Deregulation of the CEACAM Expression Pattern Causes Undifferentiated Cell Growth in Human Lung Adenocarcinoma Cells

Abstract

CEACAM1, CEA/CEACAM5, and CEACAM6 are cell adhesion molecules (CAMs) of the carcinoembryonic antigen (CEA) family that have been shown to be deregulated in lung cancer and in up to 50% of all human cancers. However, little is known about the functional impact of these molecules on undifferentiated cell growth and tumor progression. Here we demonstrate that cell surface expression of CEACAM1 on confluent A549 human lung adenocarcinoma cells plays a critical role in differentiated, contact-inhibited cell growth. Interestingly, CEACAM1-L, but not CEACAM1-S, negatively regulates proliferation via its ITIM domain, while in proliferating cells no CEACAM expression is detectable. Furthermore, we show for the first time that CEACAM6 acts as an inducer of cellular proliferation in A549 cells, likely by interfering with the contact-inhibiting signal triggered by CEACAM1-4L, leading to undifferentiated anchorage-independent cell growth. We also found that A549 cells expressed significant amounts of non-membrane anchored variants of CEACAM5 and CEACAM6, representing a putative source for the increased CEACAM5/6 serum levels frequently found in lung cancer patients. Taken together, our data suggest that post-confluent contact inhibition is established and maintained by CEACAM1-4L, but disturbances of CEACAM1 signalling by CEACAM1-4S and other CEACAMs lead to undifferentiated cell growth and malignant transformation.

Retargeting of Adenovirus Vectors through Genetic Fusion of a Single-Chain or Single-Domain Antibody to Capsid Protein IX

“…84,2010 RETARGETING ADENOVIRUS VECTORS THROUGH GENETIC FUSION 10081 A549 cells, CD66c is variably glycosylated and appears as a diffuse region of immunoreactivity by immunoblot analysis (Fig. 6B), as previously reported (69,86). AFAI is known to interact with a specific glycosylation variant of CD66c (86), and we were readily able to detect the interaction between the two proteins, suggesting that fusion of AFAI to pIX did not alter its ability to recognize CD66c.…”

“…In contrast, infection of A549 cells with AdRP2595 was decreased by only 60% by inclusion of soluble knob, and there was no further decrease in infection with increasing concentrations of fiber knob. That we observed an initial reduction in infection of A549 cells with AdRP2595 in the presence of soluble knob was not unexpected, since only approximately 40 to 50% of the cells in the culture express CD66c (69,86). Taken together, these data indicate that sdAb can be displayed on the Ad capsid through fusion to pIX and can be used to redirect virus infection.…”

“…To determine if pIX can be used to display sdAd on the capsid surface and lead to altered transduction characteristics, we generated a virus that contained a fusion protein composed of pIX and AFAI, an sdAb identified through phage panning of the A549 non-small-cell lung carcinoma cell line (86), and examined its ability to infect A549 cells. AFAI binds to CD66c (carcinoembryonic antigen-related cell adhesion molecule family member 6 [CEACAM6]), which is expressed on a subset of A549 cells in the culture (69,86). To determine if pIX-AFAI was efficiently incorporated into the Ad capsid, we examined the protein content of purified capsid by immunoblot analysis for the FLAG-tagged pIX-AFAI and fiber (loading control).…”

Distribution and surfactant association of carcinoembryonic cell adhesion molecule 6 in human lung

“…5Be and Refs. 30, 32), including type I cells, could result from gene expression and/or shedding and membrane insertion of CEACAM6, a known property of GPI proteins (27) and of CEACAM6 in A549 cells (31). We, therefore, further examined this issue as summarized in Fig.…”

CEACAM1-3S Drives Melanoma Cells into NK Cell-Mediated Cytolysis and Enhances Patient Survival

“…Melanocytes are CEACAM negative (13), while high expression levels of CEACAM1 have been detected in melanoma (14) and adenocarcinoma (15). CEACAM1 was reported to inhibit cell proliferation in several tumor entities, excepting melanoma (13,16,17). On the tumor cell surface, the CEA-CAM1 protein has been shown to interact directly with CEA-CAM1 on immune cells, leading to functional inhibition of those cells (18)(19)(20)(21), or to indirectly modulate cancer cell immunogenicity by downregulating their cell surface expression of MHC class I-related molecule A and B (MICA/B) and UL-16-binding protein1 (ULBP; ref.…”