Colorectal cancer cells express functional cell surface-bound TGFbeta.

Disruptions to the TGFbeta signaling pathway have been implicated in most human adenocarcinomas. In addition to its role in cancer cell migration and metastasis, TGFbeta has been implicated in tumor-mediated immunosuppression. Membrane-bound TGFbeta has previously been reported to be expressed on a subset of regulatory T cells and was shown to be critical to their immune suppressive function. In the present study, we document expression of a signaling competent, endogenously derived form of cell surface-bound TGFbeta on colorectal cancer cells. While antibodies against only the mature form of TGFbeta failed to label cells, surface-bound TGFbeta was clearly detected by antibodies specific for both the latent and mature forms of the cytokine. Confirming the notion that the surface TGFbeta was in latent form, brief acid pulsing of the cells increased the amount of detectable membrane-associated TGFbeta. In coculture assays, this cell-bound TGFbeta could be activated and utilized in a paracrine fashion both by other cancer cells and by CD8+ intraepithelial lymphocytes. This effect was abrogated by the use of a furin inhibitor which decreased the membranous expression of TGFbeta on the tumor cells. Signaling competent membrane-bound TGFbeta on cancer cells is thus likely to be a key player in regulating tumor cell interactions with each other as well as with other cells in their microenvironment.