Article

GPI-anchored CEA family glycoproteins CEA and CEACAM6 mediate their biological effects through enhanced integrin alpha5beta1-fibronectin interaction.

Department of Biochemistry and McGill Cancer Centre, McGill University, Montreal, Quebec, Canada.
Journal of Cellular Physiology (Impact Factor: 4.22). 04/2007; 210(3):757-65. DOI: 10.1002/jcp.20887
Source: PubMed

ABSTRACT Carcinoembryonic antigen (CEA) and CEA family member CEACAM6 are glycophosphatidyl inositol (GPI)-anchored, intercellular adhesion molecules that are up-regulated in a wide variety of human cancers, including colon, breast, and lung. When over-expressed in a number of cellular systems, these molecules are capable of inhibiting cellular differentiation and anoikis, as well as disrupting cell polarization and tissue architecture, thus increasing tumorigenicity. The present study shows that perturbation of the major fibronectin receptor, integrin alpha5beta1, underlies some of these biological effects. Using confocal microscopy and specific antibodies, CEA and CEACAM6 were demonstrated to co-cluster with integrin alpha5beta1 on the cell surface. The presence of CEA and CEACAM6 was shown to lead to an increase in the binding of the integrin alpha5beta1 receptor to its ligand fibronectin, without changing its cell surface levels, resulting in increased adhesion of CEA/CEACAM6-expressing cells to fibronectin. More tenacious binding of free fibronectin to cells led to enhanced fibronectin matrix assembly and the formation of a polymerized fibronectin "cocoon" around the cells. Disruption of this process with specific monoclonal antibodies against either fibronectin or integrin alpha5beta1 led to the restoration of cellular differentiation and anoikis in CEA/CEACAM6 producing cells.

0 Bookmarks
 · 
55 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) inhibits anoikis and affects the malignant phenotype of cancer cells. In this study, we analyzed CEACAM6 as a gene that is highly upregulated in colon cancer tissues, and examined the assertion that CEACAM6 might be a suitable candidate tumor marker for the diagnosis of colon cancer. METHODS: CEACAM6 gene expression in human colon tissues was performed by tissue microarray and analyzed using RT-PCR (each of normal and tumor tissue, n=40) and immunohistochemical and clinicopathological (colon cancer patients, n=143) analyses. RESULTS: CEACAM6 transcriptional and translational levels were significantly upregulated in human tumor tissues compared to non-tumor regions, and clinicopathological analysis revealed a significant correlation between CEACAM6 protein expression and Dukes' stage (p<0.001). High expression levels of CEACAM6 were significantly associated with lower overall survival (p<0.001) and shorter recurrence-free survival (p<0.001). We demonstrated that knockdown of CEACAM6 with CEACAM6-specific small interfering RNA in colorectal cancer cells attenuated invasivity (35%); conversely, the overexpression of CEACAM6 increased invasiveness. CONCLUSIONS: CEACAM6 is significantly upregulated in colon cancer tissues and is closely associated with poor prognosis, indicating that CEACAM6 might be used as a tumor biomarker and a potential therapeutic target for colon cancer.
    Clinica chimica acta; international journal of clinical chemistry 09/2012; 415C:12-19. · 2.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) shows increased expression in a wide variety of human cancers, and its over-expression is associated with enhanced migration, invasion, and in vivo metastasis. Here, we reported that CEACAM6 was up-regulated in gastric cancer (GC) cell lines and tumor tissues. Over-expression of CEACAM6 in MKN-45 and SGC-7901 GC cells promoted migration and invasion in vitro and metastasis in athymic mice, whereas migration and invasion of MKN-28 and SNU-16 GC cells were suppressed by knockdown of CEACAM6. We also observed that steroid receptor coactivator (C-SRC) phosphorylation was increased when CEACAM6 was over-expressed in SGC-7901 cells. Taken together, these results suggested that CEACAM6 functions as an oncoprotein in GC and may be an important metastatic biomarker and therapeutic target.
    Acta Biochimica et Biophysica Sinica 02/2014; · 1.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Carcino-embryonic antigen-related cell adhesion molecule 6 (CEACAM6), one of the members of human carcino-embryonic antigens, is a multifunctional regulatory protein involved in various cellular processes in cancers. Its role in malignant transformation and the clinical significance has been extensively studied in colonic and pancreatic cancers. However, relatively few studies have been done on breast cancers. In the current study, CEACAM6 expression in two independent cohorts of invasive breast cancers were evaluated immunohistochemically and correlated with clinico-pathological features, biomarker profiles and patient survival. In the primary cohort, CEACAM6 expression was detected in 37.1 % (312/840) of primary invasive cancers. It was positively correlated with HER2 (p < 0.001). Concordantly, HER2-OE subtype showed the highest CEACAM6 expression (62.7 %) among all molecular subtypes; whereas, other subtypes also showed substantial CEACAM6 expression (21.8-37.5 %). Interestingly, a significantly worse overall survival was found in high pN stage HER2 positive cancers with CEACAM6 positivity (log-rank = 4.452, p = 0.035) and this could be validated in an independent cohort. Additionally, HER2 signaling was found to induce SMAD3 phosphorylation and CEACAM6 expression in a cell line model. Likewise, in the primary tumors, a positive association was found between HER2 and SMAD3 phosphorylation in CEACAM6 positive cancers (p = 0.012). Overall, CEACAM6 was widely expressed in different molecular subtypes, but highest and significantly in HER2-OE breast cancer. Within this group, CEACAM6 was associated with adverse high nodal stage patient outcome. Given the wide expression of CEACAM6 in all breast cancers, its roles as prognostic marker and therapeutic target warrant further evaluation.
    Breast Cancer Research and Treatment 11/2013; · 4.47 Impact Factor