2023-06-22 09:57:22
This loss, which in men occurs in various types of cancer such as 10-40% of bladder tumors, however allows the tumor to be more sensitive to treatment.
Although the specific mechanisms underlying the differences between the sexes in terms of cancer incidence, clinical outcomes, and tumor biology are not well understood, some research suggests that the Y chromosome, precisely the Y chromosome, may play an important role in this explanation. that determines the male sex. Its loss is a feature observed in multiple types of cancer, although its clinical and biological significance is unclear.
The study published this Thursday by Nature and carried out by researchers from the Cedars-Sinai Cancer Center pivots along these lines, which analyzes how the loss of the Y chromosome can favor the growth of cancer, specifically bladder cancer. “This study for the first time connects the loss of the Y chromosome and the immune system’s response to cancer in a way that had never been done before,” explains Dan Theodorescu, director of that institution and one of the authors of the research, who continues: “We found that the loss of the Y chromosome allows bladder cancer cells to evade the immune system and grow very aggressively.”
Each cell has a pair of sex chromosomes: in the case of women there are two X chromosomes and in the case of men one X chromosome and one Y chromosome. In men, chromosome loss has been observed in several types of cancer, for example, between 10 and 40% of bladder cancers. This loss of the Y chromosome has also been associated with heart disease and Alzheimer’s disease.
The Y chromosome contains the codes or blueprints for certain genes. Based on the way these genes are expressed in healthy cells of the bladder wall, the researchers devised a scoring system to measure Y chromosome loss in tumors. They then reviewed data from two groups of men with bladder cancer: one group had a muscle-invasive tumor (when it grows and affects the muscles of the bladder) and had this organ removed, but they were not treated with punctal inhibitors. immune control; the other group participated in a clinical trial and received treatment with an immune checkpoint inhibitor.
The researchers found that patients with Y chromosome loss had a worse prognosis in the first group and much better overall survival rates in the second group. To understand why this happens, they then compared the growth rates of bladder tumor cells in mice. To do this, they grew cancer cells in a dish where they were not exposed to immune cells. They also grew cancer cells in mice that lacked a type of immune cell, T cells or lymphocytes. In both cases the tumors, with and without the Y chromosome, grew at the same rate.
In mice with intact immune systems, tumors without the Y chromosome grew much more rapidly than tumors with the intact Y chromosome. “The fact that we only see a difference in tumor growth rate when the immune system is at stake is the key to the effect of Y loss in bladder cancer,” Theodorescu explains, adding that these results imply that when cells lose the Y chromosome, they deplete the T cells, and without cancer-fighting T cells the tumor grows aggressively.”
From the results in humans and mice, Theodorescu and his team reached yet another conclusion: Tumors lacking the Y chromosome, while more aggressive, are also more vulnerable and more responsive to immune checkpoint inhibitors ( inhibitors of PD-L1 in tumor cells and PD-1 in T cells). This therapy, one of the two leading bladder cancer treatments available to patients today, reverses that depletion of T cells and enables the immune system to fight the cancer.
“Fortunately, this aggressive cancer has an Achilles heel, in that it is more sensitive than tumors with an intact Y chromosome to immune checkpoint inhibitors,” says Hany Abdel-Hafiz, an associate professor at the Cedars-Cancer Center. Sinai and lead author of the study along with Johanna Schafer, a postdoctoral fellow, and Xingyu Chen, a research bioinformatician at the same center.
Preliminary data not yet published show that loss of the Y chromosome also makes prostate cancers more aggressive, Theodorescu stresses. “Our researchers believe that the loss of the Y chromosome is an adaptive strategy that tumor cells have evolved to evade the immune system and survive in multiple organs,” adds Shlomo Melmed, vice president of Academic Affairs and dean of the Cedars-Cedars School of Medicine. Sinai. “This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment in the future.”
Implications for women too
Scientists need to do more research to understand the genetic connection between Y chromosome loss and T cell depletion. “If we could understand those mechanics, we could prevent that T cell depletion. We can partially reverse it with checkpoint inhibitors, but if we could prevent it from happening in the first place, there is a lot of potential to improve patient outcomes.”
Although women do not have a Y chromosome, Theodorescu suggests that these findings could have implications for them as well. The Y chromosome contains a set of related genes (paralog genes) on the X chromosome and these may play a role in both females and males. More research is needed to determine what that role might be.
“Awareness of the impact of Y chromosome loss will focus on the importance of considering sex as a variable in all scientific research in human biology,” says Theodorescu. And he concludes: “The new knowledge that we contribute with this study may explain why certain types of cancer are worse in both men and women, and what is the best way to treat them. It also shows that the Y chromosome has more functions than simply determining a person’s biological sex.” RR Garcia Abadillo
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