CXCL14 Blockade of CXCL12/CXCR4 Signaling in Prostate Cancer Bone Metastasis
Abstract
Over 240,000 new cases of prostate cancer will be diagnosed this year in the United States. Five-year survival rates for men diagnosed with local and regional prostate cancer are nearly 100%. However, this rate drops to 29% in men who develop distant disease. Bone is the most common site for metastasis resulting in disorganized bone formation, pain, fractures, and nerve compression syndromes. Once cancer has spread to bone, the disease is incurable. Current Food and Drug Administration-approved targeted therapies for prostate cancer bone metastasis, such as zoledronic acid and denosumab, reduce the progression of but do not cure bone metastasis. Dr. Stephen Paget was an English surgeon who asserted the first accurate description of how bone metastases form. In his 1889 "seed and soil" hypothesis, he stated that bone provides the cancer cells with the essential ingredients to thrive. The prostate cancer cells, in turn, influence the bone and "cultivate" the soil for further invasion of prostate cancer cells. Despite this idea being proposed more than 100 year ago, the notion that prostate cancer cells and bone "talk" is accurate. Our search for prostate cancer-secreted proteins that cultivate the soil led us to the discovery of a chemokine protein called CXCL14. Chemokines are proteins secreted by cells that instruct nearby cells to approach. The direction in which movement occurs is dependent on the chemokine. Some of these attract and others repel. In all, 48 different chemokines have been discovered. We have discovered that prostate cancer cells secrete CXCL14 when these cells have metastasized to bone, but not after metastasis to other organs or in the primary cancer itself. These data suggest that prostate cancer CXCL14 plays a unique and specific role in bone. Recent evidence from our laboratory and others support that CXCL14 is an inhibitor of another chemokine, CXCL12. The skeleton itself makes CXCL12 that attracts prostate cancer cells that express the CXCL12 receptor, CXCR4. In animal experiments, blocking the ability of CXCL12 to bind CXCR4 reduced the homing of metastatic prostate cancer cells to bone. Since CXCL14 is expressed only after prostate cancer cells have arrived to bone, we hypothesize that this chemokine blocks the actions of CXCL12 to promote residence and growth in bone. The first aim of this proposal will examine the actions of CXCL14 on the mobility of prostate cancer cells. A critical characteristic of aggressive cancer cells is the ability to quickly move from the site of primary disease to other organs. These experiments will examine the extent to which expression of CXCL14 before arrival to bone, a time when CXCL14 is not normally found, prevents the homing of prostate cancer to bone. The second aim will examine how knockdown of CXCL14 expression in prostate cancer cells reduces growth in bone. This will be accomplished by knocking down CXCL14 expression of prostate cancer cells at two time points, before arrival to bone and in established bone lesions. We expect that these interventions will prevent the formation of bone lesions and treat existing bone lesions. Considerable advances have been made in the treatment of early prostate cancer. Newer delivery methods of external radiation, implantation of radioactive pellets, and hormonal therapies to reduce circulating androgens have less side effects resulting in higher quality of life. However, prostate cancer often progresses to an advanced stage despite suppressive measures such as androgen deprivation therapy. The aims of this proposal will answer fundamental questions of prostate cancer bone metastasis. How does prostate cancer control the metastasis and homing to bone? What is the role of chemokines to maintain prostate cancer in bone? It is expected that these studies will translate into the development of CXCL14 inhibitors that prevent and treat prostate cancer metastasis to bone.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510703
Entities
People
- Gregory A. Clines
Organizations
- Ann Arbor VA Medical Center
- United States Army