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Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological

Annalisa Petrelli1, Paola Circosta, Luisa Granziero

  • 1Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, 10060 Candiolo, Italy.

Proceedings of the National Academy of Sciences of the United States of America
|March 21, 2006
PubMed

Insights

Monoclonal antibody DN30 targets the hepatocyte growth factor receptor, inhibiting cancer cell growth and spread. This antibody works by cleaving the receptor, leading to its degradation and enhanced anti-cancer effects.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Targeting tyrosine kinase receptors (RTKs) with antibodies is a key cancer therapy strategy.
  • The precise mechanisms of antibody action against RTKs are not fully understood.
  • Hepatocyte growth factor (HGF) receptor signaling is implicated in cancer progression.

Purpose of the Study:

  • To investigate the molecular mechanisms of a monoclonal antibody (DN30) targeting the HGF receptor.
  • To evaluate the efficacy of DN30 in inhibiting cancer cell growth and metastasis.

Main Methods:

  • In vitro studies using carcinoma cell lines treated with DN30.
  • In vivo studies involving tumor xenografts in immunodeficient mice.
  • Analysis of HGF receptor down-regulation via proteolytic cleavage and proteasomal degradation.

Main Results:

  • DN30 impaired HGF-induced signal transduction, anchorage-independent growth, and invasiveness in vitro.
  • DN30 inhibited tumor growth and lung metastasis in vivo.
  • DN30 induced double proteolytic cleavage of the HGF receptor, leading to ectodomain shedding and intracellular domain degradation.
  • Shed ectodomain acted as a decoy, enhancing DN30's inhibitory effect.

Conclusions:

  • DN30 is an effective therapeutic antibody against HGF receptor-driven cancers.
  • The antibody's mechanism involves receptor cleavage and degradation, augmented by a decoy effect.
  • Understanding these mechanisms can inform future cancer therapy development.

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