Coxsackie and adenovirus receptor promotes adenocarcinoma cell survival and is expressionally activated after transition from preneoplastic precursor lesions to invasive adenocarcinomas.
OBJECTIVE
The cell adhesion protein, coxsackie and adenovirus receptor (CAR), is differentially expressed in various human adenocarcinomas. We analyzed the role of differential CAR expression during tumorigenesis and in cell survival of adenocarcinomas.


METHODS
In a murine mammary cancer model, a syngenic preneoplastic mammary tissue was implanted into the mammary fat pads of syngenic female BALB/c mice. CAR expression was determined by semiquantitative reverse transcription-PCR in the preneoplastic noninvasive precursor lesions and the developing invasive adenocarcinomas. Cell clones overexpressing CAR were generated and tested for their response to apoptotic factors and for the expression of apoptosis relevant proteins by reverse transcription-PCR and Western blot analysis.


RESULTS
In comparison of preneoplastic precursor lesions with established adenocarcinomas, CAR expression was enhanced 2- to 5-fold in all six tissues which had survived and transformed into invasive adenocarcinomas. When stable CAR-overexpressing cell clones of the human cancer cell lines HeLa, CaSki, and A2780 were compared with the parental cell lines, 1.5- to 6-fold more cells survived application of tumor necrosis factor-related apoptosis-inducing ligand or growth factor withdrawal. CAR-enhanced cell survival was accompanied by reduced activation of caspase 3 and enhanced expression of bcl-2 or bcl-XL, depending on the cell type tested. Up-regulation of bcl-2 was found in all CAR-expressing adenocarcinomas of the murine cancer model.


CONCLUSIONS
CAR expression is enhanced after transition from preneoplastic precursor lesions to neoplastic mammary cancer outgrowths. Enhanced CAR expression can promote cancer cell survival. These data suggest differential expression of CAR as a new factor in tumorigenesis.
Brüning
Ansgar
A
Department of Obstetrics and Gynecology, Ludwig-Maximilians-University, Munich, Germany.
Stickeler
Elmar
E
Diederich
Daniel
D
Walz
Lioba
L
Rohleder
Hendrik
H
Friese
Klaus
K
Runnebaum
Ingo B
IB
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011991:Receptors, Virus; D051020:bcl-X Protein; D020169:Caspases