BioWorld International Correspondent
LONDON - Scientists at Cancer Research UK are going to test drugs designed to prevent HIV from entering cells to see if the same compounds also can stop ovarian cancer from spreading.
The team has identified a chemokine receptor that is specifically present on ovarian cancer cells, but not on normal ovarian epithelium. By coincidence, the same receptor, known as CXCR4, is that used as a co-receptor by HIV for entering cells.
Frances Balkwill, professor of cancer biology at Queen Mary, University of London, told BioWorld International, "This means that there are already small molecules out there, which can block this receptor and which have already been used in patients. It is difficult to say now how important this finding is, but the results we get over the next year will be crucial."
She and her colleagues are willing to consider collaborations with companies that have CXCR4-blocking compounds that they think would be worth testing on ovarian cancer. The group will examine how the drugs alter the spread of ovarian cancer in a range of animal models of the disease.
Balkwill and her colleagues have published their results in a paper in Cancer Research titled "Multiple Actions of the Chemokine CXCL12 on Epithelial Tumor Cells in Human Ovarian Cancer." Cancer Research UK, the UK's largest cancer research charity, funded the work.
Chemokines are a type of chemical messenger in the body. One of their roles is to direct white blood cells from the bone marrow, where they are made, to the sites in the body where they are needed to fight infection. Once white blood cells have encountered an infection, it is chemokines that guide them to lymph nodes where they can initiate and control the immune response, probably by creating a "chemical gradient" that stimulates the cells to move in a particular direction.
Several groups, including Balkwill's, already had found that tumors also produce chemokines that attract white blood cells. In a woman who presents with advanced ovarian cancer, Balkwill pointed out, only about 50 percent of the 1012 extra cells that she has in her peritoneum are tumor cells; the rest are macrophages and lymphocytes.
"These cells are not there to mount an immune response," she said. "Instead, they are there to help the tumor grow and spread. They produce factors that allow remodeling of tissue, help cells survive and stimulate growth of blood vessels. It is as though the tumor is a rogue organ and these cells are part of it."
The team theorized that perhaps cancer cells could use chemokine gradients to help them move around the body, as well as producing chemokines that would attract other cells. They already knew, for example, that when dendritic cells encounter an infectious agent they change the profile of chemokine receptors on their surface, allowing them to respond to different chemokine gradients and move to the lymph nodes to stimulate the immune response.
"We thought this aspect was worth exploring, particularly as cancer cells also spread to the lymph nodes," Balkwill said. About a year ago, they were excited to find that although cells can have many different chemokine receptors on their surfaces, cells from ovarian tumors only ever had one: CXCR4. They also found that the chemokine that binds to this receptor, called CXCL12, was present in high concentrations in the peritoneum, where ovarian tumors grow.
Further studies in the laboratory showed that CXCL12 could make cells from ovarian tumors move, spread and invade other tissues.
Their results led them to speculate that the CXCR4-CXCL12 receptor-ligand pair could play a role in the spread of ovarian cancer in the peritoneum. "We thought that perhaps the tumor cells were leaving the solid tumor and moving into the peritoneum by following a chemokine gradient," Balkwill said. "What our latest paper shows is that it is more subtle than that. The solid tumor itself is making the chemokine. Not only is CXCL12 involved in migration and spread, it is actually helping the tumor cells grow. Interestingly, it stimulates the tumor cells to make the inflammatory molecule tumor necrosis factor alpha, which itself can initiate a whole network of other inflammatory molecules."
The next step is to see what happens to the spread of ovarian cancer if the CXCR4-CXCL12 interaction is blocked. Because CXCR4 is known to be a co-receptor for HIV and the target of several antiviral drugs that are already in clinical use, the answer to that question may be available more rapidly than usual.
"We show in the paper that AMD3100, a specific CXCR4 antagonist, will stop ovarian cancer cells [from] growing and migrating. We now want to find out if it will work in animal models of this disease," Balkwill said.