Insights into the biology of lymphatic metastasis

Recent data suggest that the generation of new lymphatic vessels (i.e. lymphangiogenesis) may be a rate-limiting step in the dissemination of tumor cells to regional lymph nodes. However, efforts to study the cellular and molecular interactions that take place between tumor cells and lymphatic endothelial cells have been limited due to a lack of lymphatic endothelial cell lines available for study. ^ I have used a microsurgical approach to establish conditionally immortalized lymphatic endothelial cell lines from the afferent mesenteric lymphatic vessels of mice. Characterization of lymphatic endothelial cells, and tumor-associated lymphatic vessels revealed high expression levels of VCAM-1, which is known to facilitate adhesion of some tumor cells to vascular endothelial cells. Further investigation revealed that murine melanoma cells selected for high expression of α4, a counter-receptor for VCAM-1, demonstrated enhanced adhesion to lymphatic endothelial cells in vitro, and increased tumorigenicity and lymphatic metastasis in vivo, despite similar lymphatic vessel numbers. ^ Next, I examined the effects of growth factors that regulate lymphangiogenesis, and report that several growth factors are capable of activating survival and proliferation pathways of lymphatic endothelial cells. The dual protein tyrosine kinase inhibitor AEE788 (EGFR and VEGFR-2) inhibited the activation of Akt and MAPK in lymphatic endothelial cells responding to multiple growth factors. Moreover, oral treatment of mice with AEE788 decreased lymphatic vessel density and production of lymphatic metastasis by human colon cancer cells growing in the cecum of nude mice. ^ In the last set of experiments, I investigated the surgical management of lymphatic metastasis using a novel model of sentinel lymphadenectomy in live mice bearing subcutaneous B16-BL6 melanoma. The data demonstrate that this procedure when combined with wide excision of the primary melanoma, significantly enhanced survival of syngeneic C57BL/6 mice. ^ Collectively, these results indicate that the production of lymphatic metastasis depends on lymphangiogenesis, tumor cell adhesion to lymphatic endothelial cells, and proliferation of tumor cells in lymph nodes. Thus, lymphatic metastasis is a multi-step, complex, and active process that depends upon multiple interactions between tumor cells and tumor associated lymphatic endothelial cells. ^

Anelastic strain recovery and elastic properties of ODP Leg 123 oceanic basalt samples

A knowledge of rock stress is fundamental for improving our understanding of oceanic crustal mechanisms and lithospheric dynamic processes. However, direct measurements of stress in the deep oceans, and in particular stress magnitudes, have proved to be technically difficult. Anelastic strain recovery measurements were conducted on 15 basalt core samples from Sites 765 and 766 during Leg 123. Three sets of experiments were performed: anelastic strain recovery monitoring, dynamic elastic property measurements, and thermal azimuthal anisotropy observations. In addition, a range of other tests and observations were recorded to characterize each of the samples. One common feature of the experimental results and observations is that apparently no consistent orientation trend exists, either between the different measurements on each core sample or between the same sets of measurements on the various core samples. However, some evidence of correspondence between velocity anisotropy and anelastic strain recovery exists, but this is not consistent for all the core samples investigated. Thermal azimuthal anisotropy observations, although showing no conclusive correlations with the other results, were of significant interest in that they clearly exhibited anisotropic behavior. The apparent reproducibility of this behavior may point toward the possibility of rocks that retain a "memory" of their stress history, which could be exploited to derive stress orientations from archived core. Anelastic strain recovery is a relatively new technique. Because use of the method has extended to a wider range of rock types, the literature has begun to include examples of rocks that contracted with time. Strong circumstantial evidence exists to suggest that core-sample contractions result from the slow diffusion of pore fluids from a preexisting microcrack structure that permits the rock to deflate at a greater rate than the expansion caused by anelastic strain recovery. Both expansions and contractions of the Leg 123 cores were observed. The basalt cores have clearly been intersected by an abundance of preexisting fractures, some of which pass right through the samples, but many are intercepted or terminate within the rock matrix. Thus, the behavior of the core samples will be influenced not only by the properties of the rock matrix between the fractures, but also by how these macro- and micro-scale fractures mutually interact. The strain-recovery curves recorded during Leg 123 for each of the 15 basalt core samples may reflect the result of two competing time dependent processes: anelastic strain recovery and pore pressure recovery. Were these the only two processes to influence the gauge responses, then one might expect that given the additional information required, established theoretical models might be used to determine consistent stress orientations and reliable stress magnitudes. However, superimposed upon these competing processes is their respective interaction with the preexisting fractures that intersect each core. Evidence from our experiments and observations suggests that these fractures have a dominating influence on the characteristics of the recovery curves and that their effects are complex.

Organic matter C and N composition and N. pachyderma stable isotope ratios of ODP Hole 188-1166A sediments

We report the results of downhole stable isotopic (d13Corg [organic carbon] and d15N) and elemental measurements (total organic carbon [TOC], total nitrogen [TN], and carbon/nitrogen [C/N]) of sedimentary organic matter (SOM) along with stable isotopic measurements (d18O and d13C) of left-coiling Neogloboquadrina pachyderma planktonic foraminifers from Ocean Drilling Program Site 1166. TOC and TN measurements indicate a large change from organic-rich preglacial sediments with primary organic matter to organic-poor early glacial and glacial sediments, with mainly recycled organic matter. Results of the stable isotopic measurements of SOM show a range of values that are typical of both marine and terrestrial organic matter, probably reflecting a mixture of the two. However, C/N values are mostly high (>15), suggesting greater input and/or preservation of terrestrial organic matter. Foraminifers are only present in glacial/glaciomarine sediments of latest Pliocene to Pleistocene age at Site 1166 (lithostratigraphic Unit I). The majority of this unit has d13Corg and TOC values that are similar to those of glacial sediments recovered at Site 1167 (lithostratigraphic Unit II) on the slope and may have the same source(s). Although the low resolution of the N. pachyderma (s.) d18O and d13C data set precludes any specific paleoclimatic interpretation, downcore variations in foraminifer d18O and d13C values of 0.5 per mil to 1 per mil amplitude may indicate glacial-interglacial changes in ice volume/temperature in the Prydz Bay region.

(Table T1) Radioelement concentration and radiogenic heat production of ODP Holes 173-1067A and 173-1068A

Mean values of radiogenic heat production are derived from measurements of radioelements on the following rock types: amphibolite (0.358 ± 0.118 µW/m**3) and tonalite gneiss (0.802 ± 0.039 µW/m**3) at Site 1067 and serpentinized peridotite (0.0108 ± 0.0003 µW/m**3) at Site 1068. The results for serpentinized peridotite and amphibolite are consistent with previous measurements on samples from Sites 897 and 900. These results suggest that the thin continental crust in this region would contribute very little to the conductive heat flow.

Geochemistry on manganese deposit from the Median Valley of the Mid-Atlantic Ridge

A manganese oxide crust from an extensive deposit in the median valley of the Mid-Atlantic Ridge was found to be unusually high in manganese (up to 39.4% Mn), low in Fe (as low as 0.01% Fe), low in trace metals and deficient in Th230 and Pa231 with respect to the parent uranium isotopes in the sample. The accumulation rate is 100 mm to 200 mm/10 million year, or 2 orders of magnitude faster than the typical rate for deep-sea ferromanganese deposits. The rapid growth rate and unusual chemistry are consistent with a hydrothermal origin or with a diagenetic origin by manganese remobilized from reduced sediments. Because of the association with an active ridge, geophysical evidence indicative of hydrothermal activity, and a scarcity of sediment in the sampling area, we suggest that a submarine hot spring has created the deposit.