Increasing chronological age is the most significant risk factor for
cancer. Recently, we proposed a new paradigm for understanding the role of the aging and the tumor microenvironment in
cancer onset. In this model,
cancer cells induce oxidative stress in adjacent stromal fibroblasts. This, in turn, causes several changes in the phenotype of the fibroblast including
mitochondrial dysfunction,
hydrogen peroxide production, and aerobic glycolysis, resulting in high levels of L-
lactate production. L-
lactate is then transferred from these glycolytic fibroblasts to adjacent epithelial
cancer cells and used as "fuel" for oxidative mitochondrial metabolism. Here, we created a new pre-clinical model system to directly test this hypothesis experimentally. To synthetically generate glycolytic fibroblasts, we genetically-induced
mitochondrial dysfunction by knocking down TFAM using an sh-
RNA approach. TFAM is
mitochondrial transcription factor A, which is important in functionally maintaining the mitochondrial respiratory chain. Interestingly, TFAM-deficient fibroblasts showed evidence of
mitochondrial dysfunction and oxidative stress, with the loss of certain mitochondrial respiratory chain components, and the over-production of
hydrogen peroxide and L-
lactate. Thus, TFAM-deficient fibroblasts underwent metabolic reprogramming towards aerobic glycolysis. Most importantly, TFAM-deficient fibroblasts significantly promoted
tumor growth, as assayed using a human
breast cancer (MDA-MB-231) xenograft model. These increases in glycolytic fibroblast driven
tumor growth were independent of
tumor angiogenesis. Mechanistically, TFAM-deficient fibroblasts increased the mitochondrial activity of adjacent epithelial
cancer cells in a co-culture system, as seen using MitoTracker. Finally, TFAM-deficient fibroblasts also showed a loss of
caveolin-1 (Cav-1), a known
breast cancer stromal
biomarker. Loss of stromal fibroblast Cav-1 is associated with early
tumor recurrence,
metastasis, and treatment failure, resulting in poor clinical outcome in
breast cancer patients. Thus, this new experimental model system, employing glycolytic fibroblasts, may be highly clinically relevant. These studies also have implications for understanding the role of
hydrogen peroxide production in oxidative damage and "host cell aging," in providing a permissive metabolic microenvironment for promoting and sustaining
tumor growth.