Breast cancer risk increases with age, but while scientists have long studied cellular changes that take place in the body over time, a new study published by Bahcecioglu et al in Advanced Science examined how the extracellular matrix—an underlying network of molecules and proteins that provide the structure for tissue growth—can trigger invasive cancer–related genes.
“This is the first time we’ve been able to show direct evidence that the aging extracellular matrix itself is changing the phenotype of normal epithelial cells,” said principal study investigator Pinar Zorlutuna, PhD, the Sheehan Family Collegiate Professor of Engineering at The University of Notre Dame. “Clinical data shows that aging is a big risk factor for breast cancer, and we wanted to investigate why that is. Cellular aging has been explored, but what we didn’t know was what effect aging had on the extracellular matrix.”
Study Methods and Findings
Dr. Zorlutuna and her team studied the extracellular matrix tissue in healthy younger and older mouse models, seeding the matrixes with normal mammary epithelial cells and cancerous cells.
The research team found changes in the biochemical composition, structure, and stiffness of the aged extracellular matrix. As the tissue ages, protein levels and collagen production decrease, and collagen fibers become thinner but curlier and form a denser “mesh.” Lack of collagen production can leave the integrity of the extracellular matrix vulnerable to invasive tumor cells, while thinner and curlier fibers may contribute to the metastasis of cancer cells.
“The normal epithelial cells in the aged matrix started to express more invasiveness-related genes associated with breast cancer,” Dr. Zorlutuna said. “And we identified the gene critical to this transition, called lysyl oxidase (LOX).”
Normal epithelial cells grown on aged extracellular matrixes showed an elevated expression of LOX, preventing the formation of healthy cellular structures. In the models containing cancer cells, those cells became more motile and invasive. When LOX was inhibited, the study showed the original phenotype of the cells could be rescued—meaning the epithelial cells returned to normal and were less motile as they were in young and healthy extracellular matrix models.
The results could help scientists gain a better understanding of cell migration and invasion in aged tissues and inform new methods for the prognosis, diagnosis, and prevention of breast cancer.
Dr. Zorlutuna said she and her team will continue to study the extracellular matrix as it relates to cancer initiation and progression.
Disclosure: For full disclosures of the study authors, visit onlinelibrary.wiley.com.
