Cancerous bladder cells with a missing Y chromosome are better prepared to evade our immune system, according to a new study using mice and conducted by researchers from Cedars-Sinai Medical Center and The Ohio State University in the US.
The discovery goes some way to explaining why so many cases of specific cancers contain cells that no longer have a male sex chromosome and potentially why men are statistically more prone to cancer.
Like hair color, skin elasticity, memory, and eyesight, the Y chromosome has a habit of disappearing as we age, left behind while the rest of our genetic library is copied and transferred into a fresh new cell.
For the most part, it seems we get on relatively fine without it, at least for a while. Compared with 156,000 base pairs making up the X chromosome, the puny wad of DNA that triggers male sexual characteristics contains a mere 57,000 base pairs of information, coding for various genes that don’t seem overly critical for life.
Yet it’s clear that something in those sequences must make a difference when it comes to general health. For example, losing the chromosome in blood cell-producing tissues is bad news for heart function. Somewhere between 10 and 40 percent of bladder cancers also contain cells that lack a Y chromosome, hinting at hidden protective functions.
To find them, Cedars-Sinai urologist Dan Theodorescu led a team of scientists in an investigation of bladder cancer prognosis in mouse models, validating the results with an analysis of individual cells taken from human bladder cancers.
Cells from mice that had either naturally lost their Y chromosome or had it removed through CRISPR-Cas 9 gene editing grew more or less the same as cells with the sex chromosome when observed in-vitro.
Inside mice, the distinction became much more apparent. Cancers without a Y chromosome became far more aggressive, growing at nearly twice the rate of their genomically complete versions.
Breaking key immune genes in the Y-positive mice equalized growth rates once again, implying something in the chromosome facilitated the body’s anti-tumor adaptive immunity. Further analysis confirmed two specific genes – KDM5D and UTY – were primarily responsible for the added protection.
A scan through the proteins produced by the mouse cancer cells and comparing critical immune cells present in the two different tumor types helped further fill in the picture, suggesting cancer-fighting T lymphocytes were rapidly exhausting in their attack on cells that lacked the genes.
Sifting through databases of proteins active in human bladder cancers supported the mouse models’ findings, affirming that the presence of a Y chromosome in bladder cells produces important proteins that help the immune system’s onslaught against the growing tumor.
Not only does this give medical specialists something to look for in determining the aggression of bladder cancers, but further experimentation also showed Y negative tumors respond well to a type of cancer treatment known as an immune checkpoint inhibitor.
If you’re inspired to give your Y chromosomes a big, hearty hug and tell them you’ll never let them go, you might want to hold off.
Another recently published investigation by researchers from the University of Texas in the US assessed sex differences in colorectal cancer in mice, finding similar differences as those measured among humans.
An analysis of a known mutation found it regulates a gene on the Y chromosome that’s primarily responsible for giving tumors a leg-up in migrating around the mouse body. That Y chromosome gene happens to be KDM5D, one of the specific genes identified as protective in bladder cancer.
Depending on the tissue type, this diminutive ‘pamphlet’ of a chromosome could be a cancer-fighting weapon or a how-to manual for a tumor to set sail and invade new organs. It just depends on which disease you prefer to be at the most risk of.
With studies suggesting the Y chromosome could be on the way out as an evolutionary fashion, it’s hard to know whether we should be celebrating or lamenting.
These studies were published in Nature here and here.