Granulopoietic Growth Factor Secretion in Ovarian Carcinoma as a Mechanism for the Emergence of Immune Suppressive Myeloid Subsets

Principal Investigator: ABRAMS, SCOTT
Program: OCRP
Proposal Number: OC100137
Award Number: W81XWH-11-1-0394
Funding Mechanism: Pilot Award
Partnering Awards:
Award Amount: $357,248.00


Ovarian cancer is a devastating disease and, to this day, this disease remains a leading cause of death in women in the United States and Europe. One reason for poor clinical outcome in these patients concerns the approach to understanding how ovarian cancer progresses. It is now becoming clearer that the progression of ovarian cancer is the culmination of two major events; the first concerns all the cellular and molecular changes that occur in normal ovarian tissue that make it malignant, and the second concerns how the body responds to cancer growth. Interestingly, the body's reaction to cancer growth is manipulated by the cancer process in such a way that the host response paradoxically serves to support continued cancer growth. Thus, ovarian cancer prognosis and treatment can be greatly impacted by the contribution of host-derived elements usurped by the cancer process.

Major components of the host response that are manipulated by the cancer process are blood cells called myeloid cells, which ordinarily are vital for host defense against a wide spectrum of diseases including cancer. However, during ovarian cancer progression, these myeloid populations are expanded and become dysfunctional. One major dysfunctional myeloid cell population is termed myeloid-derived suppressor cells (MDSC). Such myeloid populations are produced in mouse models of ovarian cancer, as well as in ovarian cancer patients. As a result, animal models represent an appropriate system to study concepts and mechanisms of MDSC development. However, there is a fundamental gap in knowledge regarding how these myeloid populations develop and expand in the first place. Accordingly, a major goal of this proposal is to further understand how these myeloid populations develop. In animal models, we will investigate whether ovarian cancer cells overproduce a protein known as granulocyte-colony stimulating factor (G-CSF), which contributes to the production of these inhibitory MDSC. Then we will translate this information to ovarian cancer patients and determine whether G-CSF and MDSC levels are novel and meaningful clinical outcome measurements.

Thus, we further hypothesize that if we learn more about how these cancer-induced myeloid populations develop, we could ultimately discover novel biomarkers that track changes in ovarian cancer progression or patient outcome in much the same way as the PSA (prostate specific antigen) blood test is used in patients with prostate cancer or the CA-125 test is currently used in patients with ovarian cancer. A fundamental distinction between the approach now used in prostate and ovarian cancer compared to our idea is that we advocate monitoring changes in a tumor-derived protein affecting the host response against the disease, rather than the disease itself. This paradigm is built on the rationale that "myeloid health" impacts the tumor response and instrumental to "myeloid health" is how tumors modify their competence. In summary, MDSC represent unique population of white blood cells that accumulate in both animals and patients with ovarian cancer and are thought to embody a significant barrier to an effective anti-cancer immune response. Our research will explore the concept that these myeloid subsets arise because the cancer process produces high or inappropriate levels of a protein normally essential for controlling fundamental properties of the myeloid cell family. This work will advance our understanding of mechanisms of how ovarian cancer manipulates the host response to benefit disease progression, which will we hope will lead to the discovery of novel biomarkers or therapeutic agents.