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Heterotypic Cell Interactions in Hepatitis induced Liver Cancer

Final Report Summary - LIVERMIRCOENV (Heterotypic Cell Interactions in Hepatitis induced Liver Cancer)

Tumors are heterogeneous tissues composed of multiple cell types, in addition to the tumor cells. Particularly interesting are inflammatory cells (the “microenvironment”) which are known to possess both pro and anti-tumorigenic roles. Liver cancer, a prototype of inflammation induced cancer, is the third most common cause of cancer-related death worldwide, and its dramatic three decades-long rise makes liver cancer the fastest-growing cause of deaths from cancer in the United States; thus highlighting the need for improved understanding and better treatment options for this disease. The aim of this project was to decipher the crosstalk between inflammatory cells in the tumor microenvironment and the malignant cells themselves, specifically HCC, the most common form of primary liver. Several findings from this project significantly contributed to define the changing immune microenvironment of cancer, and may provide in the long run novel therapeutic options for HCC treatment, and possibly other types of cancer associated with an inflammatory state.

Looking for genomic changes in HCC which could affect the immune microenvironment, we identified a recurrent genomic amplification harboring a gene called VEGFA. We found that this amplification initiates a novel crosstalk between tumor and immune (inflammatory) cells. Furthermore, it is possible that a potent drug (sorafenib), known to help HCC patients, operates via disrupting this crosstalk. Thus, VEGFA amplification may serve as an important biomarker for tailoring treatment for HCC.

Inflammation usually entails a diffuse influx of immune cells, scattered throughout the inflamed tissue. However, infiltrating leukocytes often form ectopic lymphoid aggregates or even more complex structures that histologically resemble lymphoid organs. These structures are referred to as ectopic lymphoid-like structures (ELSs). We developed a unique mouse model of HCC, displaying abundant ELSs, which are similar to their human equivalents. Whereas ELSs signify good prognosis in certain malignancies, we found that in the liver ELSs indicate bad prognosis in HCC. These aberrant immune foci could be new targets for cancer therapy. We are continuing to study these fascinating structures and are searching for ways to identify pro-tumorigenic ELSs, and to turn them from pro- to anti-tumor micro organs