טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentWeinberg Uri
SubjectThe Role of MCP-1 (CCL2) and its Receptor (CCR2) in Cancer
of the Prostate: Basic Research and Clinical
Implications
DepartmentDepartment of Medicine
Supervisor Professor Nathan Karin


Abstract

We have previously shown that in attempt to attenuate the severity of T cell mediated autoimmune diseases, the immune system selectively generates an autoantibody response to few inflammatory mediators that are associated with the manifestation of each disease. Such "Beneficial Autoimmunity" counteracts the pathology of the original destructive autoimmunity, and may also be augmented for the benefit of the host, by means of passive or active immunization.

The current study questions the relevance of this regulatory mechanism in malignancy and uses it to define potentially relevant targets for therapy. By examining a platform of cancer-associated chemokines, we showed that in Prostate Cancer, a significant cause of morbidity and mortality among men in western countries, the vast majority of patients produced autoantibodies exclusively to MCP-1 (CCL2). This finding has led to a thorough investigation in search of a possible role for MCP-1, as a potential key factor in the pathogenesis of prostate cancer. Indeed, the current study demonstrated that this chemokine has multiple roles in different stages of tumor development and metastasis formation: First, MCP-1 was found to serve as a chemotactic protein which attracts prostate cancer metastatic cells expressing its CCR2 receptor, and mediates their migration. It had another paracrine function as a proliferative factor, which rescues prostate cancer cells from apoptosis. The signaling pathway of MCP-1 in prostate cancer cells was found to involve the activation of Erk but not Akt, through CCR2. Anti-MCP-1 neutralizing Abs inhibited all in vitro effects, and were therefore used to examine clinical aspects of MCP-1 neutralization, in SCID mouse model of prostate cancer. Treatment of animals with anti-MCP-1 Abs led to a significant suppression and even eradication of prostate cancer tumors, improving survival rates of treated animals. Additionally, it decreased the metastatic potential of these cells, thereby reducing the lethal characteristic of the tumor. The underlying mechanism of tumor suppression in vivo included reduced recruitment and accumulation of tumor associated macrophages (TAMs), lower VEGF secretion and lower rates of angiogenesis. Overexpression of MCP-1 by prostate cancer cell line dramatically suppressed tumor development in vivo, probably due to increased macrophage infiltration into tumors, thereby leading to their destruction.

In summary, we found the immunoregulatory mechanism of "Beneficial Autoimmunity" to participate in the regulation of malignancy. This might serve as a novel method of finding pivotal mediators which participate in various diseases, thus developing novel therapeutic strategies based on amplifying the immune system natural response.