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Experiments done on parabiotic mice have revealed that immune cells can sometimes fuse with tumor cells, aiding in cancer cell progression. A study done by A.E. Powell and other
scientists (Fusion between Intestinal Epithelial Cells and Macrophages in a Cancer Context Results in Nuclear Reprogramming) shows that in this process of cell fusion,
the immune cells (specifically macrophages) transfer information from their
genome, allowing the cells to evade the immune system and to eventually navigate
the circulatory system to metastasize.
The experiment:
As mentioned above, mice were used to test the hypothesis of cell fusion. Whole
bone marrow cells were combined with peripheral blood and transplanted with
macrophage, B-cell and T-cell isolation mixes. These were then put into mice
along with the green fluorescent protein (GFP), which acted as a sort of marker. The scientists surgically joined those mice that were given the GFP with ROSA26/ApcMin/+ mice from their elbows to knees. After about 7 weeks, they separated them again to analyze their epithelial cells. They took note of the percentage of villus units (a villus
plus its adjacent crypt) with at least one GFP-positive cell (which
fluoresced). They saw that in the intestinal tumors in the mice, the
macrophages, T-cells and B-cells all were present in the tumor's
microenvironment and could easily be used for cell fusion.
The results:
Tumor cells are already known to be fusogenic. The tumor
epithelium cells expressing both GFP and β-galactosidase (shown in Figure 1) in the surgically separated mice "strongly illustrates that cell fusion occurs in the natural context of tumorigenesis" (1).
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| Figure 1: GFP shown in green and β-galactosidase in red. Arrows point out fused cells. In image "C, cell fusion is observed in small intestinal polyps. In D–F, lymphocytes and leukocytes are present within small intestinal polyps that have undergone fusion" (1). |
They tested the ability of the three different immune cells
to fuse with the intestine epithelium of the mice and found that all showed the
ability to fuse. They then realized that some epithelial cells experienced
fusion even without mature B-cells or T-cells, thus leading them to the conclusion
that they weren't involved directly in the cell fusion process. The macrophages,
meanwhile, seemed to induce fusion. Macrophages are naturally recruited to
sites of injury and "in this context may be stimulated to fuse with
injured epithelium" (1).
Furthermore, the scientists discovered that the
GFP-expressing macrophages were able to pass into the basal lamina of the
epithelial cells, even though macrophages usually do not cross the boundary.
Thus, they figured that in order for cell fusion to occur, the macrophages must
cross into the epithelial compartment.
Among the interesting data they encountered, the group also
observed that the hybrid cells retained some of the epithelial phenotype and
were able to divide and contribute to the epithelial population. At the same
time, the new cells also had macrophage-like properties. They had some altered
genes used in metastasis, suggesting that the hybrid cells have gained
metastatic capability through the cell fusion. In conclusion, the
scientists write, "cell fusion between tumor epithelium and macrophage
populations provide an exciting explanation for how tumor cells gain the
physical macrophage-attributed properties involved in tumor metastasis such as
extravasation, migration, and immune evasion” (1).
So what?
In researching for my cancer project (immune system evasion), I had to look up what how the normal immune system functioned. I found that macrophages release cytokines which "increase the expression of adhesion molecules on endothelial cells, facilitating leukocyte [white blood cell] influx and destruction of pathogens" (3). It's strange that while the macrophages were in contact with the endothelial adenomas of the mice that they were unable to call on the leukocytes like the natural killer cells to destroy the tumors. Instead, as the group found, the macrophages and tumor cells fused. The way I understood it, the macrophages would mark the infected cells or the antigen present in the body in order for the other immune cells to find and destroy the "foreign" DNA. While macrophages are meant to protect our bodies, it seems that they end up being a double-edge sword after all. What I'm wondering is how or why cell fusion might occur instead of the destruction of the tumor cells. The article speaks about the fusogenic property of tumor cells, so my guess is that the macrophages somehow are tricked into recognizing them as similar cells.
I think I read somewhere that hybrid cells sometimes display completely different phenotypes and have different functions that the two original cells from which they arose. It's interesting that these new cells can still take part in cell division and growth and even blend in with the rest of the epithelial cells. What's even more mind-boggling is that they also have some properties of the macrophages, such as the ability to perform extravasation, a process through which macrophages are able to wander around the blood vessels and migrate into cell tissue (4). This is the most dangerous part of the fusion in that the hybrids now have a way to bypass the immune system and are able to travel along the host's bloodstream without necessarily having to make utilize their own system created through angiogenesis.
References:
1. Fusion between Intestinal Epithelial Cells and Macrophages in a Cancer Context Results in Nuclear Reprogramming (Powell, Anne E., et al. 2011.)
2. Parabiosis
