טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentHawila Elias
SubjectDissecting the Autocrine and Paracrine Roles of CCR5 and its
Ligands in Cancer of the Prostate
DepartmentDepartment of Medicine
Supervisor Professor Nathan Karin
Full Thesis textFull thesis text - English Version


Abstract


Chemokines are small structurally related cytokines that regulate cell trafficking via interactions with a subset of seven-transmembrane, G protein-coupled receptors. Growing evidence support the involvement of chemokines in inflammatory processes and cancer. CCR5 is a key CC chemokine receptor that is highly expressed on CD4 T cells and monocytes. It binds three different ligands CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES). CCR5’s involvement in various diseases such as Autoimmune Immunodeficiency Syndrome (AIDS), Multiple Sclerosis (MS) and cancer has been suggested. Our current study focuses on exploring the role of CCR5 ligands and CCR5 in prostate cancer and possible therapeutic implications. Men with a functional mutation in the chemokine receptor CCR5 display a high state of resistance to prostate cancer. Mechanisms underlying this resistance are still elusive.  We explored the hypothesis that CCR5 and its ligands have a direct autocrine role on tumor growth and a paracrine effect through the mobilization and/or colonization of bone marrow cells to the tumor site to support its development and spread.

Using CCR5-/- mice engrafted with CCR5 C1-TRAMP tumor cells and CCR5-Ig fusion protein which neutralizes CCR5 ligands, we differentiated between the direct effects of CCR5 ligands on tumor growth from the bone marrow derived (BMDR) cell contribution. Analyzing the involvement of BMDR cells, we observed that CCR5 is critical for the mobilization of CD11bGr1Ly6Clow polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) from the bone marrow to the peripheral blood followed by colonization to the tumor site. C1-TRAMP tumor cells engrafted in CCR5-/- mice lack PMN-MDSC at the tumor site and display reduced tumor development unless reconstituted with CCR5 bone marrow cells. We show that all three CCR5 ligands induce chemo attraction of these cells in-vitro and that their administration enhances the mobilization to the peripheral blood and spleen and depletion from their bank in the bone marrow.

These findings open new avenues for research where the therapeutic effects of CCR5-Ig could be explored; in particular the use of CCR5-Ig in combination with chemotherapy and in treatment of other cancers such as melanoma.