One of the mysteries surrounding prostate cancer has been its seeming predilection for bone. Is this because other tissues are not amenable to its advances or does bone send out some sort of homing signal that draws the metastasizing cells? Scientists at the National Institute of Dental and Craniofacial Research (NIDCR) now have convincing evidence that a substance in bone not only attracts the prostate cancer cells, but stimulates them to become invasive. This finding has important implications for the discovery and development of agents that might be used in the treatment of prostate cancer and other cancers that spread to bone.
Prostate cancer is the second leading cause of cancer deaths in men from both Europe and the United States. At the time of diagnosis, over 70 percent of the cases have metastasized to the pelvic lymph nodes. From there, cancerous cells show a high propensity for invading bone in the pelvis and vertebra of the lower back.
The question has been why bone rather than nearby organs like kidney, liver, or even lung. One theory has been coined "seed and soil," which likens cancer cells to seeds drifting in the wind and landing at random on different types of soil--putting down roots only where the local conditions allow. Another theory portrays cancer more like a predatory animal that is drawn by the trail of its favorite prey.
Drs. Karin Jacob and Hynda Kleinman from NIDCR's Craniofacial Developmental Biology and Regeneration Branch led an international research team to determine if there was a specific factor in bone that acts as an attractant for prostate and possibly other bone-seeking cancers, such as breast cancer. By studying the reaction of prostate cancer cells to various solutions of tissue extract, they found that a bone protein caused the cells to aggressively migrate to the bone extract. The study appears in the September 1 issue of Cancer Research.
The investigators used a technique developed by Dr. Kleinman and colleagues at NIDCR, in which cancer cells and tissue extract were placed in separate compartments of a fluid-filled chamber. The cells and tissue extract are separated from one another by a special membrane consisting of a filter containing pores that are barely large enough to allow the cancer cells to squeeze through. As an additional impediment, the side of the membrane facing the cancer cells was coated with Matrigel--a material made from the "matrix" molecules that form the structural framework of blood vessels and organs. In order to penetrate this membrane, the cancer cells had to first be stimulated to migrate to it and then have the ability to digest their way through the Matrigel. When prostate cancer cells were tested against extracts of bone, brain, liver, lung and kidney, four times the number of cells made it through the membrane to the bone extract.
When the investigators separated out the various components of the bone extract, they found a single constituent responsible for the attraction. The factor is a protein called osteonectin, which is present primarily in bone and is thought to be involved in the mineralization process. Further incriminating osteonectin as the active ingredient, the attractive ability of the bone extract could be eliminated by first treating it with an antibody that specifically bound osteonectin.
An additional test showed that osteonectin not only attracts prostate cancer cells, but also increases their invasiveness. Laboratory examination showed that cells exposed to osteonectin increased their production of enzymes that allow the cells to burrow not only into the Matrigel membrane, but also into the tissues that they home to. Osteonectin also induced enzyme activity in breast cancer cells, another type of cancer that readily spreads to bone, but was inactive against cancers that do not metastasize to bone.
Although this work is still in the laboratory stage, the investigators suggest that a compound, such as an antibody that inhibits osteonectin, may act against bone-seeking cancers by discouraging the spread of the cells to bone and also by preventing the production of invasive enzymes.
In addition to Drs. Jacob and Kleinman from the National Institute of Dental and Craniofacial Research, the team included Dr. Mukta Webber from Michigan State University and Dr. Dafna Benayahu from the Sackler School of Medicine, Tel Aviv University. Dr. Jacob was supported in part by a grant from the German Science Foundation.
Journal
Cancer Research