Roles of Fibroblasts in Microenvironment Formation Associated with Radiation-Induced Cancer

In tumor tissues, activated stromal fibroblasts, termed cancer-associated fibroblasts (CAFs), exhibit similar characteristics to myofibroblasts. CAFs promote cancer cell differentiation and invasion by releasing various factors, such as growth factors, chemokines, and matrix-degrading proteases, into neighboring tumor cells. However, the roles of tumor microenvironment in case of radiation-induced carcinogenesis remain poorly understood. We recently revealed that mitochondrial oxidative stress causes tumor microenvironment formation associated with radiation-induced cancer. Repeated low-dose fractionated radiation progressively damages fibroblast mitochondria and elevates mitochondrial reactive oxygen species (ROS) levels. Excessive mitochondrial ROS activate transforming growth factor-beta (TGF-β) signaling, thereby inducing fibroblasts activation and facilitating tumor microenvironment formation. Consequently, radiation affects malignant cancer cells directly and indirectly via molecular alterations in stromal fibroblasts, such as the activation of TGF-β and angiogenic signaling. This review summarizes for the first time the roles of mitochondrial oxidative stress in microenvironment formation associated with radiation-induced cancer. This review may help us understand the risks of exposure to low-dose radiation. The cross talk between cancer cells and stromal fibroblasts contributes to the development and progression of radiation-induced cancer.