Leukocyte recruitment in colon cancer: role of cell adhesion molecules, nitric oxide, and transforming growth factor beta1.

BACKGROUND & AIMS: A deficient leukocyte recruitment has been suggested in tumor vasculature, but little is known about the underlying molecular mechanism. To characterize leukocyte-endothelium interaction in experimental colon cancer, quantify the main endothelial cell adhesion molecules (CAMs), and evaluate the effect of tumor-derived products. METHODS: Leukocyte recruitment was assessed by intravital videomicroscopy in mice bearing HT29-derived tumors. Endothelial CAMs were measured using the dual-radiolabeled antibody technique. The role of molecules mediating leukocyte rolling (P-, E-, and L-selectin) or adhesion (intercellular adhesion molecule 1 [ICAM-1] and vascular cell adhesion molecule 1 [VCAM-1]) carcinoembryonic antigen (CEA), and transforming growth factor (TGF) beta1 was assessed through immunoblockade, whereas participation of nitric oxide (NO) and cyclooxygenase (COX) metabolites were evaluated by means of nonselective and selective inhibition. RESULTS: Basal and lipopolysaccharide-stimulated leukocyte rolling and adhesion were markedly reduced in tumor vasculature. ICAM-1 immunoblockade prevented leukocyte adhesion in both tumor and nontumor microvessels. Neither baseline nor LPS-induced endothelial ICAM-1, P-, and E-selectin expression in tumors were reduced with respect to nontumor vasculature. Although VCAM-1 expression was reduced in tumor endothelium, immunoneutralization of VCAM-1 failed to reverse LPS-induced leukocyte recruitment in this setting. CEA immunoblockade and COX inhibition did not modify the deficient leukocyte rolling. Nonselective NO inhibition partially reversed the defective adhesion response in tumor microvessels. Finally, TGF-beta1 immunoblockade partially and selectively restored impaired leukocyte rolling and adhesion in tumor microvessels. CONCLUSIONS: Impaired leukocyte recruitment in tumor vasculature cannot be attributed to a depressed expression of the main CAMs. Selective restoration after NO inhibition and TGF-beta1 immunoblockade suggests involvement of both molecules in this phenomenon.

Implantación ortotópica de fragmentos sólidos de cáncer de páncreas exocrino humano en ratones atímicos / Orthotopic solid human pancreatic cancer fragment implants in athimic rats

Introducción: el desarrollo de modelos experimentales de cáncer de páncreas exocrino es esencial para un mejor conocimiento de la enfermedad. El objetivo del presente trabajo ha sido implantar y perpetuar carcinomas de páncreas exocrino humano en el páncreas del ratón atímico (implantación ortotópica), estudiar su patrón de diseminación y las alteraciones en genes implicados en la tumorigénesis. Material y Métodos: Se implantaron, de forma ortotópica, fragmentos sólidos de 11 carcinomas de páncreas exocrino humano. Se analizó la presencia de mutaciones en los genes K-ras y p53, tanto en tumores primarios como en los tumores perpetuados. Resultados: Siete de 11 tumores implantados (63 por ciento) crecieron como ortoimplantes. En 4 tumores se evidenció diseminación a distancia (metástasis hepáticas, diseminación peritoneal, o metástasis en los ganglios linfáticos). El patrón de diseminación fue específico para cada tumor y reproducible a lo largo de múltiples pases. Los tumores primarios y los perpetuados compartían el mismo genotipo. Conclusiones: La implantación ortotópica de fragmentos sólidos de carcinomas de páncreas exocrino humano permite la perpetuación de tumores con distinto genotipo y la reproducción de diferentes patrones de crecimiento local y a distancia