Inhibition of Adhesion, Invasion, and Metastasis by Antibodies Targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic Antigen)

Abstract

CEACAM5 and CEACAM6 are overexpressed in many cancers and are associated with adhesion and invasion. The effects of three monoclonal antibodies targeting different epitopes on these antigens (NH 2 -terminal and A1B1 domains shared by CEACAM5 and CEACAM6 and the A3B3 domain restricted to CEACAM5) were evaluated in migration, invasion, and adhesion assays in vitro using a panel of human pancreatic, breast, and colonic cancer cell lines, and in the GW-39 human colonic micrometastasis model in vivo. MN-3 FabV and MN-15 FabV were both effective at inhibiting cell migration. MN-15 FabV treatment inhibited invasion, reducing cell penetration through an extracellular matrix (ECM). MN-3 FabValso decreased invasion but was less effective than MN-15 FabV in four of five cell lines. All three monoclonal antibody (mAb) Fabs decreased adhesion of tumor cells to endothelial cells by 49% to 58%. MN-15 FabV but not MN-3 or MN-14 Fabs induced a decrease in adhesion of three of six cell lines to the ECM protein, fibronectin, but adhesion to vitronectin, laminin, collagen-I, and collagen-IV was not affected. In vivo studies showed that treatment with MN-3 FabV or MN-15 FabV of mice implanted with GW-39 human colonic cancer cells increased their survival (P < 0.025 and P < 0.01, respectively). These studies show that antibody Fabs that target either CEACAM5 or CEACAM6 affect cell migration, cell invasion, and cell adhesion in vitro, and that MN-15 and MN-3 Fabs have antimetastatic effects in vivo, resulting in improved survival of mice with metastases. Thus, blocking the N and A1B1 domains of CEACAM5/CEACAM6 can impede the metastatic process.

Expression profiling of CEACAM6 associated with the tumorigenesis and progression in gastric adenocarcinoma

“…This result is consistent with the finding that CEACAM6 expression is an early event in human colorectal cancers and plays a role in both early carcinogenesis and subsequent tumor progression (Yasui et al, 2004;Jass, 2005). Previous studies using animal models support that CEACAM6 is functionally important in tumorigenesis, cellular adhesion, growth, invasion, and metastasis, and inhibition of CEACAM6 expression by RNA interference or antibody targeting improved survival of mice with metastases (Ilantzis et al, 2002;Blumenthal et al, 2005). Several experiments in vitro and in vivo demonstrated that CEACAM6 may impede myogenic, adipogenic, neurogenic, and colonic differentiation programs (Duxbury et al, 2004a,b), inhibit anoikis and apoptosis in colon and pancreatic cancer cells, disrupt cell polarization and tissue architecture (Soeth et al, 2001;Duxbury et al, 2004c), enhance liver metastasis (Capurso et al, 2006), increase chemoresistance (Duxbury et al, 2004d), and increase higher incidence of spontaneous colon tumor and lung tumor in a transgenic mouse model (Chan et al, 2006).…”

Expansion of CD133+ colon cancer cultures retaining stem cell properties to enable cancer stem cell target discovery

“…The roles of these cell membrane proteins in cancer development are well documented. For instance, expression of CEACAMs is associated with poor prognosis in colon cancer (Ishida et al, 2004) and they are considered as a therapeutic target (Blumenthal et al, 2005). Overexpression of biglycan has been identified in pancreatic cancers (Weber et al, 2001).…”

Carcinoembryonic Antigen and CD44 Variant Isoforms Cooperate to Mediate Colon Carcinoma Cell Adhesion to E- and L-selectin in Shear Flow

“…The capacity of different colorectal cell lines to grow in nude mouse spleen and liver models correlates positively with CEA production (33). CEA has emerged as a suitable target antigen for the detection of primary and metastatic colorectal and some other carcinomas (30), and it is presently being evaluated as a possible target for antibody-mediated therapy (34).…”