These studies demonstrate that, in vitro and in vivo, estradiol enhances endothelial cell activities important in neovascularization and suggest a promoting influence of estrogens on angiogenesis.

Adhesive interactions of tumor cells with the luminal side of the lymphatic and vascular endothelium are thought to be an important step in the metastatic process (Blood and Zetter, 1990). Tumor cells are likely to enter the blood stream through lymphatics and new tumor-associated blood vessels. These cells may then circulate individually, in small clusters, or in the form of tumor-cell-platelet aggregates until they adhere to the vasculature at a secondary site. Retraction of the vascular endothelium at the secondary site due to tumor-cell adhesion or neutrophil-induced injury has been suggested to facilitate the exit of tumor cells from the blood stream by exposing them to the underlying basement membrane (Kramer and Nicolson, Tumor cell adhesion to endothelial cell monolayers has been investigated in vitro as a model for metastatic invasion (see for review Blood and Zetter, 1990). Endothelial-cell monolayers constitute a practical if not an ideal experimental model for the luminal side of lymphatic vessels and post-capillary blood venules. Endothelial cell-surface receptor expression can be modulated with cytokines, growth effectors and the matrix proteins underlying the monolayer (Gamble et al., 1993). In static adhesion assays, tumor cells have been shown to adhere differentially to capillary endothelial cells isolated from different organs (Alby and Auerbach, 1984) and to cytokineactivated vascular endothelium (Rice and Bevilacqua, 1989).Recent studies implicate E-selectin, an inducible endothelial cell-surface glycoprotein, as a mediator of adhesion of some colon-carcinoma cells to cytokine-activated human umbilical-cord-vein endothelial cells. An MAb against E-selectin was shown to inhibit adhesion of HT-29 colon-carcinoma cells to endothelial-cell monolayers stimulated with interleukin-1 both after static incubation (Rice and Bevilacqua, 1989) and 1979). under flow conditions (Giavazzi et ul., 1993). In agreement with these observations, the carbohydrate antigen, sialyl Lex, a ligand for E-selectin, is overexpressed in more than 90% of human colon carcinomas (Hanski et al., 1993).In this study, the molecular mechanisms involved in the entrapment of colon and breast carcinoma cells by endothelial cells were investigated in the presence of flow comparable to that found in lymphatics and post-capillary blood venules. A parallel plate flow chamber was used to study the flowmediated interactions of breast cells and of breast-and colon-carcinoma cells with human umbilical-vein endothelial cell monolayers. The role of E-selectin in dynamic adhesion to endothelial cells was investigated utilizing function-blocking MAbs. The results suggest that E-selectin is a major homing receptor in the metastasis of some breast and colon cancers. MATERIAL AND METHODS CellsHuman umbilical vein endothelial cells (EC) were isolated from freshly delivered cords as previously described (Grant et al., 1989). These cells were grown and passaged 2-5 times in medium 199 (GIBCO, Gaithersburg, MD) containing 20% bovine calf serum (Hy...

[PSI +] yeast, containing the misfolded amyloid conformation of Sup35 prion, is cured by inactivation of Hsp104. There has been controversy as to whether inactivation of Hsp104 by guanidine treatment or by overexpression of the dominant negative Hsp104 mutant, Hsp104-2KT, cures [PSI +] by the same mechanism– inhibition of the severing of the prion seeds. Using live cell imaging of Sup35-GFP, overexpression of Hsp104-2KT caused the foci to increase in size, then decrease in number, and finally disappear when the cells were cured, similar to that observed in cells cured by depletion of Hsp104. In contrast, guanidine initially caused an increase in foci size but then the foci disappeared before the cells were cured. By starving the yeast to make the foci visible in cells grown with guanidine, the number of cells with foci was found to correlate exactly with the number of [PSI+] cells, regardless of the curing method. Therefore, the fluorescent foci are the prion seeds required for maintenance of [PSI+] and inactivation of Hsp104 cures [PSI+] by preventing severing of the prion seeds. During curing with guanidine, the reduction in seed size is an Hsp104-dependent effect that cannot be explained by limited severing of the seeds. Instead, in the presence of guanidine, Hsp104 retains an activity that trims or reduces the size of the prion seeds by releasing Sup35 molecules that are unable to form new prion seeds. This Hsp104 activity may also occur in propagating yeast.

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Purpose: Angiogenesis plays a major role in cancer. Drugs blocking the growth factor receptor in the vascular endothelium constitute a fundamental treatment in several cancers. Hypertension (HBP) and proteinuria associated with these treatments is frequent and presents in an oscillating and irregular way and is generally controlled by scarcely reliable means. Methods: We started a prospective study with the determination of microalbuminuria (MAL) in 24 hours orine samples and the execution of pre- and post-treatment 24 h-ambulatory blood pressure monitoring (ABPM) and selfmeasured of BP every 12 hours at home, during 60 days, in patients with cancer under treatment with either bevacizumab or sunitinib with a view to identifying the variations in MAL, ABPM and the onset of HBP at an early stage. For ABPM, a validated recording device was used; a recording was made prior to the start of the anti-angiogenic treatment and 20 days (at least) after the first dose. An OMRON M6 tensiometer validated by the European HBP Society was used, with the ambulatory BP figures being collected at home as per standards. MAL was measured in 24h orine samples in mg/L and mg/gr creatinine. The primary goal is to find differences of at least 16 mmHg in the mean BP between the two ABPM readings. Results: N=21. Eighteen patients received bevacizumab and three sunitinib. Mean age 57.0 years (26–79). Three patients was known to be hypertensive. Differences of 4.9 and 3.9 mmHg were found between the mean systolic and diastolic BPs before and after treatment (p<0.05). Conclusions: Our data revealed a statically significant increase of blood pressure in patients treated with antiangiongenics as determined by ABMP. The data point to a greater increase in nocturnal BP suggesting a non-dipper pattern. The self measured records shown an early onset HBP. Microalbuminuria trends to increase in this patients. All data will be shown at the meeting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A9.