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Clinical Significance of _vß₃ Integrin and Intercellular Adhesion Molecule-1 Expression in Cutaneous Malignant Melanoma Lesions¹

Departments of Immunology [P. G. N.] and Surgery [F. D., D. G.], Regina Elena Cancer Institute, 00158 Rome, Italy; Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595 [C. V. H., M. T., B. L., S. F.]; Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037 [B. F.]; and Consiglio Nazionale della Ricerche Institute of Biomedical Technologies, 00161 Rome, Italy [M. R. N.]

Several lines of experimental evidence in in vitro and animal model systems suggest that the integrin _vß₃ plays a role in the tumorigenicity of human melanoma cells and that the blocking of _vß₃ ligand binding can inhibit tumor progression. However, there is only scanty information about the role of _vß₃ in malignant melanoma in a clinical setting. Therefore, in the present study, we have analyzed the distribution in lesions of melanocyte origin and in normal tissues of the _v integrin subunit and of the _vß₃ complex and their association with histopathological and clinical parameters of malignant melanoma. We have used as probes the monoclonal antibodies (mAbs) TP36.1 and VF27.263.15, which we have shown with a combination of serological and immunochemical assays to be specific for the _v subunit and for the _vß₃ complex, respectively. In immunohistochemical assays, mAb TP36.1 stained both benign and malignant lesions of melanocyte origin. In contrast, the reactivity of mAb VF27.263.15 was restricted to malignant lesions. Both mAbs displayed differential reactivity with primary melanoma lesions of different histotypes because they stained about 50% of acral lentiginous melanoma and superficial spreading melanoma lesions, at least 80% of nodular melanoma lesions, and none of the uveal melanoma lesions tested. Both mAbs TP36.1 and VF27.263.15 stained about 60% of lymph node metastases and 80% of cutaneous metastases.

Expression of the _vß₃ complex in melanocytic lesions resembles that of intercellular adhesion molecule-1 (ICAM-1) in several respects: (a) both are expressed in a significantly (P < 0.004) larger proportion of malignant than of benign lesions; (b) expression of both molecules in primary melanoma lesions is significantly (P < 0.05) associated with lesion thickness; and (c) expression of both molecules in primary lesions from patients with stage I melanoma is significantly (P < 0.05) associated with an increased probability of disease recurrence following surgical excision. _vß₃ and ICAM-1 in primary melanoma lesions complement each other in predicting the outcome of the disease, because the association with prognosis was enhanced when primary lesions were stained by both anti-_vß₃ mAb VF27.263.15 and anti-ICAM-1 mAb CL203.4 or by neither mAb.

Because _vß₃ has been suggested as a potential target of immunotherapy, its distribution in normal tissues was investigated. _vß₃ expression is restricted because it was only detected in ductal epithelium of parotid glands, thyrocytes, basal glands of the stomach, colonic and rectal epithelium glomeruli, Bowman's capsules and proximal and distal tubules of kidneys, and endometrial epithelium. These findings suggest that renal function will be a critical clinical parameter to monitor in therapies of malignant diseases relying on systemic administration of anti-_vß₃ mAb.

¹ This work was supported by the Consiglio Nazionale delle Ricerche Progetto Finalizzato (Applicazioni Cliniche della Ricerca Oncologica), by Associazione Italiana per la Ricerca sul Cancro, by the Italian Ministry of Public Health, and by USPHS Grants CA37959, CA51814, CA67108, and CA67988 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Department of Microbiology and Immunology, Basic Science Building, Room 308, New York Medical College, Valhalla, NY 10595. Phone: (914) 993-4175; Fax: (914) 993-4176.

Received 11/25/96. Accepted 2/22/97.

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