Abstract 5417
Background
Systemic inhibition of Dll4 results in a vast reduction of cancer metastasis. Whether this effect is endothelial-mediated remains to be clarified. Therefore, we proposed to analyze the impact of endothelial Dll4 loss-of-function on metastasis induction on three early steps of the metastatic process, regulation of epithelial-to-mesenchymal transition (EMT), cancer stem cell (CSC) frequency and circulating tumour cell (CTC) number.
Methods
Lewis Lung Carcinoma (LLC) cells or LLC- green fluorescent protein marked were used to model mouse tumour metastasis in vivo, by subcutaneous transplantation into endothelial-specific Dll4 loss-of-function mice.
Results
We observed that endothelial-specific Dll4 loss-of-function is responsible for the tumour vascular regression that leads to the reduction of tumour burden. It induces an increase in tumoural blood vessel density, but the neovessels are poorly perfused, with increased leakage and reduced perivascular maturation. Unexpectedly, although hypoxia was increased in the tumour, the number and burden of macro-metastases was significantly reduced. This is likely to be a consequence of the observed reduction in both EMT and CSC numbers caused by the endothelial-specific Dll4 loss-of-function. This multifactorial context may explain the concomitantly observed two-fold reduction of the circulating tumour cell count. Furthermore, our gene transcription analysis suggests that endothelial Dll4/Notch function mediates tumour hypoxia-driven increase of EMT. We observed that the downregulation of Dll4/Notch1/Hey1 signalling caused a reduction in Snail-1 and Twist expression, known inducers of EMT.
Conclusions
These findings show that the effect of Dll4 inhibition in suppressing cancer metastasis is, at least, partially endothelial-mediated. This is accomplished through the arrest of the EMT process and reduction of CSC clone selection in the primary tumour, regulated by non-cell-autonomous endothelial signalling. Therefore, endothelial Dll4 may constitute a promising target for the prevention of metastasis.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
CIISA - Centro de Investigação Interdisciplinar em Sanidade Animal.
Funding
This work was supported by the Portuguese Foundation for Science and Technology (FCT), grants PTDC/CVT/115703/2009 to AD; PTDC/SAU-ONC/116164/2009 and PTDC/SAU-ONC/121742/2010 to AT. CIISA has provided support through project UID/CVT/00276/2019, funded by FCT. LM is a PhD student supported by a studentship from FCT (SFRH/BD/74229/2010).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5729 - Expression of mutant p53 affects cancer cell sensitivity to topotecan
Presenter: Rimma Mingaleeva
Session: Poster Display session 1
Resources:
Abstract
5725 - Breast cancer organoids a new tool for the prediction of drugs penetration and patient’outcome
Presenter: Giuseppina Roscigno
Session: Poster Display session 1
Resources:
Abstract
5680 - Aptamer-mediated exosomes detection for early breast cancer identification.
Presenter: Cristina Quintavalle
Session: Poster Display session 1
Resources:
Abstract
2460 - MicroRNA-181c promotes tamoxifen resistance in breast cancer cells via upregulation Akt/mTOR axis
Presenter: Alexander Scherbakov
Session: Poster Display session 1
Resources:
Abstract
3751 - Spatio-temporal separation of tumor infiltrating CD8+ T-cells and HER2/neu+ tumor cells in tumor-immune milieu of infiltrating ductal carcinoma of the breast
Presenter: Sandhya Sreedharan
Session: Poster Display session 1
Resources:
Abstract
4664 - Large genomic rearrangements in BRCA1 and BRCA2 genes in the Portuguese population.
Presenter: Joao Pinto
Session: Poster Display session 1
Resources:
Abstract
4611 - Non-BRCA1/2 hereditary breast and ovarian cancer: findings from a multidisciplinary program
Presenter: Ana Monteiro
Session: Poster Display session 1
Resources:
Abstract
5340 - Quantitative imaging and characterization of collagen patterns in high grade serous ovarian carcinoma (HGSOC)
Presenter: Ruby Huang
Session: Poster Display session 1
Resources:
Abstract
4209 - Semiquantitative assessment of vimentin expression in prostate cancer (PC)
Presenter: Marina Puchinskaya
Session: Poster Display session 1
Resources:
Abstract
3309 - Heat Shock Protein 90 chaperones and Protein Kinase D3 regulates androgen-independent prostate cancer development
Presenter: Attila Varga
Session: Poster Display session 1
Resources:
Abstract