title: Mechanical entrapment is insufficient and intercellular adhesion is essential for metastatic cell arrest in distant organs.
abstract: In this report, we challenge a common perception that tumor embolism is a size-limited event of mechanical arrest, occurring in the first capillary bed encountered by blood-borne metastatic cells. We tested the hypothesis that mechanical entrapment alone, in the absence of tumor cell adhesion to blood vessel walls, is not sufficient for metastatic cell arrest in target organ microvasculature. The in vivo metastatic deposit formation assay was used to assess the number and location of fluorescently labeled tumor cells lodged in selected organs and tissues following intravenous inoculation. We report that a significant fraction of breast and prostate cancer cells escapes arrest in a lung capillary bed and lodges successfully in other organs and tissues. Monoclonal antibodies and carbohydrate-based compounds (anti-Thomsen-Friedenreich antigen antibody, anti-galectin-3 antibody, modified citrus pectin, and lactulosyl-l-leucine), targeting specifically beta-galactoside-mediated tumor-endothelial cell adhesive interactions, inhibited by >90% the in vivo formation of breast and prostate carcinoma metastatic deposits in mouse lung and bones. Our results indicate that metastatic cell arrest in target organ microvessels is not a consequence of mechanical trapping, but is supported predominantly by intercellular adhesive interactions mediated by cancer-associated Thomsen-Friedenreich glycoantigen and beta-galactoside-binding lectin galectin-3. Efficient blocking of beta-galactoside-mediated adhesion precludes malignant cell lodging in target organs.
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA. glinskiivl@missouri.edu
authors.forename: Olga V
authors.initials: OV
authors.lastname: Glinskii
authors.forename: Virginia H
authors.initials: VH
authors.lastname: Huxley
authors.forename: Gennadi V
authors.initials: GV
authors.lastname: Glinsky
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Avraham
authors.initials: A
authors.lastname: Raz
authors.forename: Vladislav V
authors.initials: VV
authors.lastname: Glinsky
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary; D001943:Breast Neoplasms / Q000628:therapy; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002957:Citrus / Q000378:metabolism; D005260:Female; D037502:Galectin 3 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007930:Leucine / Q000737:chemistry; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010368:Pectins / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000628:therapy
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D037502:Galectin 3; C025991:Thomsen-Friedenreich antibodies; D010368:Pectins; D007930:Leucine