On a cold, gray Saturday morning at Yale University in February 1993, instead of just reading his laboratory’s article in a cancer journal and scanning past the rest—cancer is a profoundly wide field, and there is much to read—cancer biologist John Pawelek made time to finish the entire issue. That simple decision changed the course of his research, toward a controversial explanation for the deadliest aspect of the disease—namely, why it spreads.

The issue contained a letter from three Czech doctors asking whether the fusion of tumor cells and white blood cells could cause cancers to spread, or metastasize. At the time, Pawelek was also reading a book by evolutionary biologist Lynn Margulis, who pioneered the idea that life on earth was revolutionized by ancient cells engulfing one another and fusing together, forming hybrids that had better chances at survival. “I was really excited by the connection,” he recalls. “Since there was a precedent for hybridization in evolution, why not in cancer?”

In the past 15 years Pawelek and his colleagues have shown that cancer cells can fuse with white blood cells and become highly metastatic in lab animals. Now they are searching for the same activity in humans. The leading cause of death in cancer is metastasis—tumors are generally treatable as long as they have not moved to vital organs. So if the research reveals that such hybrids help cancer spread, it could open up new avenues to fighting cancer. As Pawelek puts it: “You have to know how metastasis starts to properly fight it.”

But maddeningly little is known about what makes cancer spread. Explaining the capabilities that metastatic cells possess—to break away from their original tumors, migrate past other cells, travel around the body via lymph or blood vessels, invade tissues, and grow—would involve understanding how cells interact with one another. “And we don’t yet have good biological tools to investigate the interactions between different cell types and organs,” explains cancer geneticist Bert Vogelstein of Johns Hopkins University.

One theory behind the origin of metastasis is that mutations in one or a few genes cause tumor cells to gain the ability to migrate. Another idea suggests that no specific mutations are needed—rather cancer cells eventually accumulate abnormal numbers of chromosomes that break down the constraints that keep any normal cell from metastasizing. In Pawelek’s view, these theories do not explain how cancer cells would acquire the right genetic changes in the right order needed to spread successfully.

Instead the 66-year-old Paw­elek suggests that cancer cells spread after fusing with white blood cells known as macrophages. Like metastatic cells, macrophages can roam around and infiltrate most parts of the body and are naturally resistant to toxic drugs. “Metastasis is a very different phase from ordinary cancer and to me is almost like a new disease superimposed on a preexisting cancer cell—maybe cancer cells inherit all these traits at once by hybridizing with white blood cells,” Pawelek speculates. Moreover, macrophages regularly engulf germs and unhealthy cells—they might occasionally fuse with tumor cells instead of destroying them, much as ancient cells once joined together into symbiotic relationships a billion years ago, he reasons.

In their first experiments, Pawelek and his colleagues took a strain of mouse melanoma cells known to be only weakly metastatic and fused them with mouse macrophages by exposing them to polyethylene glycol, which can dissolve cell membranes. They implanted these hybrids in roughly 5,000 mice. “These were massive experiments that took four years to accomplish, and we were just going on faith,” Pawelek recounts. The results were striking—roughly 55 percent of the hybrid cells proved “really, really deadly, very metastatic,” he declares, in contrast to melanoma cells fused with one another—none of them became metastatic. “I was convinced we were on to something.”

3 Comments

1. 1. bturner 07:23 PM 1/13/09

   Pawelek's hypothesis is very interesting and seems plausible, but unfortunately, the evidence in support of his hypothesis is not strong.
   
   The forensic DNA analysis approach seems to be the obvious way to go to provide stronger support for this hypothesis. An experiment could be conducted to determine whether macrophage DNA is present or comingled with tumor cell DNA. A fairly simple experiment would be to take bone marrow cells from a donor, label the DNA in the donor cells, then take some tumor cells from the host and label the DNA with another chemical marker. Then put both donor and host cells back into the host and when the cancer spreads to a new area, remove tumor cells from the new area and look for donor DNA mixed with the host's DNA in the tumor cells.
   
   I would guess that this type of experiment has already been done...maybe no one has come up with results that would back up Pawalek's hypothesis?

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2. 2. AVattay 09:16 AM 4/22/09

   Actually it may be worth taking the cell fusion theory one step further beyond metastasis, in an attempt to justify oncogenesis itself based on the following assumptions.
   Genomic fusion between cells generates diversity. This diversity can be selected upon by its environment. In the case of cancer the selection is for uncontrolled cell growth. In theory if one shuffles the genome of a cell most of the cell progeny will be not be viable however the possibility exist that the shuffling event will generate the genetic fusions that we often see in tumor cells.
   Whether or not a macrophage are involved is not the soul issue, indeed a prearranged epigenome of a macrophage should give an advantage for metastasis as compared to other cells when fused to a non metastatic tumor. However the role of cell fusion may not limited to metastasis alone, but rather contribute to the genomic instability that is often seen in cancer.
   Which raises the question, is genomic fusion the driving force in oncogenesis that leads to oncogenes? Maybe the experiment to do would be to take cells that are amendable to fusion such as stem cells, and fuse them together then select for uncontrolled growth as compared to non-fused cells. The hypothesis would be that the diversity generated by the fusion would introduce the necessary mutations to initiate oncogenesis. The counter would be that reverse fusion (mitosis) directs the rearrangement. In any event pursuing the cause of metastasis/oncogenesis whether it is fusion or reverse fusion contributes to our knowledge regardless of the outcome.
   

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3. 3. AVattay in reply to bturner 09:26 AM 4/22/09

   One aspect that should be incorporated into any experiments with cell fusion is using a fusible cell lines such as stem cells.

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