Blood, Vol. 95 No. 7 (April 1), 2000:
pp. 2397-2406
Bidirectional induction of the cognate receptor-ligand 
4/VCAM-1
pair defines a novel mechanism of tumor intravasation
Laura Bogetto,
Elena Gabriele,
Roberta Cariati,
Riccardo Dolcetti,
Paola Spessotto,
Claudio Doglioni,
Mauro Boiocchi,
Roberto Perris, and
Alfonso Colombatti
From the Divisione di Oncologia Sperimentale 2 and Divisione di
Oncologia Sperimentale 1, CRO, Aviano, Italy; the Department of
Pathology, City Hospital, Belluno, Italy; the Dipartimento di Biologia
Evolutiva e Funzionale, Università degli Studi di Parma, Parma,
Italy; and the Dipartimento di Scienze e Tecnologie Biomediche,
Università degli Studi di Udine, Udine, Italy.
Engagement of cell surface adhesion receptors with extracellular
constituents and with cellular counter-receptors is crucial for the
extravasation of blood-borne neoplastic cells and their seeding at
distant sites; however, the early events of tumor dissemination
ie, the intravasation step(s)have been largely neglected. A role for the
4
7 integrin was hypothesized to explain the high leukemogenicity exhibited by one (NQ22) among several T-cell lymphomas studied. To
clarify the mechanisms of early aggressivity, the behavior of highly
and poorly leukemogenic cell lines were compared in vitro.
Cocultivation of physically separated leukemic cells with resting
endothelial cells resulted in the up-regulation of VCAM-1 expression.
NQ22 cells expressed mRNA of different cytokines that up-regulate
VCAM-1 and at higher levels than cells of a nonaggressive lymphoma, and
they migrated more efficiently through an activated endothelial cell
layer. With the use of neutralizing antibodies against interferon-
,
granulocyte macrophage colony-stimulating factor, and tumor necrosis
factor (TNF)-, it was determined that TNF- is one of the soluble
factors released by NQ22 cells involved in the up-regulation of VCAM-1.
The finding that vascular cells within the early local growth were
strongly positive for VCAM-1 indicated that NQ22 cells could activate
endothelial cells also in vivo. Finally, cocultivation of
preleukemic 4
NQ22 cells with TNF--activated
endothelial cells induced the expression of 4 integrins on the
former cells. Reciprocal up-regulation and engagement of 4/VCAM-1
pairs determined the sequential transmigration and intravasation steps,
and similar mechanisms might affect the aggressivity of human T
lymphoblastic lymphomas.
