Tel Aviv University researchers have discovered that breast cancer tumors boost their growth by recruiting stromal cells that originate in bone marrow. While the recruitment of bone marrow-derived fibroblasts lowers the odds of surviving breast cancer, the study suggests that targeting these cells with new therapies could be an effective way of treating the disease.
Research for the study was led by Prof. Neta Erez of the Department of Pathology at TAU's Sackler School of Medicine and conducted by Prof. Erez's former doctoral students Dr. Yael Raz and Dr. Noam Cohen. The study was published in the Journal of Experimental Medicine.
Cancer cells within solid tumors are surrounded by other cell types that, though not cancerous themselves, boost tumor growth and metastasis. Breast cancer tumors, for example, contain large numbers of fibroblast cells that promote cancer cell proliferation, inflammation and the formation of new blood vessels, which then supply the growing tumor with nutrients and oxygen. Many of these cancer-associated fibroblasts derive from neighboring breast tissue, but others come from elsewhere in the body.
The TAU researchers discovered that in mice with breast cancer, a significant number of cancer-associated fibroblasts derived from bone marrow cells called mesenchymal stromal cells (MSCs).
“We transplanted bone marrow in a transgenic mouse model of breast cancer to discover the origin of a unique subpopulation of cancer-associated fibroblasts,” says Prof. Erez. “We found that the recruitment of bone marrow-derived fibroblasts is a crucial step in breast cancer progression.
“We discovered that breast tumors are actually able to recruit MSCs from the bone marrow and then cause them to develop into fibroblasts,” Prof. Erez continues. “These bone marrow-derived fibroblasts are different from other cancer-associated fibroblasts. For example, they lack a key cell-signaling protein called PDGFRα, a surface receptor. 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.'”
The researchers found that the tumors containing bone marrow-derived fibroblasts in mouse models were more vascularized and therefore grew faster than tumors that only contained breast tissue-derived fibroblasts.
Prof. Erez and colleagues also found that human breast cancers contain fibroblasts lacking PDGFRα. This suggests that human tumors also recruit bone marrow-derived cells. Moreover, tumors containing lower levels of PDGFRα tended to be deadlier.
“Our study shows that the recruitment of bone marrow-derived fibroblasts is important for promoting tumor growth, likely by enhancing blood vessel formation,” Prof. Erez concludes. “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.”