Prostate cancer (PC) is the most commonly diagnosed solid malignancy and second leading cause of cancer death in US men. PC has a specific propensity to metastasize to bone; in fact, in the majority of cases, bone metastases develop long before metastatic growth is apparent in soft viscera. Bone metastases cause pain, compression fractures, spinal cord compromise, and other complications. Organ-specific metastasis to bone can be attributed to either ¿homing¿ of circulating cancer cells to bone and/or increased growth of PC cells after their arrival in bone. The homing of circulating cells to bone is a potential target for therapy: it is conceivable that direct, ablative treatment of the primary tumor (surgical excision or radiation therapy) and its associated morbidity could be avoided by administration of an effective anti-homing strategy that prevents the initial interaction of PC cells with bone. An emerging hypothesis regarding homing is that the bone secretes substances (chemokines) that interact with chemokine receptors on the surface of cancer cells. This interaction causes the cancer cells to migrate physically to locations with higher concentrations of the chemokines (chemoattraction). A detailed understanding of the expression of the chemokines and chemokine receptors and their function in PC metastatic spread to bone could provide vital clues for the development of effective strategies targeting the homing function of cancer cells.

Recent evidence suggests that the microenvironment of the target tissue plays a key role in the development of metastasis. For instance, we have demonstrated that proteases participate in degradation of the extracellular matrix, leading to osteoblastic and osteolytic reactions in PC bone metastases. Thus, a ¿vicious cycle¿ is set up such that growth of metastatic tumors stimulates bone turnover, and bone turnover stimulates tumor growth. Chemokine molecules may play an earlier role in metastasis by acting as specific molecular attractants for circulating PC cells. In addition, the chemoattractive process may further direct cancer cells in the marrow toward endosteal surfaces so that the ¿vicious cycle¿ can be initiated. The relationship between chemoattraction and proteolysis is unknown. Our preliminary results show that bone-associated chemokines induce protease secretion by PC cells, particularly MMP-9.

Our collaborator Dr. Michael Cher, developed the ¿SCID-human model of PC metastasis to bone,¿ which mimics clinical disease on several levels: homing of PC cells to implanted human bone in SCID mice, rapid growth in bone as compared to other tissue environments, and rapid turnover of the bone extracellular matrix. We have also noticed that PC cells migrate toward endosteal surfaces after their arrival in the marrow. In this and other models, we found that PC cells growing in bone produce and/or secrete matrix metalloproteinases (MMPs), including MMP-9. These proteinases are enzymatically competent to degrade bone matrix, and they normally participate in several of the steps of bone matrix metabolism.

Using an in vivo SCID-human system, and metastatic tissues from patients, we hypothesize that: (a) PC cells home to the bone environment by means of bone-residing chemokines that interact specifically with chemokine receptors on the surface of PC cells; and (b) these chemokine-receptor interactions lead to expression of MMP-9 via specific cellular signaling mechanisms. Improved understanding of chemokine-receptor interactions and subsequent intracellular signaling pathways that play a role in expression of proteinases may lead to new therapeutic strategies aimed at interrupting the interactions between PC cells and bone.