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Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo
Heather B. Adkins, … , David Salomon, Michele Sanicola
Heather B. Adkins, … , David Salomon, Michele Sanicola
Published August 15, 2003
Citation Information: J Clin Invest. 2003;112(4):575-587. https://doi.org/10.1172/JCI17788.
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Article Oncology Article has an altmetric score of 7

Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo

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Abstract

Cripto, a cell surface–associated protein belonging to the EGF-CFC family of growth factor–like molecules, is overexpressed in many human solid tumors, including 70–80% of breast and colon tumors, yet how it promotes cell transformation is unclear. During embryogenesis, Cripto complexes with Alk4 via its unique cysteine-rich CFC domain to facilitate signaling by the TGF-β ligand Nodal. We report, for the first time to our knowledge, that Cripto can directly bind to another TGF-β ligand, Activin B, and that Cripto overexpression blocks Activin B growth inhibition of breast cancer cells. This result suggests a novel mechanism for antagonizing Activin signaling that could promote tumorigenesis by deregulating growth homeostasis. We show that an anti–CFC domain antibody, A8.G3.5, both disrupts Cripto-Nodal signaling and reverses Cripto blockade of Activin B–induced growth suppression by blocking Cripto’s association with either Alk4 or Activin B. In two xenograft models, testicular and colon cancer, A8.G3.5 inhibited tumor cell growth by up to 70%. Both Nodal and Activin B expression was found in the xenograft tumor, suggesting that either ligand could be promoting tumorigenesis. These data validate that functional blockade of Cripto inhibits tumor growth and highlight antibodies that block Cripto signaling mediated through its CFC domain as an important class of antibodies for further therapeutic development.

Authors

Heather B. Adkins, Caterina Bianco, Susan G. Schiffer, Paul Rayhorn, Mohammad Zafari, Anne E. Cheung, Olivia Orozco, Dian Olson, Antonella De Luca, Ling Ling Chen, Konrad Miatkowski, Chris Benjamin, Nicola Normanno, Kevin P. Williams, Matthew Jarpe, Doreen LePage, David Salomon, Michele Sanicola

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Figure 4

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Cripto binds directly to Act B, and binding is blocked by anti-CFC mAb A...
Cripto binds directly to Act B, and binding is blocked by anti-CFC mAb A8.G3.5. (a) Act A or Act B was immunoprecipitated with Cr-hFc prebound to protein A-Sepharose. Immunoprecipitated protein was immunoblotted using anti–Act A (left panel) or anti–Act B (right panel) mAb’s. Act A and Act B (10 ng) were loaded on each gel for comparison. (b) Act B binds to Cr-hFc in a Biacore assay. Act A (left panels) or B (right panels) was flowed over Biacore chips immobilized with Cr-hFc (top panels) or LTβR-hFc (bottom panels) and assayed for binding by surface plasmon resonance using a Biacore 2000 biosensor system (Biacore Inc.). Nonspecific binding to the blank-flow cell was subtracted from each sensorgram to obtain the specific-binding responses. RU, resonance units. (c) Purified Act B or cell supernatant containing Nodal was immunoprecipitated with Cr-hFc or CrEGFmt-hFc as described in a. (d) For antibody blocking, Cr-hFc was preincubated with 0.1–3 μg of B3.F6.17, A27.F6.1, or A8.G3.5 prior to Act B binding.IP, intraperitoneal. WB, Western blot.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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