title: Vascular cell adhesion molecule-1 is a key adhesion molecule in melanoma cell adhesion to the leptomeninges.
abstract: Leptomeningeal metastases occur in up to 8% of patients with systemic malignancies and have a poor prognosis. A better understanding of the pathophysiologic processes underlying leptomeningeal metastases is needed for more effective treatment strategies. We hypothesized that tumor cells will have to adhere to the well-vascularized leptomeninges, because the cerebrospinal fluid lacks nutrients and growth factors for efficient tumor cell proliferation. Specific receptor-ligand interactions, which are unknown until now, will mediate this adhesion process. We determined the growth characteristics of B16F-10 melanoma cells in cerebrospinal fluid. The expression levels of specific adhesion molecules on both mouse leptomeningeal cells (MLMC) and murine B16F-10 melanoma cells were measured by immunofluorescence flow cytometry. We used mAbs to determine the function of these specific adhesion molecules on B16F-10 melanoma cell adhesion to a leptomeningeal cell layer under static and (cerebrospinal fluid-like) flow conditions. B16F-10 melanoma cells did not proliferate in cerebrospinal fluid because of a lack of nutrients and growth factors. MLMC expressed low levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), beta1- and beta3-integrin subunits, and CD44. VCAM-1 expression on MLMC was shown to be up-regulated by TNF-alpha. Blocking VCAM-1 on the MLMC with a mAb resulted in a 60% inhibition of melanoma cell adhesion to a leptomeningeal cell layer under flow but not under static conditions. No additive inhibitory effect on melanoma cell adhesion was found by concomitant blocking of the beta1- and beta3-integrin subunits and CD44 with mAbs. Our experiments indicate that cerebrospinal fluid does not support B16F-10 melanoma cell proliferation, suggesting the need for melanoma cell adhesion to the well-vascularized leptomeninges. VCAM-1, expressed on MLMC, is an important mediator of in vitro melanoma cell adhesion under (cerebrospinal fluid-like) flow conditions.
authors.affiliation: Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Dieta
authors.initials: D
authors.lastname: Brandsma
authors.forename: Jaap C
authors.initials: JC
authors.lastname: Reijneveld
authors.forename: Martin J B
authors.initials: MJ
authors.lastname: Taphoorn
authors.forename: Hetty C
authors.initials: HC
authors.lastname: de Boer
authors.forename: Martijn F B G
authors.initials: MF
authors.lastname: Gebbink
authors.forename: Laurien H
authors.initials: LH
authors.lastname: Ulfman
authors.forename: Jaap-Jan
authors.initials: JJ
authors.lastname: Zwaginga
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D019040:E-Selectin / Q000032:analysis; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D019012:Integrin beta1 / Q000032:analysis; D039661:Integrin beta3 / Q000032:analysis; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008546:Melanoma, Experimental / Q000473:pathology*; D008577:Meningeal Neoplasms / Q000556:secondary*; D051379:Mice; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000502:physiology*
chemical_list: D019040:E-Selectin; D018960:Hyaluronan Receptors; D019012:Integrin beta1; D039661:Integrin beta3; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1