Why spread breast cancer cells wake up again

Why spread breast cancer cells wake up again

Scattered cancer cells. © Koto feja/ Stock

In the most common type of breast cancer, so-called estrogen receptor-positive breast cancer, metastases often appear years to decades after cancer therapy. Scientists may now have found out why this is so. Responsible is therefore a high level of the protein PDGF-C, which occurs primarily in older women and in those with previously damaged lung tissue. The increased concentration of this protein promotes the “reawakening” of disseminated cancer cells from years of dormancy and promotes their growth into metastases. The good news: In experiments with mice, a leukemia drug was able to switch off this “wake-up” and prevent metastases.

Around 80 percent of all breast cancer patients suffer from estrogen receptor-positive breast cancer (ER+). The cancer cells have docking points for the female sex hormone estrogen on their surface and their growth is promoted by the presence of the hormone. In this type of cancer, the primary tumor is usually easier to treat than in the negative variant. However, the long-term effects are particularly insidious: spread cancer cells of this type of tumor can often remain dormant in the body for years and, as “sleepers”, can withstand even aggressive chemotherapy. Only years or even decades after the apparently successful cancer treatment do these breast cancer cells “wake up” again and then generate metastases in the lungs, liver, bones and other organs. These breast cancer metastases can then be treated by trying to curb their growth. But they can no longer be eliminated.

Searching for clues in mice with cancer

However, what causes the dormant spread cancer cells to wake up again is largely unclear. Similar to other cancer metastases, however, oncologists assume that the microenvironment of these cells plays a decisive role – the environment in which the disseminated breast cancer cells have settled. Certain messenger substances, stress factors or metabolic influences can contribute to promoting the growth of metastases. A research team led by Frances Turrell from the Institute of Cancer Research in London has investigated another influencing factor. There were already indications in earlier studies that certain signaling molecules in the blood of elderly cancer patients promote the formation of metastases and can make the spread cancer cells more aggressive. Turrell and her team therefore investigated whether such a molecule might also influence the reawakening of the spread breast cancer cells.

For their study, the scientists examined mice of different ages in which they had induced estrogen receptor-positive breast cancer. In all of the mice, breast cancer cells then spread from the primary tumor to other parts of the body, including the lungs and liver. However, the investigations revealed that the spread cancer cells in the young mice multiplied and metastasized only to a very small percentage. In the older mice, on the other hand, the breast cancer cells usually grew into large secondary tumors. “The older animals had a larger number and more widespread metastases with mostly prominent lesions in the lung parenchyma,” report the researchers. This was also the case with previously damaged, scarred lung tissue.

PDGF-C proteins as an alarm clock for dormant cancer cells

Using a gene expression analysis, Turrell’s team then investigated what was happening in the test animals at the molecular level. It turned out that in the mice, which were more prone to secondary tumors, numerous genes were more active, which, among other things, activate connective tissue cells in the lungs and cause scarring. A group of genes that encode so-called PDGF-C proteins was particularly striking. These proteins are produced by connective tissue cells and certain immune cells and have long been suspected of promoting the growth of some types of cancer, as Turrell and her colleagues explain. They conclude from their results that an increased level of PDGF-C also promotes the awakening of dormant cancer cells and their growth into metastases. This would also explain why middle-aged women and those with previously damaged organs are more frequently affected.

However, the knowledge of the effect of PDGF-C on the reawakening of spread breast cancer cells also offers a starting point for new therapies: In their study, Turrell and her colleagues treated some of the diseased mice with the cancer growth blocker imatinib. Actually, this drug is used in patients with chronic myeloid leukemia. They administered an antibody against PDGF-C to a second group of mice. It was found that both imatinib and the antibody treatment significantly reduced the growth of breast cancer metastases in the animals’ lungs. It did not matter whether the drugs had been administered to the mice before or after the development of tumors. According to the researchers, there is hope that the late formation of metastases in estrogen receptor-positive breast cancer can be slowed down or even stopped completely in the future.

“We now want to better understand how patients might benefit from the existing drug imatinib, and in the longer term we want to develop more specific treatments that target the ‘reawakening’ mechanism,” explains Turrell.

Source: Frances Turrell (Institute of Cancer Research, London) et al., Nature Cancer, doi: 10.1038/s43018-023-00525-y

Recent Articles

Related Stories

Stay on op - Ge the daily news in your inbox