Pawelek and his colleagues have also found molecular similarities between metastatic cells and macrophages, such as activation of genes linked with movement. In addition, they discovered that these cancer cells apparently produce organelles known as autophagosomes, with which the cells can digest chunks of themselves. Macrophages often produce autophagosomes as a means to snack on themselves while traveling, and cancer cells may do the same.
Pawelek is not the first scientist drawn to the fusion theory. Its earliest proponent was German pathologist Otto Aichel, who proposed it in 1911. It revived again some 50 years later, thanks to experiments showing that implanted tumor cells could spontaneously fuse with cells in lab animals and spread. About the mid-1980s, however, interest faded. David Goldenberg, who conducted some of those studies and is now president of the Garden State Cancer Center in Belleville, N.J., suggests that attention waned because although scientists could see hybrids of foreign and host cells, the tools at the time could not show that such fusions were actually taking place in natural settings. After all, if fusions were happening in cancer patients, both the tumor cells and macrophages would be virtually genetically identical, making it hard to prove that metastatic cells were hybrids.
But now Pawelek believes that technology has caught up and that the evidence lies with cancer patients who received bone marrow transplants. Radiation therapy and chemotherapy kill off bone marrow, which supplies white blood cells to the body. Donated bone marrow would naturally be genetically distinct from the patient, making it possible to see if tumor cells of the host fused with macrophages from the donor.
So far Pawelek and his colleagues have found two possible examples. In one, a boy with type O blood received a bone marrow transplant from his type A brother, and when the bone marrow recipient later developed kidney cancer, the scientists found tumor cells that possessed blood type A. In the other example, a woman who received a bone marrow transplant from her son later developed kidney cancer, and the new tumor contained cells with the male Y chromosome. In both the human examples, however, the investigators could not confirm that the cells contained the host’s genome. It therefore remains possible that these cells were not hybrids but simply came from the donor. On future samples, Pawelek hopes to use forensic DNA analysis techniques that can detect genes from both host and donor in the same cells.
Any searches for hybrids are highly vulnerable to error, cautions stem cell biologist Irving Weissman of Stanford University. “I’ve seen this kind of thing over and over again—when you think you’ve seen a hybrid, it turns out there’s almost always a cell with another cell adhering to it or very close to it.” (Pawelek insists the researchers took care to ensure such mistakes were not made.)
Weissman also cites other studies that show hybrids are actually less cancerous, not more, when tumor cells are fused with normal cells, apparently because the infusion of healthy DNA helps to suppress malignant activity. Pawelek suggests that the cell type used may partially explain this discrepancy—fusions with white blood cells show enhanced malignancy, whereas cell types such as epithelial cells can suppress tumors.
But even if Pawelek shows that the fused cells become metastatic, Vogelstein says, researchers still have to see whether these hybrids account for a significant fraction of metastases or whether other mechanisms trigger most spreading cancers.
If Pawelek is right, investigators will have new ways to combat cancer. For instance, they could aim to develop drugs based on antibodies that attack fused cells that may have unique chemical signatures or to devise therapies that block molecules linked with cell fusion. “Even if he’s wrong,” Vogelstein remarks, “the pursuit of unconventional ideas often leads to novel insights.”