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Experimental and Molecular Therapeutics 4: Mechanisms of Action

In vivo promotion of human epithelial tumor growth mediated by Pa3-expressing fibroblasts

Yongke Zhang, Kevin Chen, Melody Pong, Danna Breinberg, Josh Ortiz, Robert Dubridge, Gao Liu, Ferdie Evangelista, Vanitha Ramakrishnan and Debbie Law
Yongke Zhang
Protein Design Labs, Inc., Fremont, CA
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Kevin Chen
Protein Design Labs, Inc., Fremont, CA
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Melody Pong
Protein Design Labs, Inc., Fremont, CA
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Danna Breinberg
Protein Design Labs, Inc., Fremont, CA
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Josh Ortiz
Protein Design Labs, Inc., Fremont, CA
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Robert Dubridge
Protein Design Labs, Inc., Fremont, CA
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Gao Liu
Protein Design Labs, Inc., Fremont, CA
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Ferdie Evangelista
Protein Design Labs, Inc., Fremont, CA
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Vanitha Ramakrishnan
Protein Design Labs, Inc., Fremont, CA
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Debbie Law
Protein Design Labs, Inc., Fremont, CA
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DOI:  Published April 2004
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Proc Amer Assoc Cancer Res, Volume 45, 2004

Abstract

570

In cancer, alterations in the stroma that follow the malignant change of epithelial cells help drive cancer cell invasion and metastasis. Using DNA array technology, we identified a type Ia integral membrane protein (Pa3) whose mRNA is selectively upregulated in cancer-associated stroma. Antibodies generated against Pa3 demonstrate that Pa3 is selectively expressed by tumor stromal fibroblasts in various epithelial carcinomas, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissues. Experiments indicate that Pa3 can be clipped and shed from the cell surface of Pa3-transfected cells and that a Pa3-Fc fusion protein can bind specifically to certain cancer cell lines, including MDA-MB-468. However, the biological function of Pa3 in the tumor microenvironment is unknown. To address this issue, murine fibroblasts (3T12) transfected with human Pa3 were xenografted into SCID mice together with MDA-MB-468 breast cancer cells. The presence of 3T12- Pa3 cells dramatically increased the development of subcutaneous tumors and showed an enhancement of tumor growth compared to mock or parental 3T12 cells. These data demonstrate the ability of Pa3 to potentiate tumor growth in an animal model and suggest a possible therapeutic role for functional inhibition of Pa3 activity.

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April 2004
Volume 64, Issue 7 Supplement
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In vivo promotion of human epithelial tumor growth mediated by Pa3-expressing fibroblasts
Yongke Zhang, Kevin Chen, Melody Pong, Danna Breinberg, Josh Ortiz, Robert Dubridge, Gao Liu, Ferdie Evangelista, Vanitha Ramakrishnan and Debbie Law
Cancer Res April 1 2004 (64) (7 Supplement) 132;

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In vivo promotion of human epithelial tumor growth mediated by Pa3-expressing fibroblasts
Yongke Zhang, Kevin Chen, Melody Pong, Danna Breinberg, Josh Ortiz, Robert Dubridge, Gao Liu, Ferdie Evangelista, Vanitha Ramakrishnan and Debbie Law
Cancer Res April 1 2004 (64) (7 Supplement) 132;
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Cancer Research Online ISSN: 1538-7445
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