טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentIzhak Liat
SubjectThe Interplay between CCL2 and CCR2 in the Pathogenesis
of Prostate Cancer
DepartmentDepartment of Biotechnology
Supervisor Professor Nathan Karin
Full Thesis text - in Hebrew Full thesis text - Hebrew Version


Abstract

Several studies previously conducted in our lab have shown that during autoimmune diseases the immune system selectively breaks-down the tolerance to key inflammatory mediators that drives the pathogenesis of those diseases. These breakdown of tolerance to those components is due to their preferential expression at a partially immunprivileged site undergoing a destructive process.

Similarly to autoimmunity in various cancer diseases, like cancer of the prostate (CaP), key inflammatory chemokines are expressed at the primary tumor site that also undergoes a destructive process at a restricted site. This has motivated us to extend our research to CaP.

The current study shows that of the various chemokines produced at the tumor site, CaP patients produce a high neutralizing autoantibodies titer selectively to CCL2 and that CCL2 is dominantly expressed at the human primary tumor site. We then showed that DNA based amplification of this response in an immunocompetent model of the disease suppresses tumor development and progression.

This finding has led to a thorough investigation in search of possible role for CCL2 in the pathogenesis of CaP. Indeed, the current study demonstrated ,in a xenograft model, that this chemokine particularly serves as a critical proliferative factor in an autocrin manner for the cancer cells. One of our major discoveries has been that the cancer derived CCL2 positively selects (in vivo and in vitro) auto-aggressive cancer cells .

In order to investigate the role of CCL2 in the tumor spread and the angiogenic process we developed a soluble receptor-based antagonist to CCL2 - first for the human chemokine and then for the murine one. We developed a strategy that is based on generating short recombinant proteins encoding different segments of a G protein-coupled receptor, and we tested the ability of each of them to bind and neutralize CCL2. We found out that both the human and the mouse E3 domains fused to Ig were the most effective inhibitors of CCL2. in vitro and in vivo.

Next we aimed to elucidate the role of CCL2 in the recruitment of TAMs by using CCR2-/- mice immunized with Luc+ CCR2+ tumor cells. Those mice display a reduced development and progression of the primary and secondary tumors which could be reversed by transplantation of CD11b+CCR2+ BM derived cells.

Taken together our results demonstrate that CCL2 additionally is critically involved in facilitating recruitment of tumor infiltrating macrophages into the tumor site, stimulating intratumoral angiogenesis, and driving secondary metastatic spread.