The human body couldn’t survive without fibroblasts – connective tissue cells that synthesize the extracellular matrix and collagen and play a critical role in wound healing wounds and injuries. Sensing tissue damage, they gravitate to the site of a wound, triggering an inflammatory response that mends the physical trauma.
But they are a double-edged sword. A new study was titled “NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis. Conducted by researchers at Tel Aviv University (TAU) and recently published in the prestigious journal Nature Communications, the study found that fibroblasts also play a devastating role in the development of breast cancer. In malignant tumors, fibroblasts are triggered to respond to tissue damaged by tumors and create inflammation. This inflammation facilitates tumor growth as well as metastases in the lungs.
“We have shown, for the first time, that in breast cancer, these fibroblasts activate a ‘misguided’ wound healing response, responding to the tissue damage caused by the cancerous growth,” explained Prof. Neta Erez of the university’s Sackler Faculty of Medicine who led the research for the study. “Inhibiting these inflammatory signalling pathways may be beneficial in preventing metastatic relapse of breast cancer,” she suggested.
She conducted the with former TAU student Yoray Sharon and TAU MD-PhD student Nour Ershaid in Erez’s lab at TAU’s pathology department.
According to the scientists the inflammatory response of fibroblasts not only supports local tumor growth in the breast, but it also creates a hospitable niche for metastatic growth in the lungs. “The fibroblasts are ‘activated’ and, because of this activation, they recruit immune cells and affect blood vessels,” added Erez. “In other words, breast tumors ‘hijack’ the physiologic response to tissue damage to facilitate their growth, and create a niche in a distant organ, the lungs, by ‘remote control.’ ”
Research for the study was performed using transgenic and transplantable mouse models of breast cancer and was validated in human samples of breast cancer and in human expression data.
The researchers isolated fibroblasts in transgenic mice from different stages of breast carcinogenesis and profiled the expression of all their genes. They were then able to identify that the inflammation pathway is unregulated in cancer-associated fibroblasts, as compared with fibroblasts isolated from normal mammary glands. Finally, they performed functional experiments to understand the role of this pathway in breast cancer.
“Breast cancer remains one of the leading causes of cancer-related deaths, and the most frequently diagnosed cancer in women,” they wrote. “The tumor microenvironment plays a crucial role in cancer growth and metastasis. Cancer-associated fibroblasts (CAFs) are the most prominent cell type in the microenvironment of breast tumors, and their abundance is correlated with a higher grade of malignancy and with poor prognosis. CAFs facilitate tumor progression by secreting growth-promoting factors, by enhancing angiogenesis and by remodelling the extracellular matrix. Inflammation is now established as a hallmark of cancer, and CAFs were shown to be key players in mediating tumor-promoting inflammation due to their capability to recruit immune cells and to affect the tumor-immune system interactions.” Until now, the triggers and the molecular signaling that regulate the inflammatory role of CAFs are still poorly characterized.
“Our findings encourage the design of preclinical and clinical studies to examine the benefits of targeting the inflammation pathway in breast cancer, which may be effective in blocking metastatic relapse,” concluded Erez. “We are now studying the microenvironment of metastasis in an effort to identify targets for preventive intervention that may inhibit metastatic relapse.
