Neutrophils Suppress Intraluminal NK Cell-Mediated Tumor Cell Clearance and Enhance Extravasation of Disseminated Carcinoma Cells

Immune cells promote the initial metastatic dissemination of carcinoma cells from primary tumors. In contrast to their well-studied functions in the initial stages of metastasis, the specific roles of immunocytes in facilitating progression through the critical later steps of the invasion–metastasis cascade remain poorly understood. Here, we define novel functions of neutrophils in promoting intraluminal survival and extravasation at sites of metastatic dissemination. We show that CD11b+/Ly6G+neutrophils enhance metastasis formation via two distinct mechanisms. First, neutrophils inhibit natural killer cell function, which leads to a significant increase in the intraluminal survival time of tumor cells. Thereafter, neutrophils operate to facilitate extravasation of tumor cells through the secretion of IL1β and matrix metalloproteinases. These results identify neutrophils as key regulators of intraluminal survival and extravasation through their cross-talk with host cells and disseminating carcinoma cells. SIGNIFICANCE: This study provides important insights into the systemic contributions of neutrophils to cancer metastasis by identifying how neutrophils facilitate intermediate steps of the invasion–metastasis cascade. We demonstrate that neutrophils suppress natural killer cell activity and increase extravasation of tumor cells.Human Frontier Science Program (Strasbourg, France) (fellowship LT00728/2008-L)Charles King Trust FoundationMassachusetts Institute of Technology. Ludwig Center for Cancer ResearchCancer Research Institute (New York, N.Y.) (Irvington Fellowship)National Institutes of Health (U.S.) (grant P01 CA080111)National Institutes of Health (U.S.) (grant CA163109

Age and chemical composition of apatites from five DSDP and ODP Sites in the Pacific, Atlantic and Indian Oceans

Since studies on deep-sea cores were carried out in the early 1990s it has been known that ambient temperature may have a marked affect on apatite fission track annealing. Due to sluggish annealing kinetics, this effect cannot be quantified by laboratory annealing experiments. The unknown amount of low-temperature annealing remains one of the main uncertainties for extracting thermal histories from fission track data, particularly for samples which experienced slow cooling in shallow crustal levels. To further elucidate these uncertainties, we studied volcanogenic sediments from five deep-sea drill cores, that were exposed to maximum temperatures between ~10° and 70°C over geological time scales of ~15–120 Ma. Mean track lengths (MTL) and etch pit diameters (Dpar) of all samples were measured, and the chemical composition of each grain analyzed for age and track length measurements was determined by electron microprobe analysis. Thermal histories of the sampled sites were independently reconstructed, based on vitrinite reflectance measurements and/or 1D numerical modelling. These reconstructions were used to test the most widely used annealing models for their ability to predict low-temperature annealing. Our results show that long-term exposure to temperatures below the temperature range of the nominal apatite fission track partial annealing zone results in track shortening ranging between 4 and 11%. Both chlorine content and Dpar values explain the downhole annealing patterns equally well. Low chlorine apatite from one drill core revealed a systematic relation between Si-content and Dpar value. The question whether Si-substitution in apatite has direct and systematic effects on annealing properties however, cannot be addressed by our data. For samples, which remained at temperatures 30°C, the predictions of the Laslett et al. (1987) model agree with the measured MTL data within error levels. With few exceptions, predictions by the Ketcham et al. [Ketcham R., Donelick R. and Carlson W. (1999) Variability of apatite fission-track annealing kinetics. III: Extrapolation to geological time scales. Am. Mineral. 84/9, 1235–1255] annealing model are consistent with the measured data for samples which remained at temperatures below ~30°C. For samples which experienced maximum temperatures between ~30 and 70°C, and which are rich in chlorine, the Ketcham et al. (1999) model overestimates track annealing