Related Experiment Video

Updated: Jun 25, 2026

Isolation and Culture Expansion of Tumor-specific Endothelial Cells
10:15

Isolation and Culture Expansion of Tumor-specific Endothelial Cells

Published on: October 14, 2015

Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy

Stefano Indraccolo1, Sonia Minuzzo, Massimo Masiero

  • 1Istituto Oncologico Veneto-IRCCS, Padua, Italy. stefano.indraccolo@unipd.it

Cancer Research
|February 12, 2009
PubMed

Insights

Tumor microenvironment Dll4 expression activates Notch3 signaling in leukemia and colorectal cancer cells, promoting tumor growth. Blocking Dll4 or Notch3 inhibits cancer cell proliferation and survival.

Area of Science:

  • Oncology
  • Cell Biology
  • Cancer Research

Background:

  • The Notch ligand Dll4 regulates endothelial cell (EC) activity in angiogenesis.
  • The role of Dll4 in Notch signaling within tumor cells is not well understood.

Purpose of the Study:

  • To investigate the impact of Dll4 on Notch signaling in tumor cells.
  • To elucidate the mechanism linking endothelial and tumor cells in cancer progression.

Main Methods:

  • Assessed Dll4 expression in tumor microenvironments.
  • Analyzed Notch3 signaling in T-cell acute lymphoblastic leukemia (T-ALL) and colorectal cancer cells.
  • Utilized Dll4 neutralization and Notch3 silencing (RNA interference).
  • Evaluated effects on tumor cell proliferation, apoptosis, and tumorigenicity in vitro and in vivo.

Main Results:

  • Dll4 expression correlated with tumor cell escape from dormancy and increased Notch3 signaling.
  • Angiogenic factors induced Dll4 in ECs, enhancing Notch3 activation in cocultured T-ALL cells.
  • Dll4 neutralization reduced Notch3 activation and blocked tumorigenesis.
  • Notch3 silencing exhibited anti-proliferative and pro-apoptotic effects on T-ALL cells, reducing tumor growth.

Conclusions:

  • Dll4 expressed by the tumor microenvironment directly promotes tumor cell survival and growth via Notch3 signaling.
  • Targeting the Dll4-Notch3 axis represents a potential therapeutic strategy for T-ALL and colorectal cancer.

More Related Videos

Assessing Tumor Microenvironment of Metastasis Doorway-Mediated Vascular Permeability Associated with Cancer Cell Dissemination using Intravital Imaging and Fixed Tissue Analysis09:42

Assessing Tumor Microenvironment of Metastasis Doorway-Mediated Vascular Permeability Associated with Cancer Cell Dissemination using Intravital Imaging and Fixed Tissue Analysis

Published on: June 26, 2019

Three-Dimensional (3D) Tumor Spheroid Invasion Assay12:19

Three-Dimensional (3D) Tumor Spheroid Invasion Assay

Published on: May 1, 2015

Related Concept Videos

Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
Notch Signaling Pathway03:14

Notch Signaling Pathway

The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
Role Of Notch Signalling In Intestinal Stem Cell Renewal01:12

Role Of Notch Signalling In Intestinal Stem Cell Renewal

Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Metastasis02:30

Metastasis

Metastasis is the spread of cancer cells from the original site to distant locations in the body. Cancer cells can spread via blood vessels (hematogenous) as well as lymph vessels in the body.
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
The Tumor Microenvironment02:17

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
Tumor Progression02:07

Tumor Progression

Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...