What makes you, you?
Every human cell has a pair of chromosomes that give the body a blueprint for how to grow and develop, starting as a single cell inside the uterus.
But in a new study from Cedars-Sinai Cancer Center, scientists have found that chromosomes are not only the building blocks of human life, they may also play an important role in fighting disease.
Dan Theodorescu, director of Cedars-Sinai Cancer and corresponding author of the study, and a group of leading researchers from around the country published their findings in Nature on June 21.
The cells of those born male contain an X chromosome and a Y chromosome that form a pair and provide instructions for which genes should be expressed in the body, the researchers said.
As men age, they begin to lose some of their Y chromosomes due to rapid cell division, the study said.
“This study makes, for the first time, a never-before-seen link between the loss of the Y chromosome and the immune system’s response to cancer,” Theodorescu said in a June 21 release. “We found that loss of the Y chromosome allows bladder cancer cells to evade the immune system and grow very aggressively.”
The researchers identified two groups of men, divided by the amount of Y chromosomes in their bodies.
The group included 300 men, ages 34 to 90, of many races, all with locally advanced muscle-invasive bladder cancer.
“The Y chromosome contains the blueprints for certain genes,” the announcement reads. “Based on how these genes are expressed in normal bladder cells, the researchers developed a scoring system to measure the loss of the Y chromosome in cancers.”
Study participants were given a high or low ‘Y chromosome subscription’ score and their progress was followed over time.
The researchers found that “patients with (a) low level of Y chromosome gene expression had significantly worse overall survival compared to those with higher expression,” the study said.
The test showed that the Y chromosome played a role, but the researchers didn’t know why. So they tried another test on mice.
Understanding the process
The researchers grew bladder cancer cells in mice with intact immune systems. They grew tumors in some mice that had full Y chromosomes and some that lacked Y chromosomes.
The researchers found that the bladder cancer cells grew “much faster” in mice with fewer Y chromosomes compared to those with many, according to the release.
“The fact that we only see differences in growth rate when the immune system is at play is the key to the ‘loss-of-Y’ effect in bladder cancer,” Theodorescu said in the release. “These results indicate that when cells lose the Y chromosome, they exhaust T cells.” And without T cells to fight the cancer, the tumor grows aggressively.”
Previous studies have shown that loss of the Y chromosome is present in many types of cancer in men, including between 10 and 40 percent of bladder cancers, according to the release.
Losing Y chromosomes has also been linked to heart disease and Alzheimer’s, both diseases that have a higher prevalence in older people.
The aggressive nature of the cancers does not mean that they cannot be treated.
“Fortunately, this aggressive cancer has an Achilles’ heel, as it is more sensitive than cancers with an intact Y chromosome to immune checkpoint inhibitors,” co-author Hany Abdel-Hafiz said in the release.
Little soldiers of the body
Immune checkpoint inhibitors work by preventing the exhaustion of T cells by the immune system that fight cancer cells. T cells attack cancer cells and cause them to swell and die, but your body makes a limited amount of T cells, and if there’s too much cancer to fight, T cells can’t keep up, according to Cancer . network.
Immune checkpoint inhibitors prevent your body from getting too few T cells, and they are one of the preferred bladder cancer treatments, according to the release.
“T-cell exhaustion can be partially reversed with sedation inhibitors, but if we could prevent it from happening in the first place, there is great potential to improve patient outcomes,” Theodorescu said in the release.
Although the study was conducted only on Y chromosomes, individual males, Theodorescu said that the results of the study can be applied to all genders because chromosomal changes can also occur on the X chromosome.
“The new fundamental knowledge we provide here could explain why certain cancers are worse in men or women and how best to treat them.” It also shows that the Y chromosome does more than determine a person’s biological sex,” Theodorescu said.
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