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Measuring Changes in Brain Endothelial Barrier Integrity with Two Impedance-based Biosensors in Response to Cancer Cells and Cytokines
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Endothelin B receptor blockade inhibits dynamics of cell interactions and communications in melanoma cell progression

Anna Bagnato1, Laura Rosanò, Francesca Spinella

  • 1Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy. bagnato@ifo.it

Cancer Research
|February 20, 2004
PubMed

Insights

Activation of the endothelin B receptor (ET(B)R) by endothelin-1 and ET-3 promotes melanoma progression by altering cell adhesion and increasing invasion. An ET(B)R antagonist inhibited melanoma growth, suggesting a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • The endothelin B receptor (ET(B)R) is implicated in cutaneous melanoma progression.
  • ET(B)R presents a potential therapeutic target for melanoma treatment.

Purpose of the Study:

  • To investigate the role of ET(B)R activation in melanoma cell signaling and progression.
  • To evaluate the therapeutic potential of ET(B)R antagonists in melanoma.

Main Methods:

  • Melanoma cells were treated with endothelin-1 (ET-1) and ET-3 to activate ET(B)R.
  • Changes in cell adhesion molecules (E-cadherin, N-cadherin), intercellular communication (connexin 43), integrin expression, and matrix metalloproteinases (MMPs) were assessed.
  • Downstream signaling pathways (FAK, ERK1/2) were analyzed.
  • Melanoma growth was evaluated in vivo using an ET(B)R antagonist (A-192621) in nude mice.

Main Results:

  • ET(B)R activation led to decreased E-cadherin and increased N-cadherin expression, disrupting cell adhesion.
  • Intercellular communication was inhibited by 60% via connexin 43 phosphorylation.
  • Increased expression of alpha(v)beta(3) and alpha(2)beta(1) integrins, MMP-2, MMP-9, and membrane type-1-MMP was observed.
  • Downstream activation of FAK and ERK1/2 pathways promoted cell proliferation, migration, and invasion.
  • The ET(B)R antagonist A-192621 significantly inhibited melanoma tumor growth in vivo.

Conclusions:

  • ET(B)R activation by ET-1 and ET-3 drives melanoma progression through modulation of cell adhesion, communication, and invasion pathways.
  • Targeting ET(B)R signaling offers a promising novel therapeutic strategy for cutaneous melanoma.

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