The function of CUB domain-containing
protein 1 (CDCP1), a recently described transmembrane
protein expressed on the surface of hematopoietic stem cells and normal and malignant cells of different tissue origin, is not well defined. The contribution of CDCP1 to
tumor metastasis was analyzed by using HeLa
carcinoma cells overexpressing CDCP1 (HeLa-CDCP1) and a high-disseminating variant of prostate
carcinoma PC-3 naturally expressing high levels of CDCP1 (PC3-hi/diss). CDCP1 expression rendered HeLa cells more aggressive in experimental
metastasis in immunodeficient mice. Metastatic colonization by HeLa-CDCP1 was effectively inhibited with subtractive immunization-generated, CDCP1-specific
monoclonal antibody (mAb) 41-2, suggesting that CDCP1 facilitates relatively late stages of the metastatic cascade. In the chick embryo model, time- and dose-dependent inhibition of HeLa-CDCP1 colonization by mAb 41-2 was analyzed quantitatively to determine when and where CDCP1 functions during
metastasis. Quantitative PCR and immunohistochemical analyses indicated that CDCP1 facilitated
tumor cell survival soon after vascular arrest. Live cell imaging showed that the function-blocking mechanism of mAb 41-2 involved enhancement of
tumor cell apoptosis, confirmed by attenuation of mAb 41-2-mediated effects with the
caspase inhibitor
z-VAD-fmk. Under proapoptotic conditions in vitro, CDCP1 expression conferred HeLa-CDCP1 cells with resistance to
doxorubicin-induced apoptosis, whereas
ligation of CDCP1 with mAb 41-2 caused additional enhancement of the apoptotic response. The functional role of naturally expressed CDCP1 was shown by mAb 41-2-mediated inhibition of both experimental and spontaneous
metastasis of PC3-hi/diss. These findings confirm that CDCP1 functions as an antiapoptotic molecule and indicate that during
metastasis CDCP1 facilitates
tumor cell survival likely during or soon after extravasation.