Immune system response points way to beating cancer
An innate response that results in cells destroying themselves could provide a less toxic alternative to chemotherapy. Ariella Heffernan-Marks reports.
After so many decades of searching for a cure for cancer, new research suggests a solution might have been within our own natural immune system the whole time.
Angelika Amon, a biologist with the Massachusetts Institute of Technology in Boston, and colleague suggest exactly this in a study published in Developmental Cell. They report finding that cells with a high level of ‘chromosome mis-segregation’ – also known as ‘aneuploidy’ – elicit an innate immune response that results in their own cell-specific death.
If this response could be replicated in cancer cells, the researchers say, it might provide a mechanism for their successful elimination.
Aneuploidy occurs when chromosomes do not separate evenly during cellular division. This results in a chromosomal – and therefore genetic – imbalance in the cell. DNA damage, cellular stress, metabolic defect and alterations in gene dosage can also occur.
Many diseases and disorders have consequently been associated with aneuploidy – including 70–90% of cancer tumours. It has been suggested that alterations in gene dosage can lead to changes in cancer-driver genes, resulting in the erratic proliferation patterns seen in cancer cells.
Despite aneuploidy being confirmed as a hallmark of cancer, however, there is still debate over the exact link. Not all tumours show the same aneuploidy phenotype, and non-cancer sufferers with aneuploidy phenotypes, such as Down syndrome, tend to demonstrate lower chances of developing cancer, according to the Koch Institute for Integrative Cancer Research, with which Amon is also associated.
Most normal tissues do not demonstrate aneuploidy. Even mutations in chromosome-alignment proteins do not result in high numbers of aneuploid cells, according to research published in Molecules and Cells.
Thus the question is: what happens to the aneuploid cells?
A popular explanation has been a “p53-activated mechanism”, whereby the complex karyotype (or chromosomal arrangement) of an aneuploid cell activates the protein p53, which stimulates mitotic arrest and cell death.
Amon and her team, however, discovered this was not the case; rather, arrest and death was the result of an innate immune system response. Using live cell imaging and immunofluorescence, they observed chromosome mis-segregation through mutating chromosome alignment proteins and recorded the time to mitotic arrest. The p53 protein was activated regardless of chromosomes being mis-segregated.
Amon and her colleague investigated the level of DNA damage due to aneuploidy by analysing protein gamma-H2AX, which is found only during double-strand DNA breaks. Elevated levels were found in aneuploid cells, indicating significant DNA stress and damage due to chromosome mis-segregation. Immunofluorescence confirmed this was generating complex karyotypes. “These cells are in a downward spiral where they start out with a little bit of genomic mess,” Amon explains, “and it just gets worse.”
Additional gene analysis also indicated these cells had higher levels of innate immune cells compared to normal cells. Re-exposing both normal and aneuploid cells to these factors confirmed that specific factors were acting to selectively destroy aneuploid cells – most commonly the natural killer cell NK92. It is believed this could be in response to signals from DNA damage, cellular stress or irregularities in protein levels.
So what does this mean with regards to finding the “cure to cancer”?
Cancer cells have found a way to evade this cellular culling strategy. If researchers can find a way to re-activate this mechanism in aneuploid cancer cells, cancer treatment could use a NK92-mediated elimination method instead of toxic and expensive radioactive therapy.
“We have really no understanding of how that works,” Amon concedes. “If we can figure this out, that probably has tremendous therapeutic implications, given the fact that virtually all cancers are aneuploid.”