CAR mediates efficient tumor engraftment of mesenchymal type lung cancer cells

Abstract

The coxsackie-adenovirus receptor (CAR) is a developmentally regulated intercellular adhesion molecule that was previously observed to be required for efficient tumor formation. To confirm that observation, we compared the tumorigenicity of clonally derived test and control cell subsets that were genetically modified for CAR. Silencing CAR in lung cancer cells with high constitutive expression reduced engraftment efficiency. Conversely, overexpressing CAR in lung cancer cells with low constitutive expression did not affect tumor formation or growth kinetics. A blocking antibody to the extracellular domain of CAR inhibited tumor engraftment, implicating that domain as being important to this process. However, differences in adhesion properties attributable to this domain (barrier function and aggregation) could not be distinguished in the test groups in vitro, and the mechanisms underlying CAR's contribution to tumor engraftment remain elusive. Because high CAR cells displayed a spindle-shaped morphology at baseline, we considered whether this expression was an accompaniment of other mesenchymal features in these lung cancer cells. Molecular correlates of CAR were compared in model epithelial and mesenchymal type lung cancer cells. CAR expression is associated with an absence of E-cadherin, diminished expression of a-and g-catenin, and increased Zeb1, Snail, and vimentin expression in lung cancer cells. In contrast, epithelial type (NCI-H292, Calu3) lung cancer cells show comparatively low CAR expression. These data suggest that if the mesenchymal cell phenotype is an accurate measure of an undifferentiated and invasive state, then CAR expression may be more closely aligned with this phenotype of lung cancer cells.

Coxsackie and adenovirus receptor is a target and a mediator of estrogen action in breast cancer

“…Indeed, it was shown that CAR antagonizes the action of apoptosis inducing agents and in turn increases breast cancer cell survival (Bruning et al 2005). In a similar manner, as for lung cancer in which CAR silencing reduces tumor growth (Veena et al 2009), we show that CAR antibodies or CAR siRNA inhibit the estrogendependent growth of MCF-7 cells. We did not observe any sign of mortality when cells were treated with the CAR antibody, which suggests that CAR affects mainly cell proliferation than survival.…”

“…Most studies have shown in bladder, cervical, ovary cancers, and glioma that CAR was repressing cell proliferation (Okegawa et al 2001, Kim et al 2003, Bruning & Runnebaum 2004, Huang et al 2005, Wang et al 2005, Zhang et al 2007, whereas others have shown mitogenic properties for CAR in lung cancer (Qin et al 2004, Veena et al 2009). The situation in breast cancer might be unique compared with other cancers.…”

Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis

“…To test the possible role of Daxx in disrupting Slug DNA-binding ability, we performed chromatin immunoprecipitation (ChIP) assays. In CL1–5 cells, Slug protein was recruited to the E-cadherin promoter and the CAR promoter, another validated Slug target gene39; however, this recruitment was decreased by co-expression of Daxx (Fig. 2f; Supplementary Fig.…”

The CD44high Tumorigenic Subsets in Lung Cancer Biospecimens Are Enriched for Low miR-34a Expression

“…To investigate a possible association, karyotype analysis was performed on the three MPE samples. Normal fibroblast GM 05399 and the lung cancer cell line NCI-H2122 were used as controls to represent non tumorigenic and immortalized tumor cell models [20]–[23]. All three MPE samples M-1, M-2 and M-3 showed extensive chromosomal changes with hyperdiploid number of chromosomes 83, 67, and 74 respectively (Figure 5B, D, F).…”

“…It was subsequently deposited into ATCC (NCI-H2122 [H2122] ATCC® CRL-5985™) [21]. The cell line is maintained in our laboratory in RPMI-1640 medium in presence of 10% FBS [22], [23]. Both the cell lines are publicly available.…”