Objective
Hepatocellular carcinoma (HCC) is caused by chronic hepatitis and is the third most common cause of cancer-related death worldwide, with a rising incidence in first world countries. To date no effective therapies other than liver transplantation are available for this disease.
Previous studies have provided evidence that inflammatory signalling pathways (e.g. the NF-b pathway) are crucial modulators of liver cancer development. However, the exact mechanisms driving hepatitis-induced liver damage and cancer formation remain elusive. Among others, aberrant expression of cytotoxic cytokines is thought to be critically involved.
We have recently shown that the inflammatory cytokines lymphotoxin (LT) and are specifically upregulated in livers of patients suffering from hepatitis C and B virus-induced liver inflammation or HCC and that liver specific expression of LT and in mice (AlbLT) suffices to induce inflammation-induced liver cancer development. We could further demonstrate that this depended on the presence of functional lymphocytes.
My proposal is pillared by three main approaches that all aim to elucidate the exact cellular and molecular mechanisms underlying chronic liver damage and HCC development in humans as well as in mouse models of inflammation- or carcinogen-induced liver cancer.
First, we will identify the particular immune cell type(s) (e.g. B- or T-lymphocytes; macrophages; NK-T cells) involved in HCC development. Although inflammatory signalling and immune cells appear to be important in HCC development it remains elusive, which immune cell type(s) contribute to inflammation induced liver cancer development.
Secondly, we will investigate how inflammatory signalling pathways induce chromosomal aberrations. It is known that inflammatory signalling cascades cause chromosomal aberrations; however, the detailed mechanisms by which this occurs are not fully understood. Additionally, we will determine how inflammatory signalling influences the pathways involved in DNA repair, replication and chromosomal segregation culminating in chromosomal aberrations and cancer.
Finally, we will examine the role of oval cells in liver cancer formation. Oval cells, which are putative liver-cancer stem cells, differentiate into either hepatocytes or cholangiocytes, proliferate under inflammatory conditions, and are found within HCC. However, their exact functional role in liver carcinogenesis is unknown. We will biochemically characterize proliferating and HCC-associated ovals cells in mouse models of inflammation-induced HCC and in diseased human liver tissues. This will pave the way for the development of the first genetic tools to deplete or express genes in an oval cell-specific manner.
The new scientific knowledge gained by these studies investigating how immune cells and inflammatory signalling induce chronic liver damage and cancer on a mechanistic level, and how oval cells contribute to HCC will provide the basis for future novel pharmacological approaches to treating inflammatory liver diseases and HCC in humans.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences clinical medicine oncology liver cancer
- medical and health sciences health sciences infectious diseases
- medical and health sciences basic medicine immunology
- medical and health sciences medical biotechnology cells technologies stem cells
- medical and health sciences clinical medicine hepatology
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
ERC-2010-StG_20091118
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Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Host institution
85764 Neuherberg
Germany
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.