Functional role of cell surface CUB domain-containing protein 1 in tumor cell dissemination.
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.
Deryugina
Elena I
EI
Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Conn
Erin M
EM
Wortmann
Andreas
A
Partridge
Juneth J
JJ
Kupriyanova
Tatyana A
TA
Ardi
Veronica C
VC
Hooper
John D
JD
Quigley
James P
JP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D000951:Antigens, Neoplasm; D017209:Apoptosis / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D048430:Cell Shape / Q000187:drug effects; D002642:Chick Embryo; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019000:Phosphotyrosine / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D014410:Tumor Stem Cell Assay
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; D019000:Phosphotyrosine; D004317:Doxorubicin