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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)575-587
Number of pages13
JournalJournal of Clinical Investigation
Volume112
Issue number4
DOIs
Publication statusPublished - Aug 2003

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Antibodies
Growth
Nodal Signaling Ligands
Neoplasms
Heterografts
Carcinogenesis
Breast Neoplasms
Ligands
Activins
Immunoglobulin Isotypes
Testicular Neoplasms
Epidermal Growth Factor
Colonic Neoplasms
Embryonic Development
Cysteine
Intercellular Signaling Peptides and Proteins
Membrane Proteins
Colon
Homeostasis
activin B

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Adkins, H. B., Bianco, C., Schiffer, S. G., Rayhorn, P., Zafari, M., Cheung, A. E., ... Sanicola, M. (2003). Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo. Journal of Clinical Investigation, 112(4), 575-587. https://doi.org/10.1172/JCI200317788

Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo. / Adkins, Heather B.; Bianco, Caterina; Schiffer, Susan G.; Rayhorn, Paul; Zafari, Mohammad; Cheung, Anne E.; Orozco, Olivia; Olson, Dian; De Luca, Antonella; Chen, Ling Ling; Miatkowski, Konrad; Benjamin, Chris; Normanno, Nicola; Williams, Kevin P.; Jarpe, Matthew; LePage, Doreen; Salomon, David; Sanicola, Michele.

In: Journal of Clinical Investigation, Vol. 112, No. 4, 08.2003, p. 575-587.

Research output: Contribution to journalArticle

Adkins, HB, Bianco, C, Schiffer, SG, Rayhorn, P, Zafari, M, Cheung, AE, Orozco, O, Olson, D, De Luca, A, Chen, LL, Miatkowski, K, Benjamin, C, Normanno, N, Williams, KP, Jarpe, M, LePage, D, Salomon, D & Sanicola, M 2003, 'Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo', Journal of Clinical Investigation, vol. 112, no. 4, pp. 575-587. https://doi.org/10.1172/JCI200317788
Adkins HB, Bianco C, Schiffer SG, Rayhorn P, Zafari M, Cheung AE et al. Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo. Journal of Clinical Investigation. 2003 Aug;112(4):575-587. https://doi.org/10.1172/JCI200317788
Adkins, Heather B. ; Bianco, Caterina ; Schiffer, Susan G. ; Rayhorn, Paul ; Zafari, Mohammad ; Cheung, Anne E. ; Orozco, Olivia ; Olson, Dian ; De Luca, Antonella ; Chen, Ling Ling ; Miatkowski, Konrad ; Benjamin, Chris ; Normanno, Nicola ; Williams, Kevin P. ; Jarpe, Matthew ; LePage, Doreen ; Salomon, David ; Sanicola, Michele. / Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo. In: Journal of Clinical Investigation. 2003 ; Vol. 112, No. 4. pp. 575-587.
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AU - Normanno, Nicola

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