eprintid: 35348
rev_number: 14
eprint_status: archive
userid: 8413
dir: disk0/00/03/53/48
datestamp: 2024-09-02 13:55:33
lastmod: 2024-09-12 14:33:17
status_changed: 2024-09-02 13:55:33
type: doctoralThesis
metadata_visibility: show
creators_name: Argos Vélez, Paula
title: Angiocrine factors in hepatocellular carcinoma: Modelling hepatocarcinogenesis to investigate Wnt signaling
subjects: ddc-570
subjects: ddc-610
divisions: i-140001
adv_faculty: af-14
abstract: Liver cancer is a global health problem. Hepatocellular carcinoma (HCC) is the most common subtype, and its incidence is increasing. It arises from chronic liver damage. Endothelial cells (ECs) regulate liver metabolic zonation in physiological conditions. Endothelial secretion, so called angiocrine effect, in particular Wnt signaling, mediates this phenomenon. ECs also play a major role in liver disease, including cancer. Interestingly, in other tumor entities, Wnt signaling derived from the tumor microenvironment (TME) has been reported to have both, pro- and anti-tumorigenic effects. In the liver, despite being extensively investigated in the physiological context, the role of angiocrine Wnt signaling in HCC remains elusive.
This thesis aimed to study the role of angiocrine Wnt signaling in HCC initiation. To answer this question, it was crucial to first establish in vivo models that would accurately recapitulate hepatocarcinogenesis. Therefore, I established a focal electroporation model based on the introduction of plasmids to target hepatocytes. The introduced genetic material encoded some of the most commonly mutated genes found in HCC. This model was complemented by a multifocal (genetically engineered mouse) GEM model based on SV40 TAg expression. In addition, tumor-derived organoids were generated from both in vivo models. Thereafter, the Wnt enhancer Rspo3 and the Wnt secretion factor Evi/Wls were the candidate genes selected for this study, based on their role in the physiological liver. Expression of both was decreased in tumor endothelial cells (TEC) in comparison to the healthy liver ECs in both in vivo models. This differential expression was statistically significant in the case of Rspo3, and also validated in humans. Consistent with this finding, endothelial deletion of Rspo3, either alone or in combination with Evi/Wls, resulted in earlier tumor formation. Deletion of Evi/Wls endothelial secretion induced no changes, or the opposite, in either model. These data indicated that Rspo3, and to a lesser extent, Evi/Wls secretion, acted as gatekeepers of the healthy liver endothelium and deletion of both created a protumorigenic TME. Interestingly, at the autocrine level, deletion of Rspo3 and/or Evi/Wls induced vessel regression and maturation in HCC tumors. Focusing on the direct interactions between tumor cells and (tumor) ECs, tumor-derived factors induced the decreased expression of Rspo3 and Evi/Wls as described in tumor ECs compared to healthy liver ECs. This indicated the existence of a positive feedback loop between tumor and tumor ECs aiming to reduce Wnt signaling expression in the TME to support tumorigenesis. In particular, deletion of Rspo3 in vitro from liver ECs enhanced proliferation of tumor cells. Consequently, supplementation of Rspo3 in the medium of murine HCC cell line and tumor derived organoids reduced tumor cell proliferation. In conclusion, these data suggested Rspo3 as a potential antitumorigenic candidate in HCC.
date: 2024
id_scheme: DOI
id_number: 10.11588/heidok.00035348
ppn_swb: 1902460421
own_urn: urn:nbn:de:bsz:16-heidok-353489
date_accepted: 2024-06-19
advisor: HASH(0x55de57c0d548)
language: eng
bibsort: ARGOSVELEZANGIOCRINE
full_text_status: public
place_of_pub: Heidelberg
citation:   Argos Vélez, Paula  (2024) Angiocrine factors in hepatocellular carcinoma: Modelling hepatocarcinogenesis to investigate Wnt signaling.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/35348/1/Dissertation-Thesis_Paula%20Argos%20V%C3%A9lez.pdf