By Dean A. Haycock
Special to BioWorld Today
Has it spread?
Among the many questions and fears that follow the diagnosis of a tumor, the question of metastasis ranks at or near the top. The spread of malignant cells from their site of origin to other parts of the body is a key factor in cancer-related deaths. Like other aspects of the disease, details about the cellular and molecular factors that influence or regulate metastasis are poorly understood.
Oncologists do know, of course, that migrating cancer cells travel via the lymphatic system and bloodstream. They also know that certain types of cancer cells show a distinct preference for specific organs. Breast cancer, for example, has a predilection for establishing outposts in lymph nodes, lung, bone and liver, while other organs are largely spared.
Now researchers from the United States, Germany and Mexico have found an intriguing clue that may explain why some organs are especially receptive to hosting traveling cancer cells. Their article, "Involvement of chemokine receptors in breast cancer metastasis," appears in today's issue of Nature, dated March 1, 2001.
Anja M|ller of the DNAX Research Institute, a part of the Schering-Plough Research Institute in Palo Alto, California, and her co-authors sought clues to the mystery of metastasis in the activity of chemokines. This group of chemotactic polypeptides, which are similar to growth factors, act as beacons for white blood cells equipped with the appropriate cell surface receptors. The researchers reasoned that if chemokines can direct immune cells to specific organs, then perhaps they might play a role in directing cancer cells to specific organs as well.
Others had reported in vitro data showing single chemokine receptors in tumor cell lines. But, M|ller told BioWorld Today, "there was nothing really comprehensive that provided an overview of the expression of all chemokine receptors in a certain malignant disease and that combined this [receptor] expression with certain functions in vitro and in vivo."
The authors therefore screened tissues from patients with breast cancer for the presence of specific chemokines and chemokine receptors.
Genomic Studies Pay Off
"The major breakthrough, in a way, came from the power of genomic studies," Jonathan Sedgwick, director of the Department of Immunology at DNAX, told BioWorld Today. "At DNAX, we had been using gene expression analysis [to study] different chemokine receptors and chemokines in tissues. It was really this technology that enabled this group to type tumor cells and then to use high-throughput screening to say that certain chemokines receptors are expressed preferentially in breast tumor, for example, as opposed to other receptors. That sort of technology has really only been available in the last few years," Sedgwick explained.
The screens turned up an interesting pair: the chemokine CXCL12 and the chemokine receptor CXCR4. The pair attracted interest because, first, there was more CXCR4 in breast cancer tissue than in cancer-free breast tissue. Second, CXCL12 could be found in lymph nodes, bone and lung, organs vulnerable to invasion by wandering breast cancer cells.
Furthermore, in the test tube, CXCL12 induced breast cancer cells to adopt traits characteristic of cells that spread the disease. Exposure to this chemokine caused malignant cells to send out probing extensions of cytoplasm, to migrate and even to cross extracellular matrices, all of which they would need to do to establish secondary tumors. Significantly, the scientists also found that antibodies to CXCR4 blocked metastasis in immunodeficient mice in which human breast cancer cells usually spread.
Small-Molecule Antagonists May Be Useful
The findings lead the authors to propose in the conclusion of their paper "that small-molecule antagonists of chemokine receptors, such as CXCR4, may be useful to interfere with tumor progression and metastasis in tumor patients."
Sedgwick cautions that all the study has done is identify a new and interesting target through which tumors can be treated, particularly in the context of metastasis. "I want to make clear that this is work that has been done in a laboratory in an artificial mouse model system. The implications and relevance to humans is not really yet known," he said. "One would imagine that this certainly would trigger interest in that area."
Unfortunately, Sedgwick pointed out, "There aren't any [antagonists] so far. There are ongoing attempts at a variety of places to make inhibitors of CXCR4 but that is all I can say. I'm not aware of a lot of progress in that area. The other issue here is that CXCR4 is one of the co-receptors for HIV, so there is a lot of activity in that context to try and find inhibitors of that pathway."
In a "News and Views" article in the same issue of Nature, Lance Liotta, of the National Cancer Institute of the National Institutes of Health in Bethesda, Md., writes, "It is unclear whether such treatment would have any effect on patients who already have established metastases." He goes on to note that there are high levels of CXCR4 in primary breast cancer cells, but not in normal breast tissue. This suggests to him that "the selection process is probably already complete before metastasis takes place. It will be important to see whether CXCR4 levels are high in premalignant breast cancer, which does not yet have the ability to invade or metastasize."
M|ller and her colleagues are thinking along similar lines. While the search for viable inhibitors continues, they "would like to study the role of this pathway in several stages of the disease, in more advanced stages as well in as earlier stages," she said. "We would also like to know, of course, whether this is applicable only to breast cancer or whether other malignant diseases use, for instance, other chemokine receptors during the process of metastasis."