CLINICAL-SIGNIFICANCE OF ALPHA(V)BETA(3) INTEGRIN AND INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSION IN CUTANEOUS MALIGNANT-MELANOMA LESIONS

Several lines of experimental evidence in in vitro and animal model sy stems suggest that the integrin alpha(v) beta(3) plays a role in the t umorigenicity of human melanoma tells and that the blocking of alpha(v ) beta(3) ligand binding can inhibit tumor progression. However, there is only scanty information about the role of alpha(v) beta(3) in mali gnant 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 alpha(v) integrin subunit and of the alpha(v ) beta(3) complex and their association with histopathological and cli nical parameters elf malignant melanoma, We have used as probes the mo noclonal antibodies (mAbs) TP36.1 and VF27.263.15, which we have shown with a combination of serological and immunochemical assays to be spe cific for the alpha(v) subunit and for the alpha(v) beta(3) complex. r espectively. In immunohistochemical assays, mAb TP36.1 stained both be nign and malignant lesions of melanocyte origin, In contrast, the reac tivity of mAb VF27.263.15 was restricted to malignant lesions. Both mA bs displayed differential reactivity with primary melanoma lesions of different histotypes because they stained about 50% of acral lentigino us melanoma and superficial spreading melanoma lesions, at least 80% o f nodular melanoma lesions, and none of the uveal melanoma lesions tes ted. Both mAbs TP36.1 and VF27.263.15 stained about 60% of lymph node metastases and 80% of cutaneous metastases. Expression of the alpha(v) beta(3) complex in melanocytic lesions resembles that of intercellula r adhesion molecule-1 (ICAM-1) in several respects: (a) both are expre ssed in a significantly (P < 0.004) larger proportion of malignant tha n of benign lesions; (b) expression of both molecules in primary melan oma lesions is significantly (P < 0.05) associated with lesion thickne ss: and (c) expression of both molecules in primary lesions from patie nts with stage I melanoma is significantly (P < 0.05) associated with an increased probability of disease recurrence following surgical exci sion. alpha(v) beta(3) and ICAM-1 in primary melanoma lesions compleme nt each other in predicting the outcome of the disease, because the as sociation with prognosis was enhanced when primary lesions were staine d by both anti-alpha(v) beta(3) mAb VF27.263.15 and anti-ICAM-1 mAb CL 203.4 or by neither mAb. Because alpha(v) beta(3) was been suggested a s a potential target of immunotherapy, its distribution in normal tiss ues was investigated, alpha(v) beta(3) expression is restricted becaus e it was only detected in ductal epithelium of parotid glands, thyrocy tes, basal glands of the stomach, colonic and rectal epithelium glomer uli, Bowman's capsules and proximal and distal tubules of kidneys, and endometrial epithelium. These findings suggest that renal function wi ll be a critical clinical parameter to monitor in therapies of maligna nt diseases relying on systemic administration of anti-alpha(v) beta(3 ) mAb.