Down-regulation of CEACAM1 in human prostate cancer: correlation with loss of cell polarity, increased proliferation rate, and Gleason grade 3 to 4 transition.

Many cancers have altered expression of various cell adhesion molecules. One of these is CEACAM1, which has been found to be downregulated in several carcinomas, including prostate cancer. We explored its immunohistochemical expression in a set of 64 total prostatectomy specimens and compared it with that of the epithelial cell adhesion molecule E-cadherin and occludin, a tight junction-associated molecule. The luminal surface of the epithelial cells of normal prostate glands and ducts showed a dense expression of CEACAM1. This pattern prevailed in prostate cancer of Gleason grades 1 to 3 as long as the cells maintained their polarity and formed individual glands. With "fusion" of glands (ie, in the transition to Gleason grade 4), the expression of CEACAM1 was lost in polygonal nonpolar cells and was lost or focally very weak in cells lining a lumen in the cribriform complexes. E-cadherin, which outlined the basolateral cell membranes of contacting neighboring epithelial cells was also downregulated in prostate carcinomas. However, the loss of E-cadherin expression in higher grades was gradual and not related to the Gleason 3 to >4 transition. Occludin was also lost in polygonal (ie, unpolarized) cells of Gleason grades 4 and 5, but remained expressed in all cells facing a lumen in all grades of cancer, which CEACAM1 was not. In conclusion, downregulation of CEACAM1 as well as that of occludin in prostate cancer is associated with loss of cell polarity. It coincides with the formation of the complex glandular architecture of Gleason grade 4 pattern or complete loss thereof in Gleason grade 5 patterns. The proliferative activity, measured as Ki67 labeling index, showed a fourfold increase in the carcinoma cells with lost CEACAM1 expression, supporting previous observations that CEACAM1 regulates cell proliferation. Immunohistochemical analysis of CEACAM1 expression patterns may be useful in assessment of the malignant potential of prostate carcinoma.

[1]  Y. Sun,et al.  Essential role of biliary glycoprotein (CD66a) in morphogenesis of the human mammary epithelial cell line MCF10F. , 1999, Journal of cell science.

[2]  Ewert Bengtsson,et al.  A New Method for Segmentation of Colour Images Applied to Immunohistochemically Stained Cell Nuclei , 1997, Analytical cellular pathology : the journal of the European Society for Analytical Cellular Pathology.

[3]  T. Stamey,et al.  Biological determinants of cancer progression in men with prostate cancer. , 1999, JAMA.

[4]  J. Isaacs,et al.  CD44 is a metastasis suppressor gene for prostatic cancer located on human chromosome 11p13. , 1997, Cancer research.

[5]  W. Isaacs,et al.  Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer. , 1994, Cancer research.

[6]  S. H. Lin,et al.  Tumor suppressive role of an androgen-regulated epithelial cell adhesion molecule (C-CAM) in prostate carcinoma cell revealed by sense and antisense approaches. , 1995, Cancer research.

[7]  E. Ruoslahti,et al.  Common principles in cell adhesion. , 1996, Experimental cell research.

[8]  Robert S. Kerbel,et al.  E-Cadherin–dependent Growth Suppression is Mediated by the Cyclin-dependent Kinase Inhibitor p27KIP1 , 1998, The Journal of cell biology.

[9]  M. Neumaier,et al.  Dysregulation of carcinoembryonic antigen group members CGM2, CD66a (biliary glycoprotein), and nonspecific cross-reacting antigen in colorectal carcinomas. Comparative analysis by northern blot and in situ hybridization. , 1997, The American journal of pathology.

[10]  Gerhard Christofori,et al.  A causal role for E-cadherin in the transition from adenoma to carcinoma , 1998, Nature.

[11]  L. Egevad,et al.  A New Method for Handling Radical Prostatectomies Enabling Fresh Tissue Harvesting, Whole Mount Sections, and Landmarks for Alignment of Sections , 1998 .

[12]  B. Obrink,et al.  Cell-cell contacts mediated by E-cadherin (uvomorulin) restrict invasive behavior of L-cells , 1991, The Journal of cell biology.

[13]  Y. Yamashita,et al.  Expression of four CEA family antigens (CEA, NCA, BGP and CGM2) in normal and cancerous gastric epithelial cells: Up‐regulation of BGP and CGM2 in carcinomas , 1998, International journal of cancer.

[14]  S. H. Lin,et al.  Application of a tumor suppressor (C-CAM1)-expressing recombinant adenovirus in androgen-independent human prostate cancer therapy: a preclinical study. , 1995, Cancer research.

[15]  O. Cussenot,et al.  Co-ordinated changes in expression of cell adhesion molecules in prostate cancer. , 1997, European journal of cancer.

[16]  M. Neumaier,et al.  Biliary glycoprotein, a potential human cell adhesion molecule, is down-regulated in colorectal carcinomas. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Y. Doki,et al.  Aberrant expression and phosphorylation of beta-catenin in human colorectal cancer. , 1998, British Journal of Cancer.

[18]  K. Tanaka,et al.  Decreased expression of biliary glycoprotein in hepatocellular carcinomas , 1997, International journal of cancer.

[19]  L. Riethdorf,et al.  Differential Expression of CD66a (BGP), a Cell Adhesion Molecule of the Carcinoembryonic Antigen Family, in Benign, Premalignant, and Malignant Lesions of the Human Mammary Gland , 1997, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[20]  M. Neumaier,et al.  CD66a (BGP), an adhesion molecule of the carcinoembryonic antigen family, is expressed in epithelium, endothelium, and myeloid cells in a wide range of normal human tissues. , 1996, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[21]  D Bilder,et al.  Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. , 2000, Science.

[22]  N. Beauchemin,et al.  Inhibition of colonic tumor cell growth by biliary glycoprotein. , 1995, Oncogene.

[23]  I. Scheffrahn,et al.  The tumor growth-inhibiting cell adhesion molecule CEACAM1 (C-CAM) is differently expressed in proliferating and quiescent epithelial cells and regulates cell proliferation. , 2000, Cancer research.

[24]  W. Zimmermann,et al.  Redefined nomenclature for members of the carcinoembryonic antigen family. , 1999, Experimental cell research.

[25]  W. Birchmeier,et al.  Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. , 1994, Biochimica et biophysica acta.

[26]  C. Wood,et al.  Suppression of tumorigenicity of breast cancer cells by an epithelial cell adhesion molecule (C-CAM1): the adhesion and growth suppression are mediated by different domains , 1997, Oncogene.

[27]  N. Beauchemin,et al.  The expression of mouse biliary glycoprotein, a carcinoembryonic antigen-related gene, is down-regulated in malignant mouse tissues. , 1993, Cancer research.

[28]  L. Riethdorf,et al.  Dysregulated expression of CD66a (BGP, C-CAM), an adhesion molecule of the CEA family, in endometrial cancer. , 1998, The American journal of pathology.

[29]  M. Monden,et al.  Beta-catenin expression in human cancers. , 1996, The American journal of pathology.

[30]  C. Dinney,et al.  Suppression of human bladder cancer growth by increased expression of C-CAM1 gene in an orthotopic model. , 1996, Cancer research.

[31]  I. Nagaoka,et al.  Biliary glycoprotein mRNA expression is increased in primary lung cancer, especially in squamous cell carcinoma. , 1994, American journal of respiratory cell and molecular biology.

[32]  B. Öbrink.  CEA adhesion molecules: multifunctional proteins with signal-regulatory properties , 1997, Current Opinion in Cell Biology.

[33]  Thomas,et al.  Consistent expression of an epithelial cell adhesion molecule (C-CAM) during human prostate development and loss of expression in prostate cancer: implication as a tumor suppressor. , 1995, Cancer research.

[34]  B. Obrink,et al.  Alterations in the expression of a hepatocyte cell adhesion molecule by transplantable rat hepatocellular carcinomas. , 1985, Cancer research.