- Patients with estrogen receptor (ER)-positive breast cancer are at risk of cancer recurrence even decades after treatment.
- This is because cancer cells that spread to other organs can remain dormant for many years before reawakening to form tumors.
- A new study found that disseminated cancer cells remain dormant in the lungs of young, healthy mice, but in older mice or mice with lung damage, they grow rapidly to form tumors.
- The researchers attribute this difference to a protein called PDGF-C, which is present in low levels in the lungs of young, healthy mice, but is elevated in older mice or mice with lung damage.
- These findings suggest that blocking PDGF-C using a drug could potentially prevent cancer recurrence in patients with ER-positive breast cancer.
Estrogen receptor (ER)-positive breast cancer is the most common breast cancer subtype, accounting for approximately 67%–80% of breast cancers in women. In this type of breast cancer, the cancer cells have receptors that bind to the hormone estrogen.
Research suggests that ER- and progesterone receptor-positive breast cancer is associated with better survival.
However, patients who recover from ER-positive breast cancer have a 10%–41% risk of cancer recurrence after stopping hormone cancer therapy. This is because ER-positive breast cancer cells can spread (or disseminate) to other parts of the body— a process called metastasis.
These ‘disseminated cancer cells’ can stay hidden and inactive for a long time before ‘reawakening’ to form new tumors.
Research has shown that the environment where the disseminated cancer cells settle in the body (known as the ‘microenvironment’) determines whether or not they survive and become active again.
However, researchers are still trying to understand how the environment around disseminated cancer cells controls their reactivation.
Now, new research published in Nature Cancershows how a protein found in aging or damaged lung tissues can trigger dormant cancer cells to ‘reawaken’ and develop into tumors.
Dr. David A. Cheresh, a distinguished professor and vice chair in the Department of Pathology at UC San Diego, who was not involved in the study, told Medical News Today:
“This study is significant in that it reveal[s] a mechanism to account for the role that age plays in cancer progression. It is well known that age is associated with increased incidence and death linked to many forms of cancer including ER+ breast cancers, however, this remains poorly understood at the molecular level.”
Breast cancer in young vs. old mice
To uncover the mechanism of ER-positive breast cancer recurrence, Dr. Clare M. Isacke, professor of molecular cell biology at the Institute of Cancer Research in London, and her coworkers studied mice with ER-positive mammary tumors.
Since ER-positive breast cancer can come back decades after the primary tumor, the researchers used aged mice and mice with lung damage, which mimic the environment of the aging body.
In mice with aging or damaged lungs, disseminated cancer cells rapidly grew into large tumors.
In contrast, disseminated cancer cells in the lungs of young mice with a healthy immune system did not develop into large tumors.
How dormant cancer cells get activated
A protein called “platelet-derived growth factor C” (PDGF-C) helps cancer cells to survive and grow by activating cells (fibroblasts) associated with cancer.
In this study, the researchers found that disseminated ER-positive breast cancer cells produce PDGF-C in low levels, which are sufficient for their survival, but not enough to support tumor growth.
Previous research has shown that levels of PDGF-C are low in healthy lungs but increase significantly when the lungs are damaged.
Based on their findings, Professor Isacke and her coworkers concluded that, in aging or damaged lungs, high levels of PDGF-C create an environment that promotes the growth of lung tumors. In young, healthy lungs, the low level of PDGF-C is insufficient to support tumor growth.
“This study provides solid evidence in mice that PDGF-C levels are increased in the lungs of older mice relative to younger mice and this is associated with increased metastasis in the aged animals.”
— Dr. David Cheresh
“Interestingly, tumor cells expressing PDGF-C seem to have a metastatic advantage in mice. The findings are substantiated in various models by genetic and pharmacological approaches. […] In addition, the investigators were able to find increased fibrosis and PDFG-C levels in humans as a function of age which provides correlative evidence that their findings in mice may have relevance in patients,” said Dr. Cheresh.
Potential to prevent cancer recurrence
After establishing the link between PDGF-C and the reactivation of dormant cancer cells in the lungs, the researchers explored whether the reactivation of dormant cancer cells could be stopped by using a drug that blocks PDGF-C activity.
They treated the mice with a PDGF-C blocking drug (imatinib) or with a PDGF-C blocking antibody. For both treatment groups, lung tumor growth was significantly reduced.
Since imatinib is already used to treat chronic myeloid leukemia in both old and young patients and is well-tolerated, it presents a promising route to prevent cancer recurrence in ER-positive breast cancer patients.
Targeting the tumor ‘reawakening’ mechanism
Dr. Frances K. Turrell, study first author and postdoctoral training fellow in the Division of Breast Cancer Research at The Institute of Cancer Research, said in a press release
“We now plan to better unpick how patients might benefit from the existing drug imatinib, and in the long term aim to create more specific treatments targeted at the ‘reawakening’ mechanism.”
Professor Clare Isacke said: “Next we need to pinpoint when these age-related changes happen and how they vary between people so that we can create treatment strategies that prevent cancer cells ‘reawakening’.”
In his comments to MNT, Dr. Cheresh expressed hope that the mechanism of cancer recurrence described in this study for ER-positive breast cancer could also apply to other types of cancer.
“One question that […] will be important to address is: how general is this phenomenon? Given that many cancers are more aggressive in elderly patients, it would be important to establish whether the mechanism outlined in this study relates to other cancers that also metastasize to the lung and or other organs.”
— Dr. David Cheresh
“It would seem unlikely that PDGF-C levels found in older patients is linked exclusively to the progression of ER+ breast cancer,” he added.
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