Aberrant expression of G1-phase cell cycle regulators in flat and exophytic adenomas of the human colon.
OBJECTIVE
The G1/S-phase controlling mechanism known as the RB pathway is commonly deregulated in human malignancies. Here, the abundance and localization of key components of the retinoblastoma (RB) pathway were determined in exophytic and flat colorectal adenomas.


METHODS
Samples of normal colonic mucosa (n = 41) and flat (n = 45) and exophytic (n = 26) adenomas were examined immunohistochemically using antibodies to cyclins D1, D2, D3, cyclin-dependent kinase (CDK) 4, retinoblastoma protein (pRB), and the CDK inhibitors p16INK4a, p18INK4c, and p19INK4d.


RESULTS
In normal colonic epithelium, cyclin D2 was undetectable; expression of cyclin D1, CDK4, and pRB correlated with proliferation; and p16, p18, p19, and cyclin D3 were most abundant in quiescent, differentiated cells. Adenomas showed elevated expression of cyclin D1 and pRB, frequent induction of cyclin D2, and absence of p16. No obvious abnormalities were found for p18, p19, or cyclin D3. Overexpressed cyclin D2 was more common among exophytic and pRB among flat adenomas, respectively. Elevated cyclin D1, D2, and CDK4 correlated with enhanced dysplasia.


CONCLUSIONS
Aberrant expression of cyclins D1, D2, CDK4, p16, and pRB occur in significant subsets of exophytic and flat adenomas, particularly among cases with high-grade dysplasia. Such defects of the RB pathway may perturb cell-cycle control and thereby contribute an early step in colorectal tumorigenesis.
Bartkova
J
J
Department of Cell Cycle and Cancer, Institute of Cancer Biology, Copenhagen, Denmark.
Thullberg
M
M
Slezak
P
P
Jaramillo
E
E
Rubio
C
C
Thomassen
L H
LH
Bartek
J
J
D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000032:analysis; D056742:Cyclin D2; D056743:Cyclin D3; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D018844:Cyclin-Dependent Kinases / Q000032:analysis; D016213:Cyclins / Q000032:analysis; D005260:Female; D016193:G1 Phase; D006801:Humans; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000032:analysis
C080336:CCND2 protein, human; C534696:CCND3 protein, human; D056742:Cyclin D2; D056743:Cyclin D3; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases