Colorectal carcinoma is the second most lethal cancer in the United States and the liver is the most frequent site of visceral metastasis. Carcinoembryonic antigen (CEA), a 180 kDa glycoprotein secreted by bowel carcinomas, promotes colonization of the liver by weakly metastatic human colorectal carcinoma (CRC) cells injected into the spleen. This intrasplenic injection model is clinically useful because serum levels of CEA are increased in most patients with liver metastases and the model mimics the steps of implantation, extravasation, and proliferation that occur during metastasis. The model demonstrates that 1) CRC implant in periportal venules, 2) more highly than weakly metastatic CRC cells survive 24 hours after implantation, and 3) systemic pretreatment with CEA increases the survival of weakly metastatic CRC cells. Previously, we tested the hypothesis that CEA acts as an intercellular adhesion molecule to enhance experimental metastasis. While CEA is an adhesion molecule associated with CD44 and beta1-containing integrins, CRC do not use CEA to adhere to hepatic venules. Our current hypothesis is that soluble CEA in the portal circulation promotes metastasis by inducing Kupffer cells, the fixed macrophages of the liver, to produce cytokines that either directly enhance CRC cell implantation and proliferation in the periportal venules or that induce host cells to facilitate the implantation and extravasation of CRC cells in the liver. The following specific aims will test this hypothesis: 1) To determine whether early survival of implantation by CRC cells in liver is a selective or random process; 2) To determine whether transfection of CEA into weakly metastatic, non-CEA-expressing CRC enhances liver colonization by increasing early survival after hepatic implantation; 3) To determine whether inhibition of adhesion receptor function by CRC cells inhibits liver colonization; and 4) To determine whether inhibiting the response to CEA in vivo by Kupffer cells prevents the CEA-mediated facilitation of liver colonization by weakly metastatic CRC. Our data suggest that the number of CRC cells surviving implantation determines metastatic potential and that early survival of CRC cells is increased by proteins secreted by the tumor. Our long term goal remains to determine how CEA enhances metastasis and then to develop a treatment to inhibit that enhancement.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042857-12
Application #
2856268
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Jhappan, Chamelli
Project Start
1986-07-01
Project End
1999-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
12
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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