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[Cancer Research 64, 6377-6380, September 15, 2004]
© 2004 American Association for Cancer Research

Advances in Brief

A Novel Role for the Coxsackie Adenovirus Receptor in Mediating Tumor Formation by Lung Cancer Cells

Min Qin1, Brian Escuadro1, Mariam Dohadwala1, Sherven Sharma1 and Raj K. Batra1,2

1 Department of Medicine and The Lung Cancer Research Program, 2 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California at Los Angeles and Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
The Coxsackie Adenovirus Receptor (CAR) has primarily been studied in its role as the initial cell surface attachment receptor for Coxsackie and group C adenoviruses. Recent reports suggest that CAR mediates homotypic intercellular adhesion as part of the tight and/or adherens junction. Thus, CAR is well positioned to participate in intercellular interactions and signaling. Using an antisense (AS)-CAR plasmid vector, we silenced surface CAR expression in lung cancer cells that possessed a high basal expression of this molecule and monitored the resultant tumorigenesis. AS-CAR transfectants exhibit a profound loss in the ability to generate xenografts in scid/scid mice. The emergence of delayed-onset tumors in animals that received injection with AS-CAR transfectants correlates with the resurfacing of CAR expression, suggesting that such expression and tumor emergence are temporally related. To study the mechanism underlying the differences in tumorigenicity, control and AS-CAR cells were compared in terms of their in vitro growth potential. Whereas only subtle differences in the proliferative capacity of the two populations were evident when assayed with growth on plastic, significant differences became apparent when one compared the relative ability of these populations to form colonies in soft agar. These data indicate that silencing surface CAR expression abrogates xenograft tumorigenesis in vivo and colony formation in vitro and invoke the novel possibility that CAR expression is needed for the efficient formation of tumors by a subset of lung cancer cells.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
The Coxsackie Adenovirus Receptor (CAR) has primarily been studied in its role as the initial cell surface attachment receptor for Coxsackie and group C adenoviruses (Ads). The cDNA for CAR encodes for a 365-amino acid protein, and sequence comparison suggests that it belongs to the immunoglobulin family of proteins (1) . The molecule displays putative N-glycosylation sites in the extracellular domain and four potential phosphorylation sites on cytoplasmic tyrosine residues (1) . Of these residues, tyrosine 318 has been reported to serve in promoting cellular sorting of CAR in polarized epithelia (2) . Membrane-proximal palmitylation sites (3) and a COOH-terminal PDZ-binding motif (2) for the potential creation of signaling scaffolds have also been described. However, the cellular function of CAR is unclear. Recent reports suggest that CAR mediates homotypic intercellular adhesion as part of the tight and/or adherens junction (4 , 5) . The distal extracellular IgV-like domain of CAR that mediates adhesion also serves as the primary attachment site for the Ad fiber protein (6) , and the structural basis for these interactions has been characterized (7, 8, 9, 10) . For Ad entry, viral attachment to CAR triggers a clustering of cell surface integrins and viral endocytosis using coated pit mechanisms by a process that requires cellular actin stabilization, activation of p130CAS, phosphatidylinositol 3'-kinase, and the rho family GTPases (11, 12, 13, 14) . Implicit in this process is the suggestion that ligand (e.g., the Ad fiber protein) binding to CAR promotes clustering of integrins on the cell surface and that CAR binding impacts on the cytoskeleton and endocytotic processes that may require components of cellular focal adhesions. CAR may also have a role in tumorigenesis. In this respect, CAR expression has been correlated with both tumor suppression (15, 16, 17, 18) and malignant transformation (19) . Given that CAR is well positioned (as a putative adhesion and signaling molecule) to participate in these roles, we silenced its expression in lung cancer cells with high basal expression of CAR to monitor the resultant phenotype. Silencing surface CAR expression abrogates xenograft tumorigenesis in vivo and colony formation in vitro and invokes the novel possibility that CAR expression is needed for the efficient formation of tumors by a subset of lung cancer cells.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS AND DISCUSSION
 REFERENCES
 
Cell Lines.
NCI-H1703 non–small-cell lung cancer (NSCLC) cells, a gift of Dr. Herbert Oie (National Cancer Institute, Bethesda, MD) were maintained in RPMI 1640 (Irvine Scientific, Santa Ana, CA) with 10% fetal bovine serum (Gemini, Woodland, CA) and penicillin (100 units/mL)/streptomycin (100 µg/ml) [complete growth medium]. Parental NCI-H1703 cells are characteristically easily transduced with Ad vectors and exhibit high surface CAR expression (20) .

Plasmid Vectors and Cell Selection.
CAR expression in these cells was silenced using antisense (AS) methodology. A full-length (2.4-kb) CAR insert was digested (BamHI and XhoI) out of pcDNA3-CAR (a gift of Joanne Douglas, UAB Gene Therapy Center, Birmingham, AL) and ligated into the linearized pLEGFP-N1 (Clontech, Becton Dickinson Biosciences, Palo Alto, CA) vector in the AS orientation downstream of the cytomegalovirus promoter/enhancer sequence. Plasmid DNA was isolated from transformed DH5{alpha}, and the orientation of the CAR insert was confirmed with XbaI digestion. Empty and AS-CAR vectors were amplified (large-scale plasmid prep; Qiagen, Valencia, CA) and transfected into lung cancer cells using Effectene reagent (Qiagen). Pooled populations of NCI-H1703 were selected after G418 selection (500 µg/mL) over 4 weeks.

Characterization of Transfectants.
The presence of vector with or without the AS-CAR insert was confirmed by DNA polymerase chain reaction primed by sequences flanking the multiple cloning site in the pLEGFP-N1 and AS-CAR transfectants. Functionally, the pooled populations of AS-CAR and vector transfectants were evaluated for CAR expression by Ad transduction and by measuring surface CAR expression directly by flow cytometry.

Coxsackie Adenovirus Receptor Expression by Flow Cytometry.
RmcB, a murine monoclonal antibody that recognizes the extracellular NH2 terminus region of CAR (21) , was purified from hybridoma (CRL-2379; American Type Culture Collection, Manassas, VA) severe combined immunodeficient mouse ascites using protein G affinity chromatography (Amersham Pharmacia Biotech, Piscataway, NJ) and used to specifically detect cellular CAR expression by flow cytometry. Cells (1 x 106) were preincubated in 100 µL of 0.1% bovine serum albumin (BSA) in PBS (20 minutes, room temperature) before primary antibody (RmcB; mouse IgG1; 1:100 dilution in PBS/0.1% BSA, 90 minutes, room temperature) was admixed on an orbital shaker. Cells were then sedimented and washed three times with PBS/0.1% BSA, incubated with secondary antibody (phycoerythrin-conjugated sheep antimouse F(ab')2; Sigma, St. Louis, MO; 1:200 dilution in PBS/0.1% BSA, 30 minutes, room temperature in the dark), washed three times, and resuspended in 500 µL of PBS for flow cytometry by FACScan [University of California Los Angeles (UCLA) Jonsson Comprehensive Cancer Center Cytometry Core Facility, Los Angeles, CA] using CellQuest software (Becton Dickinson, Mountain View, CA). For all data acquisitions and analyses, gates were based on the forward and side scatter profiles of unstained cells, and surface expression of target proteins was normalized to that of cells that had been incubated with secondary antibody alone.

Tumorigenesis Assays.
Four- to 6-week–old female (scid/scid) host mice (UCLA Jonsson Comprehensive Cancer Center Core Mouse Facility, Los Angeles, CA) received subcutaneous injection in the flanks with 8 x 106 cells per mouse for tumor xenoengraftment using an institutionally approved protocol. Tumor dimensions were estimated based on bisecting diameters measured with a caliper, and the tumor volume was approximated using the formula 0.4(ab2), where a is the long measured axis of the tumor, and b is the short measured axis of the tumor. For some experiments, "mature" tumors were extirpated, minced, and suspended in 4 IU/mL collagenase (type II collagenase; Sigma) in RPMI 1640 at 4°C overnight. Cells were washed and reseeded in growth medium for characterization of CAR expression by fluorescence-activated cell sorting as described above. For colony formation in soft agar, 1,000 cells were suspended in 0.25% soft agar in growth medium, and the suspension was overlaid onto 0.40% Noble Agar cooled to room temperature in 60-mm plates. Macroscopically visible colonies stained with P-iodonitrotetrazolium violet were counted from scanned photographs by a blinded observer 3 weeks later.

Statistical Methods.
The mean and SD of values within all transduction, surface labeling, and tumorigenesis experiments were compared for differences using the unpaired t test, or one-way analysis of variance on ranks followed by Bonferroni group comparisons, using GraphPad InStat software (GraphPad Software Inc., San Diego, CA). A statistically significant difference was defined as P < 0.05 between the groups compared.


   RESULTS AND DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
REFERENCES
 
Substantial inhibition of CAR expression was achieved in a pooled population of NCI-H1703 AS-CAR transfectants selected with G418 (from 99.9% gated with mean channel fluorescence of 55.2, to 30.8% gated with mean channel fluorescence of 14.9; see Table 1Citation ). As expected, Ad transduction studies of AS-CAR transfectants confirmed a marked reduction in Ad gene transfer efficiency in vitro (Fig. 1A)Citation , results congruent with flow cytometric analysis. Thus, these results indicated that we had successfully selected populations of vector and AS-CAR NSCLC transfectants that seemingly differed only in terms of surface CAR expression. To confirm that this surface phenotype persisted in vivo, control and AS-CAR transfectants were implanted in the flanks of scid/scid mice. However, this assessment could not be undertaken because the AS-CAR transfectants exhibited a profound loss in the ability to generate xenografts in scid/scid mice (Fig. 1B)Citation .


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  		Table 1 Cell surface CAR expression

 


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  		Fig. 1. A and B, silencing surface CAR expression decreases sensitivity to Ad transduction and inhibits the ability of cancer cells to form tumor xenografts. A, comparison of in vitro transduction efficiency at AdLacZ multiplicity of infection of 10 or 100 in H1703 cells transfected with the pLEGFP-N1 vector ({blacksquare}) versus pLEGFP-N1 encoding the complete AS sequence to CAR (AS-CAR; {square}). Transduction efficiency after a 1-hour exposure of cells to AdLacZ is depicted as a surrogate measure of CAR expression, and asterisk denotes P < 0.05 by the unpaired t test for a significant difference between the groups. B, 10 (scid/scid) host mice received injection of 8 x 106 vector-transfected or AS-CAR–transfected cells in the right flank region. Tumor volume ± SD is depicted on day 40 after implantation. Asterisk denotes P < 0.001 for a significant difference between tumor formation by vector control versus AS-CAR transfectants.

 
These unexpected results prompted us to follow up this observation with a formal tumorigenesis and survival study. Fig. 2A and BCitation depict the tumor growth and "survival curves" (using institutional criteria for euthanasia in terms of skin breakdown, tumor burden, impaired mobility, or tumor cachexia as the end point). Again, whereas no palpable tumors were evident in the group implanted with the AS-CAR transfectants, 100% of the animals implanted with the control population had succumbed to tumor-related euthanasia by day 52 (Fig. 2A and B)Citation . To evaluate whether tumor formation with the AS-CAR transfectants was only delayed rather than prevented, mice implanted with AS-CAR transfectants were maintained in a protected facility and monitored for tumor growth over an additional 3 months. Over this prolonged monitoring period, one of the five mice implanted with the AS-CAR transfectants was observed to develop a palpable tumor (Fig. 2C)Citation , nearly 12 weeks after the initial tumor cell injection. The tumor was allowed to grow over the ensuing 5 weeks, at which time it was extirpated, minced, and grown in primary culture. Four days later, the CAR expression of the adherent primary-passaged tumor cells was evaluated by flow cytometry and noted to be similar to that of wild-type or vector control (see Table 1Citation , primary tumor). This observation suggested that this tumor was an outgrowth that originated from an oligoclonal population within the AS-CAR transfectants that had high CAR expression or that CAR expression had resurfaced in CAR-silenced cells for tumorigenesis to proceed.



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  		Fig. 2. A–C, kinetics of tumor growth and survival of animals that received injection with AS-CAR versus control vector transfectants. A, five (scid/scid) mice per group received injection with 8 x 106 vector ({blacksquare})-transfected or AS-CAR–transfected cells ({circ}) in the right flank region. Tumor volumes were measured every other day for 8 weeks and then measured twice per week for the surviving animals to a total of 120 days. Mean tumor volume ± SD is depicted within each group of animals. B, survival curves of mice grouped in A. In the control vector-transfected set ({blacksquare}), two mice were sacrificed on day 35, one was sacrificed on day 42, and one was sacrificed on day 52 because institutional criteria for euthanasia were met. Surviving animals were monitored twice per week for delayed tumor growth (see C). C, one of five mice that received injection with AS-CAR transfectants showed delayed tumor growth approximately 3 months after the initial injection of 8 x 106 cells into the right flank. The growth pattern of this delayed tumor outgrowth ({circ}) is depicted. CAR expression analysis of primary cells harvested from this tumor revealed reversion to wild-type CAR expression as shown in Table 1Citation .

 
To differentiate between these two possibilities, clonal populations with near complete loss of surface CAR expression have been isolated by limited dilution from the pooled AS-CAR transfectants. Tumorigenicity and survival studies using these clones have reliably mimicked the results depicted with those seen with pooled AS-CAR transfectants (data not shown). Accordingly, a generalized inhibition of tumorigenesis, with rare delayed tumor growth, is associated with these AS-CAR clonal populations. And when these delayed-onset tumors are extirpated and evaluated for CAR expression, the cells are again observed to have "reacquired" exuberant surface CAR, suggesting that such expression and tumor emergence are temporally related. This postulate is also bolstered by accruing data, which indicate that tumor initiation is likely inhibited when CAR function is immunologically blocked in NCI-H1703 cells. In summary, coinjection of blocking antibody (RmcB; ref. 21 ) with tumor cells, but not control murine immunoglobulin subtype, interferes with tumor formation by CAR-expressing NSCLC cells (data not shown). In contrast, tumor infiltration with RmcB does not induce established tumor regression (data not shown). Thus, although the precise role needs to be determined, both genetic and immunologic data indicate that CAR plays a prominent role in tumorigenesis.

To study the mechanism underlying the differences in tumorigenicity between cells that differ solely in surface CAR expression, we evaluated the vector and AS-CAR clones in terms of their in vitro growth potential. Only subtle (nonsignificant) differences in the proliferative capacity of the controls versus AS-CAR cells were evident when assayed with growth on plastic (Fig. 3A)Citation . However, significant differences were apparent when one compared the relative ability of these populations to form colonies in soft agar (Fig. 3B)Citation . The evidence suggests that AS-CAR cells form a reduced number of colonies. Although cell aggregation assays do not discriminate between AS-CAR and vector control cells, the colonies formed by these populations appear morphologically different in soft agar (i.e., the AS-CAR colonies are more spread out than control colonies). These data indicate that an in vitro correlate for the observed differences in tumor formation in vivo may require growth in three-dimensional matrices.



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  		Fig. 3. A and B, growth parameters of vector control and AS-CAR transfectants on plastic and colony formation on soft agar. A, 50,000 cells per well were seeded in triplicate into 12-well plates on day 0, and the growth kinetics of parental NCI-H1703 cells ({square}), NCI-H1703 vector transfectants ({circ}), and H1703 AS-CAR transfectants ({triangleup}) was measured by direct counting using a hematocytometer after detachment of adherent cells. Abscissa, time (in days) after plating; ordinate, mean cell numbers (x104). B, 1,000 cells suspended in 0.25% soft agar in growth medium were overlaid onto 0.40% Noble Agar cooled to room temperature in 60-mm plates. Macroscopically visible colonies stained with p-Iodonitrotetrazolium violet were counted from scanned photographs by a blinded observer 3 weeks later. Values are the means ± SD of day 21 colony counts from three different experimental sets. *, P < 0.01 for a significant difference between colony formation by vector control versus AS-CAR transfectants.

 
In summation, our studies implicate a novel role for the CAR in tumor formation. On the surface, this role contrasts with that implied by earlier reports (15, 16, 17, 18) , which characterize CAR as a global tumor suppressor. However, there are commonalities between our data and earlier observations, despite differences in interpretation and analysis. Thus, similar to previous reports, we also note that different cancer cell lines with varying surface CAR expression exhibit differences in growth potential. For example, lung cancer cells with low surface CAR expression (e.g., NCI-H460 or NCI-H2122) exhibit a higher in vitro and in vivo proliferative index than another lung cancer subtype with high surface CAR expression (e.g., NCI-H226 or NCI-H1703; data not shown). However, such differences in growth may not be seen when comparing parental or vector-modified cells with the same cells that have been genetically modified to specifically alter CAR expression. In fact, in analyzing such paired cell populations, we note only subtle differences in proliferation in vitro and marked decreases in colony formation and in vivo tumor growth with AS-CAR cells (Figs. 1Citation 2Citation 3)Citation .

We realize that CAR expression is not a prerequisite for tumor formation because lung cancer cells that have low basal expression of CAR can still generate tumors (20) . However, primary lung tumors can possess a wide range of biological phenotypes, as reflected in their categorization within 4 major subtypes and over 40 subtypes by the World Health Organization. In this context, our observations suggest that silencing or blocking CAR expression in tumor cells with relatively high basal expression of this molecule greatly inhibits their ability to develop xenografts in host scid/scid mice. This observation forms the foundation for our hypothesis that CAR expression may play a prominent role in the pathogenesis of certain lung cancers and warrants further study toward delineating the mechanisms underlying the role of CAR in tumorigenesis and/or in modulating the malignant phenotype.


   ACKNOWLEDGMENTS
 
We wish to thank S. K. Tran for assistance with manuscript preparation.


   FOOTNOTES
 
Grant support: National Institutes of Health grant R01-CA78654, Veterans Administration Medical Research Funds, the American Lung Association Career Investigator Award, The UCLA Specialized Programs of Research Excellence in Lung Cancer (grant NIH-P50-90388), and the UCLA-Jonsson Comprehensive Cancer Center Flow Cytometry Facility.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Raj K. Batra, David Geffen School of Medicine at UCLA and Division of Pulmonary and Critical Care Medicine, Veterans Administration Greater Los Angeles Health Care System, 111Q, 11301 Wilshire Boulevard, Los Angeles, CA 90073. Phone: 310-268-3418; Fax: 310-268-4712; E-mail: rbatra{at}ucla.edu

Received 4/30/04. Revised 7/22/04. Accepted 7/29/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
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Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
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