The aging extracellular matrix has been shown to upregulate cancer-related genes and drives aggressive and invasive cancer-like phenotypes.
Currently, breast cancer is the second biggest cause of death in women in the United States, with an estimated 284,200 new cases expected this year, and more than 40,000 women are predicted to die from breast cancer this year.
Breast cancer can affect women of all ages, but the risk of breast cancer increases with age. There are several reasons for the age-related increased risk of cancer, with age-related genetic alterations in cells one of the most studied. A new study recently conducted by researchers at the University of Notre Dame has revealed another potential cancer trigger, with the study suggesting the extracellular matrix could be triggering invasive cancer genes in older women.
The extracellular matrix (ECM) is an intricate three-dimensional network of extracellular molecules and minerals that provides structural and biochemical support to cells. The researchers found that the aging ECM in breast tissue is sufficient, by itself, to trigger normal healthy mammary epithelial cells to change into an invasive, cancer-like phenotype and that the ECM network promotes the motility and invasiveness of breast cancer (DA-MB-231) cells.
The researchers analyzed ECM tissue from young and old mouse models and introduced normal, healthy breast epithelial cells and cancer cells. The researchers identified age-related changes in the biochemical composition, structure, and stiffness of the ECM from older mice, which is due to a decrease in collagen production and a fall in protein levels. With aging, the structure of collagen changes, resulting in the fibers becoming more curvier and thinner which forms a more compacted collagen network. The researchers note that the reduction in collagen production with aging leaves the ECM vulnerable to invasive cancer cells and the curvier fibers may contribute to cancer cells metastasizing.
In their study, the researchers found that normal epithelial cells added to the aged ECM matrix started expressing more genes associated with the invasiveness of breast cancer, with one gene in particular critical to the transition – lysyl oxidase (LOX) – overexpressed.
When normal epithelial cells were grown on the ECM of older mice there was elevated expression of LOX, which prevented healthy cellular structures from forming. When cancer cells were introduced into the ECM of older mice, the cells became more motile and invasive. When the researchers inhibited LOX, the epithelial cells returned to their normal, healthy phenotype and matched the phenotype of the epithelial cells in the ECM tissue of younger mice.
“These results show for the first time that the aging ECM harbors key biochemical, physical, and mechanical cues contributing to invasive and cancer-like behavior in healthy and cancer mammary cells,” explained the researchers in the paper. “Differential response of cells to young and aged ECMs can lead to identification of new targets for cancer treatment and prevention.”
You can read more about the research in the paper – Aged Breast Extracellular Matrix Drives Mammary Epithelial Cells to an Invasive and Cancer-Like Phenotype – which was recently published in Advanced Science. DOI: 10.1002/advs.202100128