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Activation of the Autocrine Transforming Growth Factor Pathway in Human Squamous Carcinoma Cells¹

Department of Medicine, Section of Medical Oncology, and Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06517

Transforming growth factor is an autocrine mitogen for nonneoplastic keratinocytes, which exerts its function by binding to the receptor for epidermal growth factor. In order to determine whether this autocrine pathway is activated in squamous carcinoma cells, we analyzed the production of transforming growth factor as well as the expression and regulation of epidermal growth factor receptors in a panel of human squamous carcinoma cell lines. Immunoreactive transforming growth factor was detectable in squamous carcinoma cells as well as in quiescent nonneoplastic keratinocytes. However, in the absence of exogenous mitogens, only the squamous carcinoma cells secreted the growth factor into the medium, whereas untransformed keratinocytes did not.

Each of the squamous carcinoma cell lines expressed significantly greater numbers of cell surface epidermal growth factor receptors than normal keratinocytes. The epidermal growth factor receptor gene was amplified and overexpressed in three of the squamous carcinoma cell lines (A431, CaSki, SqCC/Y1). Two of the squamous carcinoma cell lines (C4-1 and CE-48) displayed a relative inability to down-regulate epidermal growth factor receptors in response to epidermal growth factor. The mechanism of receptor overexpression in the remaining three cell lines (A253, CaLu-1, FaDu) is unexplained. Thus, human squamous carcinoma cell lines frequently exhibit a combination of the constitutive secretion of transforming growth factor and the overexpression of epidermal growth factor receptors. Treatment of these tumor cells with an antibody directed against the ligand-binding domain of the epidermal growth factor receptor inhibited their growth by approximately 50%. These findings suggest that designing strategies to interrupt the transforming growth factor autocrine pathway might lead to new modalities to treat this class of malignant tumors.

¹ Supported in part by USPHS Grant CA-41556 of the National Cancer Institute.

² To whom requests for reprints should be addressed, Section of Medical Oncology, Department of Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510.

Received 6/19/91. Accepted 9/23/91.

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