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
3157 - Efficacy and safety of anlotinib in advanced leiomyosarcoma: Subgroup analysis of a phase IIB trial (ALTER0203)
Presenter: Yihebali Chi
Session: Poster Display session 1
Resources:
Abstract
3710 - The effect of treatment line on the efficacy of Anlotinib hydrochloride in advanced alveolar soft part sarcoma patients
Presenter: Zhiwei Fang
Session: Poster Display session 1
Resources:
Abstract
3184 - Prior exposure to pazopanib (PAZ) did not minor efficacy of regorafenib (REG) in non-adipocytic soft tissue sarcoma patients (pts)
Presenter: Nicolas Penel
Session: Poster Display session 1
Resources:
Abstract
798 - Pexidartinib (Pex) for locally advanced tenosynovial giant cell tumor (TGCT): characterization of hepatic adverse reactions (ARs)
Presenter: Sebastian Bauer
Session: Poster Display session 1
Resources:
Abstract
6117 - VEGFR2 and ITGA polymorphisms as novel pan-sarcoma biomarkers for sensitivity prediction as well as toxicity prevention anti-angiogenesis therapy in pediatric and young adult
Presenter: Qiyuan Bao
Session: Poster Display session 1
Resources:
Abstract
5450 - Reversion of resistance to mTOR inhibitors with the addition of exemestane in patients with malignant PEComa.
Presenter: Roberta Sanfilippo
Session: Poster Display session 1
Resources:
Abstract
4279 - Efficacy and Safety of VEGFR2 Inhibitor Apatinib combined with chemotherapy for Sarcoma in Stage IV
Presenter: Zhiwu Ren
Session: Poster Display session 1
Resources:
Abstract
5929 - Outcomes of metastatic soft tissue sarcoma treated with Pazopanib from dedicated medical oncology sarcoma clinic: A holistic care approach from a developing country
Presenter: Akhil Kapoor
Session: Poster Display session 1
Resources:
Abstract
2469 - Inhibition of mTOR signaling enhances Trabectedin activity in Soft Tissue Sarcoma
Presenter: David Moura
Session: Poster Display session 1
Resources:
Abstract
4210 - Efficacy and safety of apatinib for advanced gastrointestinal stromal tumors after failure of imatinib and sunitinib: An open-label, multicenter, single-arm, phase II trial
Presenter: Zhaolun Cai
Session: Poster Display session 1
Resources:
Abstract