In 2019, just before the COVID-19 pandemic struck, oncology researcher Barry Hudson moved his laboratory from the University of Miami to Georgetown University. Many universities dialed down research activities due to the pandemic, causing a slight delay in setting up the new lab.
“What that led to was, we ended up with…a lot of mice,” said Hudson. By the time the team restarted their work, the majority of the mice were more than one year old, reaching old age. Hudson recognized a unique opportunity to study cancer in these older animals, which is particularly relevant since older people experience worse outcomes in some cancers, including breast cancer.1
Despite this fact, most breast cancer researchers use two- to three-month-old mice for their work, which are equivalent in age to 15-20-year-old humans.2 “People didn't really know what happened to cancers in older mice,” said Hudson.
Now, by using aged mice, Hudson and his team discovered that aging significantly increased breast cancer metastasis via a cell surface receptor that contributes to inflammation.3 Their findings, published in Communications Biology, highlight how aging alters the host environment to boost cancer aggression and offer potential therapeutic targets to contain metastasis in older patients with cancer.
A few researchers have shown that aged microenvironment in mice is more permissive to metastasis compared to young ones, said Frances Turrell, a cancer biologist at Manchester Cancer Research Centre, who investigates how aging influences tumors and their metastasis, and was not involved in the study. “[This] is another study that really demonstrates that we need to be studying breast cancer metastasis in an aged setting.”
Breast Cancer Metastasis Increases with Aging
For their study, Hudson and his team implanted different types of breast cancer cells either into three-month-old mice corresponding to young 20-year-olds, or into 21-month-old mice comparable in age to 65-year-old people. Aged mice showed significantly higher lung metastasis compared to younger mice, even when primary tumor growth was similar across the ages.
While Hudson expected heightened cancer aggression with age, he was surprised by the extent. “When I first saw it, I didn’t believe it,” he recalled. “It was very striking.”
The researchers next investigated the molecular mechanisms underlying this observation. They focused on the receptor for advanced glycation end-products (RAGE), a proinflammatory molecule that binds ligands involved in aging and cancer. Researchers have previously shown that RAGE enhances tumor cell survival and invasion, promoting breast cancer metastasis.4
When they injected breast cancer tumors into old mice lacking genes encoding RAGE, Hudson and his team observed significantly less metastasis compared to wild type mice. Consistent with this, the researchers also observed increased levels of molecules that activate RAGE in tumors and metastasized tissue of older mice.
Fluorescence microscopy revealed that these ligands localized with myeloid immune cells, suggesting that immune cells in the tumor microenvironment, rather than tumor cells themselves, produce RAGE ligands in aged mice. The researchers also observed enhanced secretion of proinflammatory and tumor progression-promoting cytokines in older wild type mice, which was absent in RAGE-knockout animals. This indicated that host RAGE contributes to a pro-metastatic tumor microenvironment in aged animals.
This evidence indicating the crucial role of RAGE in age-dependent metastasis was “pretty satisfying,” said Hudson.
Immunofluorescence of lung tissue from an aged mouse with metastatic breast cancer revealed inflammatory cells expressing a RAGE ligand (red), RAGE (green), and nuclei (blue).
Sunita Chopra (Hudson Laboratory), Georgetown Lombardi Comprehensive Cancer Center
Clinical Implications of RAGE-Dependent Cancer Aggression in Aging
Finally, Hudson and his team investigated the clinical relevance of their findings by analyzing data from more than 1,000 people with breast cancer. They observed that higher expression of the gene encoding RAGE was linked with worse patient outcomes, and this correlation was even greater in women over the age of 55.
Hudson said that these results could offer potential therapeutic targets specifically in older people with cancer. Studying cancer in young mice reflects a different host state, he added. “Some of the reasons why drugs don't work [could be that] they're developed in an immune state that isn't there in most the people who are getting the disease,” he explained.
Turrell agreed. “By studying these processes in [young] mice, we're missing out on a lot of relevant biological mechanisms that are underpinning metastasis,” she said. “[This study] highlighted some age-dependent mechanisms.”
However, Turrell noted that the researchers only investigated lung metastasis. “In breast cancer, we get metastasis at other sites as well: the bone, the liver, and the brain,” she said. She added that it remains to be seen whether these pathways also drive increased metastasis in other breast cancer subtypes as well as other cancers.
Turrell also noted that the researchers used a whole-body RAGE knockout model. “So, you don't really know which cells or compartments were really contributing and important in that phenotype. So, it’s quite difficult to pin down the mechanism,” she said.
“We really sort of scratched the surface in terms of mechanism,” agreed Hudson. “We hinted towards it, but we didn’t delve into…what is the major cell type that's driving this in the microenvironment.” He added that RAGE is likely just one of the molecules contributing to age-associated metastasis.
The researchers plan to investigate this further and also study the effect of drugs targeting RAGE in cancer metastasis in older mice. “[Age] is the strongest risk factor for cancer out there,” said Hudson. While people can’t modify their chronological age for better cancer outcomes, “Can we use molecules and approaches like this to influence how people respond to cancer therapy?” he said.
- Jackson EB, et al. Does age affect outcome with breast cancer? Breast. 2023;70:25-31.
- Wang S, et al. Correlation between mouse age and human age in anti-tumor research: Significance and method establishment. Life Sci. 2020;242:117242.
- Miller P, et al. Aging promotes a RAGE-dependent increase in breast cancer metastasis. Commun Biol. 2026
- Kwak T, et al. Targeting of RAGE-ligand signaling impairs breast cancer cell invasion and metastasis. Oncogene. 2017;36(11):1559-1572.
