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EGFR and ErbB2 are functionally coupled to CD44 and regulate shedding, internalization and motogenic effect of CD44

Zsuzsanna Pályi-Krekk1, Márk Barok, Tamás Kovács

  • 1Department of Biophysics and Cell Biology, Medical and Health Science Center, University of Debrecen, 1 Egyetem Square, H-4010 Debrecen, Hungary. krekkzs@dote.hu

Cancer Letters
|February 16, 2008
PubMed

Insights

Monoclonal antibodies like trastuzumab and pertuzumab target ErbB receptors in cancer. This study reveals they also impact CD44 shedding and cell motility, offering new insights into cancer treatment mechanisms.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • ErbB receptor tyrosine kinases are crucial in human cancers.
  • ErbB signaling is modulated by growth factors and targeted by monoclonal antibodies (trastuzumab, pertuzumab).
  • ErbB receptors interact with non-ErbB proteins like CD44.

Purpose of the Study:

  • To investigate the effect of epidermal growth factor (EGF) and heregulin on CD44 shedding and cellular motility in trastuzumab-resistant, ErbB2-overexpressing JIMT-1 cells.
  • To determine the role of monoclonal antibodies (trastuzumab, pertuzumab) in modulating these processes.

Main Methods:

  • Utilized JIMT-1 cell line, an ErbB2-overexpressing model.
  • Administered EGF and heregulin to induce CD44 shedding and assess cellular motility.
  • Applied trastuzumab and pertuzumab to block or modulate these effects.
  • Investigated CD44 internalization and intramembrane proteolysis.
  • Examined xenograft tumors in vivo and conducted in vitro experiments with hyaluronan oligosaccharides.

Main Results:

  • EGF and heregulin induced CD44 shedding, internalization, proteolysis, and enhanced motility in JIMT-1 cells.
  • Pertuzumab blocked these EGF/heregulin-induced effects.
  • Trastuzumab inhibited heregulin/hyaluronan oligosaccharide-induced CD44 shedding, internalization, and motility.
  • Trastuzumab also inhibited CD44 shedding in JIMT-1 xenograft tumors.
  • Hyaluronan oligosaccharides increased trastuzumab internalization rate in vitro.

Conclusions:

  • ErbB-targeted monoclonal antibodies have a novel mechanism of action involving CD44 modulation.
  • These findings provide new insights into the therapeutic effects of trastuzumab and pertuzumab in cancer treatment.
  • The interplay between ErbB signaling, CD44, and antibody therapy warrants further investigation.

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