Bladder cancer, if the cells lose the Y chromosome the disease is more aggressive

Bladder cancer, if the cells lose the Y chromosome the disease is more aggressive

The loss of the Y chromosome is a natural process that occurs in the course of male aging in some cell types more than in others, to a different extent from individual to individual. Now, thanks to research by Cedars-Sinai Cancer, we know that bladder cancer cells that have lost the Y escape the attack of the immune system, to the full advantage of the disease, which becomes more aggressive due to the lost chromosome. However, be careful, according to the same study, which is published in Nature, the same condition that makes the tumor worse also transforms it into a mass more sensitive to treatment with immune checkpoint inhibitors, a cure that patients already have available. Now, it goes without saying that, if before treating men with bladder cancer we went looking for the Y chromosome in their cells (if there is any and how much there is), oncologists could treat the disease with greater awareness, using more targeted and more effective drugs for their individual patient. The study therefore added an important piece to the knowledge of tumor biology, because it found a connection "never before found, between the loss of the Y chromosome and the immune system's response to cancer", as stated by Dan Theodorescu, director of Cedar -Sinai and co-author of the publication. But it has also laid the foundations for a new possibility of tailoring oncology to the individual patient even better and better.

A great loss

Males have an X chromosome and a Y chromosome in each somatic cell (in spermatozoa, which are germ cells, there is either a Y or an X) but over the years, due to a natural process of accumulation of mutations over time, a part of their cells begin to lose the Y chromosome. The loss occurs mainly in cells with rapid turnover, such as blood cells, and does not occur in reproductive cells (therefore it cannot be transmitted to children). The authors of a study published in 2022 in Science estimated that loss of Y occurs in about 40% of 70-year-olds. A phenomenon already associated with heart disease and Alzheimer's disease. And also to different types of cancer. For example, in 10-40% of cases, bladder cancer.

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The positive effects of the discovery

The discovery published in Nature may help oncologists tailor treatments for a disease whose numbers are growing everywhere. In Italy, in 2022 bladder cancer diagnoses were 8% more than in 2017, with 29,200 cases, 23,000 of which concerned males. It is therefore clear that measuring the loss of Y in male patients can help to better define the therapeutic. And in fact the researchers are developing a test that allows to quantify the presence of Y within the cells surrounding the bladder starting from the proteins expressed by some genes present on this chromosome.

Two groups and a tumor with an easier life

But let's go back to the studio. The authors reviewed all data from two groups of men: those in the first group had muscle invasive bladder cancer and had undergone surgical removal of the organ, but had not been treated with an immune checkpoint inhibitor. The other group, on the other hand, consisted of men with the same disease but in the context of a clinical trial they had been treated with an immune checkpoint inhibitor. The authors found that patients with loss of Y from the first group (i.e., those not treated with an immune checkpoint) had a worse prognosis, but those without Y from the second group (i.e., treated with an immune checkpoint) had a very poor overall survival. improve.

Through a long series of experiments conducted both in vitro (using cultured tumor cells) and in vivo (using laboratory mice), both in the presence and absence of the Y chromosome and an intact immune system, the authors concluded that disappearance of Y would make men lose T cells, and without these cells that deal with the body's defense, the tumor has a much easier life. “When cells lose their Y chromosome, they run out of T cells. But without T cells, bladder cancer grows aggressively,” Theodorescu wrote.

Achilles heel

But the weapon that makes him stronger (the loss of the Y chromosome) is the same that weakens him in the presence of immune checkpoint inhibitors. A therapy, as the Cedar-Sinai researchers explained, which is capable of reversing the depletion of T lymphocytes (basically blocking the process), putting the immune system back in a position to be able to effectively attack bladder cancer. And perhaps not only that of the bladder, among other things, since preliminary data not yet published indicate that the loss of the Y chromosome also makes prostate tumors more aggressive.

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The link between Y and T

But to understand the genetic link between Y-chromosome loss and T-cell depletion, further studies are needed. "If we could understand those mechanisms, we could prevent T-cell exhaustion," Theodorescu continued. "T-cell depletion can be partially reversed with checkpoint inhibitors," he added, but if we could stop it from happening sooner, patient outcomes would be better.

An adaptation and a step forward

"Our researchers believe that the loss of the Y chromosome could be an adaptive strategy that the tumor has developed to evade the immune system and survive multiple different organs," commented Shlomo Melmed, executive vice president of Academic Affairs and dean of the Faculty of Science. medicine of Cedars-Sinai. "This exciting advance adds to our understanding of cancer biology and could have far-reaching implications for future cancer treatment," he said.

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The Y chromosome and women

Women do not have a Y chromosome, as we know. But it is said that this study in Nature could not have positive effects for them too. The Y chromosome in fact contains genes that are related to other genes found on the X chromosome. They are the so-called paralogous genes, i.e. different genes which however derive from a single ancestral gene and which retain an affinity, perhaps even in their functions. Well, paralogous genes could play a similar role in both women and men: to understand what role it is, we need to work.

"Understanding what it means to lose the Y chromosome will stimulate discussion about how important it is to consider sex as a variable in all scientific research in human biology," said Theodorescu. For example, “the new fundamental knowledge that we provide – he added and concluded – can explain why some types of cancer are more aggressive in men, or in women, as well as the best way to treat them. And they also tell us that the Y chromosome doesn't just determine human biological sex."

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