Abstract 10P
Background
Engraftment of cancer cells to liver pre-metastatic niches requires complex interaction with liver sinusoidal endothelial cells (LSECs). Intracellular gap (iGap) formation in LSECs is caused by the destruction of fenestrae and appears under pathological conditions. Here, we aimed to explore the novel role of LSECs-iGap in liver metastasis of cancer cells.
Methods
Mouse models using acetaminophen (APAP) or thioacetamide (TAA) followed by intrasplenic injection of hepatocellular carcinoma (HCC) cell line, Hepa1-6 cells, to assess the LSECs-iGap formation. Functional effects of LSECs-iGap on cancer cells were analyzed using MMPs inducer, monocrotaline and inhibitor, doxycycline and MMP2/9 inhibitor. Morphological and molecular features of LSECs-iGap were examined using in vivo mouse models and in vitro co-culture system with electron microscopy, 3 dimensions tomographic reconstruction image (3D-TRI), RNA-sequencing, cytokine array and endothelial trans-endothelial migration assay. Biopsy specimens from 98 patients with HCC were statistically evaluated.
Results
APAP-induced liver injury and TAA-induced fibrotic liver resulted in LSECs-iGap formation, which positively correlated with increased numbers of metastatic foci after Hepa1-6 cells injection. In addition, Hepa1-6 cells induced IL-23-dependent TNF-α secretion by LSECs and triggered LSECs-iGap formation, toward which their processes protruded to transmigrate into the liver parenchyma. TNF-α caused depolymerization of F-actin and increased MMP9, ICAM1, and CXCLs expression in LSECs. Moreover, high expression of ICAM1 and MMP9 was significantly associated with intrahepatic metastasis and overall survival of patients with HCC. Blocking MMP9 activity by doxycycline or MMP-2/9 inhibitor eliminated LSECs-iGap formation and attenuated liver metastasis of Hepa1-6 cells.
Conclusions
This study revealed that cancer cells induced LSEC-iGap formation via pro-inflammatory paracrine mechanisms and proposed MMP9 as a novel target for blocking cancer cell metastasis to the liver.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
H.H. Truong.
Funding
Japan Agency for Medical Research and Development.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
46P - Effect of coadministration of antioxidant chlorophyllin with docetaxel on invasion and metastasis in triple-negative breast cancer in vivo/in vitro
Presenter: Ayse Burus
Session: Poster session 09
47P - An ozone delivery system by cisplatin prodrug self-assembling micelles combining microwave to sensitizing immune checkpoint inhibitor in triple-negative breast cancer
Presenter: Dan Zheng
Session: Poster session 09
48P - Non-steroid anti-inflammatory treatment enhances the efficacy of modulated electro hyperthermia on triple-negative breast cancer and melanoma cancer models in vivo
Presenter: Nino Giunashvili
Session: Poster session 09
49P - Circulating miRNA signatures to predict recurrence in patients with pathological complete response of triple-negative breast cancer
Presenter: Ana Julia de Freitas
Session: Poster session 09
50P - Application and mechanism of tarloxotinib in HER2-positive breast cancer
Presenter: Xinyi Shao
Session: Poster session 09
51P - Nanoengineered sonosensitive platelets for synergistically augmented sonodynamic breast tumour therapy by glutamine deprivation and cascading thrombosis
Presenter: Liqiang Zhou
Session: Poster session 09
53P - Treatment of cancer cells based on circulating tumor cell’s expression profile using off-label drugs
Presenter: Panagiotis Apostolou
Session: Poster session 09
54P - Enhanced oxidative phosphorylation of metastasis-initiating cells facilitates esophageal tumor cell seeding in lymph nodes
Presenter: Shanshan Li
Session: Poster session 09
55P - Transcriptional profiles of engineered T cells stimulated with different receptor structures and co-stimulatory domains
Presenter: Ungue Shin
Session: Poster session 09
56P - SLC34A2-ROS1 L2026M+G2032R confers resistance to ROS1 tyrosine kinase inhibitors in Ba/F3 cells through a reduced ATP binding pocket volume
Presenter: Christa Dijkhuizen
Session: Poster session 09