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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate DMBA-TPA
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Incomplete Dll4/Notch signaling inhibition promotes functional angiogenesis supporting the growth of skin papillomas

Dusan Djokovic1, Alexandre Trindade2, Joana Gigante3

  • 1Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Universidade de Lisboa (ULisboa), Lisbon, Portugal. dusan.d.djokovic@gmail.com.

BMC Cancer
|August 29, 2015
PubMed
Abstract

Insights

Low Dll4 levels promote tumor growth by enhancing functional angiogenesis in early skin papillomas. This effect, mediated by increased VEGFR2 signaling, can counteract therapies targeting VEGFR, highlighting a critical consideration for Dll4 inhibition strategies.

Area of Science:

  • Oncology
  • Vascular Biology
  • Molecular Signaling

Background:

  • Invasive cancers often exhibit enhanced non-functional blood vessel growth upon Dll4/Notch signaling inhibition.
  • This inhibition typically limits tumor progression by reducing blood perfusion.

Purpose of the Study:

  • To investigate the impact of Dll4 (Delta-like ligand 4) genetic reduction during early tumor development.
  • To analyze its effects on chemically induced skin papillomas, focusing on tumor growth and vascular characteristics.

Main Methods:

  • Chemically induced skin papillomas in wild-type and Dll4 (+/-) mice.
  • Comparative analysis of tumor growth, histology, and vascularization.
  • Assessment of angiogenesis-related gene expression, including VEGFR family members.

Main Results:

  • Dll4 down-regulation in pre-cancerous papillomas promoted functional angiogenesis, leading to increased tumor growth.
  • This was associated with elevated endothelial activation and an increased VEGFR2/VEGFR1 ratio.
  • The enhanced VEGFR2 signaling amplified sensitivity to endogenous VEGF, promoting angiogenesis and tumor growth, and neutralizing sorafenib's effect.

Conclusions:

  • Reduced Dll4 levels can paradoxically promote tumor growth in early stages by enhancing functional angiogenesis.
  • Therapeutic strategies involving Dll4 inhibition must account for this tumor-promoting effect, especially in conjunction with VEGFR-targeting agents.

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