Cloning and functional characterization of a new phosphatidyl-inositol anchored molecule of a metastasizing rat pancreatic tumor.
We have described recently a panel of metastasis-associated antigens expressed on a rat pancreatic tumor. One of these molecules, recognized by the monoclonal antibody C4.4 and named accordingly C4.4A, was under physiological conditions expressed only in the gravid uterus and on epithelial of the upper gastrointestinal tract. The cDNA of the antigen has been isolated and cloned. The 1,637 b cDNA codes for a 352 amino acid long glycosylphosphatidyl-inositol (GP) anchored molecule, whose molecular weight varies in different cells between 94-98 kD according to the degree of N- and O-glycosylation. Data base searches have revealed a low degree of homology to the receptor for the plasminogen activator (uPAR). After intrafootpad and intravenous application of C4.4A transfected and mock-transfected tumor cells, an increased number of lung nodules was detected with the former, whereby the individual metastatic nodules amalgamated without any encapsulation of the tumor tissue. Furthermore, C4.4A is involved in adhesion to laminin and, although transfection of a non-metastasizing tumor line with the molecule was not sufficient, constitutively C4.4A-positive tumor cells penetrated through matrigel. This process could be completely prevented by C4.4. Finally, we could demonstrate that uPA, albeit weakly, bound to the C4.4A molecule. In view of the observed influence of C4.4A on metastasis formation and matrix penetration it is tempting to speculate that this newly described metastasis-associated molecule may exert functional activity similar to the uPAR, i.e. via activation of matrix degrading enzymes. By the very restricted expression of the molecule in the adult organism, modulation of C4.4A could well be of therapeutic interest.
Rösel
M
M
Department of Tumor Progression and Immune Defense, German Cancer Research Center, Heidelberg.
Claas
C
C
Seiter
S
S
Herlevsen
M
M
Zöller
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics*; D001483:Base Sequence; D019556:COS Cells; D003001:Cloning, Molecular; D003094:Collagen; D018076:DNA, Complementary; D004338:Drug Combinations; D058851:GPI-Linked Proteins / Q000235:genetics*; D007797:Laminin; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011509:Proteoglycans; D051381:Rats; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; C115145:C4.4 monoclonal antibody; D018076:DNA, Complementary; D004338:Drug Combinations; D058851:GPI-Linked Proteins; D007797:Laminin; C571407:Lypd3 protein, rat; D009363:Neoplasm Proteins; D010716:Phosphatidylinositols; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen