Despite extensive research, breast cancer remains one of the leading causes of cancer-related deaths in women in the Western world. One case of such a malignancy can be very different from another. Some patients undergo surgery and recover, while other women (and, in one in 100 cases, men) struggle with radiotherapy, chemotherapy and immunotherapy but still have difficulty fighting it because the tumors are resistant to treatment and spread to other organs.
Basic scientists are eagerly trying to find out what causes the differences and how to help patients who have more complicated cases.
Researchers in Israel have now discovered that breast tumors can boost their growth by recruiting “mesenchymal stromal cells” (MSCs) originally formed in the bone marrow. The study, just published in the Journal of Experimental Medicine, reveals that the recruitment of biological cells of connective tissue called fibroblasts that develop in the bone marrow lowers the odds of surviving breast cancer. Fibroblasts play a critical role in wound healing. Knowing all this, the researchers suggest that targeting these cells could be an effective way of treating the disease.
Within solid tumors, cancer cells are surrounded by other cell types that, though not cancerous themselves, boost tumor growth and their spread to other organs in the body (metastasis). Breast tumors, for example, contain large numbers of fibroblast cells that promote the spread of cancer cells, inflammation and the formation of new blood vessels to supply the growing tumor with nutrients and oxygen. Many of these cancer-associated fibroblasts are derived from the neighboring breast tissue, but others seem to come from elsewhere in the body.
Dr. Neta Erez and her colleagues at the Tel Aviv University’s Sackler School of Medicine performed their experiments using six- to eight-week old female mice with breast cancer. They discovered that a significant number of cancer-associated fibroblasts are derived from bone marrow cells called MSCs. The researchers found that breast tumors can recruit MSCs from the bone marrow and cause them to develop into fibroblasts.
These bone marrow-derived fibroblasts are different from other cancer-associated fibroblasts. They lack, for example, a key cell signaling protein called PDGFRα. But bone marrow-derived fibroblasts are particularly effective at stimulating the formation of new blood vessels because they produce large amounts of a protein called “clusterin.” Tumors containing bone marrow-derived fibroblasts therefore had more blood vessels that provide oxygen to the cells. The tumors thus grew faster than tumors that only contained fibroblasts that originated in the breast.
Erez and colleagues found that human breast cancers also contain fibroblasts lacking PDGFRα, suggesting that human tumors may also recruit bone marrow-derived cells. Moreover, tumors containing lower levels of PDGFRα tended to be deadlier, suggesting that the recruitment of bone marrow-derived fibroblasts is a crucial step in breast cancer progression.
“Our study shows that the recruitment of bone marrow-derived fibroblasts is important for promoting tumor growth, likely by enhancing blood vessel formation,” Erez explained. “Understanding the function of these cancer-associated fibroblasts could form the basis of developing novel therapeutic manipulations that co-target bone marrow-derived fibroblasts as well as the cancer cells themselves.”