. Rare metastatic GBM lesions are primarily mesenchymal and show additional mutations absent in the primary tumor.
Asunto(s)
Neoplasias Encefálicas/patología , Glioblastoma/patología , Células Neoplásicas Circulantes/patología , Animales , Biomarcadores de Tumor/sangre , Neoplasias Encefálicas/sangre , Transición Epitelial-Mesenquimal , Expresión Génica , Glioblastoma/sangre , Humanos , RatonesRESUMEN
The aim of this study was to analyze the physiological responses to a tap dance choreography and to compare with those observed during a maximal treadmill exercise test, in tap dancers. Eight women (19.6 +/- 2.4 years; 162.3 +/- 4.4 cm; 54.0 +/- 2.3 kg; 20.5 +/- 1.4 kg.m; and 5.1 +/- 2.6 years of tap dance training) were submitted to the following procedures: (a) graded exercise test (GXT) on a treadmill until volitional exhaustion with 0.8 km.h of increment at each 3 and 1 minute of interval between stages and (b) tap dance choreography (TAP)-"The Shim Sham Shimmy"-consisting of 9 stages of 3 minutes with 1-minute rest between stages. Expired gas analyses were performed in all experimental sessions, providing breath-by-breath values for respiratory exchange rate (RER), oxygen uptake (VO(2)), and carbon dioxide production (CO2). Heart rate (HR) and rate of perceived exertion (RPE) were also measured. During the rest period between stages, blood samples (25 microl) were collected from the ear lobe for lactate threshold (LT) determination. It was observed that at the end of the TAP, subjects achieved an average of 83.8 +/- 6.2% of the HRmax and 68.9 +/- 11.3% of the VO(2)max, both previously identified in the GXT. The choreography demanded 204.7 +/- 31.3 kcal, an average RER of 0.88 +/- 0.05 and mean RPE of 13 +/- 2. The VO(2), HR, and RPE values did not significantly differ from those at the LT intensity identified during the GTX. Based on the present results, it was concluded that the TAP performance in the "The Shim Sham Shimmy" choreography elicited acute physiologic responses similar to those observed at the LT intensity, thus suggesting that Tap Dance constitutes a useful exercise modality for aerobic fitness and cardiovascular health improvements.