The Y Chromosome Puzzle and Its Impact on Bladder Cancer Resistance

Recent research indicates that the progressive loss of Y chromosomes in aging men significantly impairs the body's capacity to combat bladder cancer.

The study, published in the scientific journal Nature, found that loss of the Y //chromosome helps bladder cancer cells evade the body's immune system, said the researchers from Cedars-Sinai Medical Center ().

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Bladder cancer occurs due to abnormal cell growth in the urinary bladder. The most common kind usually is urothelial cancer or transitional cell carcinoma.

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Age's Toll on Immunity

"This study for the first time makes a connection that has never been made before between loss of the Y chromosome and the immune system's response to cancer," said Dan Theodorescu, director of Cedars-Sinai Cancer, who initiated the research.

"We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively."

In humans, each cell normally has one pair of sex chromosomes; men have one X and one Y chromosome, while women have two X chromosomes. In men, loss of the Y chromosome has been observed in several cancer types, including 10 percent - 40 percent of bladder cancers. Loss of the Y chromosome also has been associated with heart disease and Alzheimers disease.

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Men's Immune Response and Chromosomal Changes

The Y chromosome contains the blueprints for certain genes. Based on the way these genes are expressed in normal cells in the bladder lining, investigators developed a scoring system to measure the loss of the Y chromosome in cancers.

The team reviewed data on two groups of men. One group had muscle-invasive bladder cancer and had their bladders removed, but were not treated with an immune checkpoint inhibitor -- a standard bladder cancer treatment.

The other group participated in a clinical trial and was treated with an immune checkpoint inhibitor. The results showed that patients with loss of the Y chromosome had a poorer prognosis in the first group but much better overall survival rates in the latter.

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Unveiling the Link

To determine why this happens, the investigators grew cancer cells in a dish where the cells were not exposed to immune cells. The researchers also grew the diseased cells in mice that were missing a type of immune cell called T-cells. In both cases, tumors with and without the Y chromosome grew at the same rate.

In mice with intact immune systems, tumors lacking the Y chromosome grew at a much faster rate than tumors with the intact Y chromosome.

"The fact that we only see a difference in growth rate when the immune system is in play is the key to the 'loss-of-Y' effect in bladder cancer," Theodorescu said. "These results imply that when cells lose the Y chromosome, they exhaust T-cells. And without T-cells to fight cancer, the tumor grows aggressively."

Reference:

Y chromosome loss in cancer drives growth by evasion of adaptive immunity - (https://www.nature.com/articles/s41586-023-06234-x)

Source-IANS