Journal of the National Cancer Institute Advance Access originally published online on September 9, 2008
JNCI Journal of the National Cancer Institute 2008 100(18):1279-1281; doi:10.1093/jnci/djn336
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© Oxford University Press 2008.
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Cell Fusion Theory: Can It Explain What Triggers Metastasis?
In 1992, John Pawelek, Ph.D., was working with melanoma cells when he read an article that asked whether the fusion of cancer cells and white blood cells could lead to metastasis. Intrigued, he found that his cells fused easily to white blood cells called macrophages and that these hybrids resembled metastatic melanoma cells.
"Since then, I haven’t looked back," said Pawelek, a senior research scientist at Yale School of Medicine in New Haven, Conn., whose primary research focus is now the cell fusion theory of metastasis. In a May 2008 article in Nature Reviews Cancer, Pawelek and Ashok K. Chakraborty, Ph.D., also at Yale, lay out the case for the theory, which could explain one of the mysteries of metastasis: What is the trigger that enables cells to break free from the original tumor and travel to distant sites?
Still unproven, cell fusion theory "is very speculative," said Robert Weinberg, Ph.D., at the Massachusetts Institute of Technology in Cambridge, who is also studying metastasis. But preclinical studies have convinced Pawelek and others that it is an intriguing and worthwhile possibility.
His results make it appear likely that cell fusion happens, he said, but to what extent and whether it results in metastasis is still under investigation.
Fusion theory is not new. Digging into the literature, Pawelek found that the German pathologist Otto Aichel had proposed the idea in 1911. While viewing cancer biopsy samples under the microscope, Aichel saw that white blood cells attacked tumor cells. He proposed that cancer cells and white blood cells might join, resulting in the greater number of chromosomes common in cancer cells and conferring a malignant cell with the ability to move through the bloodstream as white blood cells do.
Scientists know what a cell must do to metastasize. First, the original tumor must develop blood vessels. These vessels form a conduit that nourishes the tumor and provide a path for cells to enter the bloodstream. These mobile cells then must land at another tissue and survive until they can form more blood vessels.
But no one is sure what drives this process. One idea is that the gene mutations that lead to tumors also can result in a cancer cell's becoming metastatic. Another is the epithelial mesenchymal transition theory, according to which tumor epithelial cells become more mobile by turning on transcription factors used in early embryonic development. Weinberg's group at MIT has identified several transcription factors expressed by metastatic cells that can contribute to their migration and ability to form blood vessels. Some of these are also expressed in immune cells, such as macrophages, during wound healing.
The fusion theory is consistent with existing knowledge of macrophages. Part of their job is to travel throughout the body where needed. "Whenever or for whatever, they’ll be there," said Agnes Vignery, D.D.S., Ph.D., who studies macrophage fusion at the Yale School of Medicine. They act as the immune system's first defense against invaders, such as viruses and bacteria, and as a repair system in wound healing, bringing more blood to the injury. Macrophages also cluster around cancer cells and have been associated with a poor prognosis.
Macrophages fuse as part of their job. They join to form giant cells that wrap around an intruder so that it can’t travel throughout the body. Macrophages also fuse to become osteoclasts, cells that recycle bone. According to Vignery, three macrophages that merge into one can absorb 10 times as much bone as they can working separately.
Evidence from laboratory studies shows that when macrophages fuse with malignant cells, tumors are more likely to metastasize. Pawelek has made more than 75 hybrid clones of human melanoma cells and macrophages and found that more than half of them were more metastatic in mice than melanoma cells alone. He injected the hybrid cells under the skin, killed the animals at 5 months or before, and found that the cancer had spread in 75% of the cases compared with the original melanoma cell line, which spread only 10%–15% of the time.
Moreover, human melanoma pathology and macrophages share some common characteristics. Cytological tests show that when aggressive melanoma cells break through the epidermis and spread to the next layer of skin, the dermis, they express a protein commonly found on macrophages.
Studies since the late 1960s have reported examples of cancer cells fusing with host cells in animals and becoming metastatic, although identifying the type of host cell involved is difficult. In the early 1970s, scientists injected human brain cancer cells into the cheeks of hamsters. Harvesting the metastatic cells, they found human and hamster genes in the cells’ chromosomes.
In one experiment, Pawelek put melanoma cells in an albino mouse that could not produce pigment because of a mutation in the tyrosinase gene. He found cells in a metastatic tumor in the lung that produced pigment. Through fusion, they had gained the working copy of the tyrosinase gene. Pawelek said he can’t say for certain that it was macrophages with which the melanoma cells fused, but he did see macrophages surrounding the tumor, and the cancer cells produced certain sugars that macrophages produce.
Also consistent with the fusion theory, researchers have found fused cells in areas of inflammation. A 2008 study in mice reported that transplanted bone marrow–derived cells that included white blood cells often fused with brain neurons affected by encephalitis and severe dermatitis. The finding is intriguing to cell fusion researchers because of evidence associating chronic inflammation with some cancers.
"There is logical evidence for this theory in pathology," said Andrzej Slominski, M.D., Ph.D., an investigator at the University of Tennessee Health Science Center in Memphis, who studies tumor progression.
But the tricky part will be proving it in people, said Dominik Duelli, Ph.D., of Rosalind Franklin University of Medicine and Science, who studies cancer cell fusion caused by viruses. Researchers can’t ethically inject foreign cancer cells into healthy humans to see whether cancer hybrids form. And examining hybrid cells from a cancer patient won’t give much insight because all a person's cells have the same genes.
However, some studies suggest that cancer cell fusion is happening in people. A 2006 study by Thomas L. Andersen of Southern Denmark University and colleagues published in the Journal of Pathology found that 30% of osteoclasts collected from a group of multiple myeloma patients had a gene translocation specific to myeloma cancer cells. "This is a suggestion that fusion is happening, but it doesn’t go beyond that," Duelli said.
Patients who receive bone marrow transplants and later develop cancer also show evidence of cell fusion. A woman suffering from lymphoma 20 years ago received a bone marrow transplant from her son. Years later she developed a renal cell carcinoma. Pawelek studied a piece of the tumor, which had cells with male Y chromosomes. He has looked at three similar cases. His focus in the next years is to study more examples of cancer cell fusion in patients to learn how often it occurs.
In October 2007, Pawelek helped organize the first meeting on cell fusion and cancer in Sweden. Seventy-five scientists attended, suggesting that interest in the field has expanded since Pawelek rediscovered Aichel's work 16 years ago. But those interested in the idea agree that ultimately it will have to be documented in humans to have any clinical relevance. "Until you can find it in people, it's still just an idea," Duelli said.
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