Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

Abstract

Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.

CD318 is a ligand for CD6

“…CD318 has been proposed as a novel molecular target for treatment of malignant neoplasms (30,49,50); the realization that it is engaged by CD6 will create a perspective from which to assess such possibilities. An anti-CD6 monoclonal antibody has been administered to 12 patients with multiple sclerosis, with insufficient clinical data from this series to assess efficacy (51).…”

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

“…CDCP1 | lipid droplets | FAO | metastasis | TNBC T he transmembrane glycoprotein, CUB-domain containing protein 1 (CDCP1), is a driver of migration and invasion in multiple forms of carcinoma, including renal (1, 2), ovarian (3,4), prostate (5), pancreatic (6,7), colon (8)(9)(10)(11)(12), and triple-negative breast (TNBC) (13,14) carcinomas, among others. Furthermore, CDCP1's role in tumor metastasis was confirmed in vivo in lung (15,16), ovarian (17), prostate (5), and colon (9) cancers.…”

Anti-metastatic action of FAK inhibitor OXA-11 in combination with VEGFR-2 signaling blockade in pancreatic neuroendocrine tumors

“…TOV21G, IGROV1, OVCAR3, and OVCAR5 immortalized ovarian adenocarcinoma cells were used because of FAK overexpression in many ovarian cancers [34–39]. MDA-MB-361 human breast cancer cells were also used in some experiments [40].…”