Cancer-associated fibroblasts fuel breast cancer growth
Jill Russell, Ph.D.
Researchers at MD Anderson have discovered that cancer-associated fibroblasts (CAF) help fuel the growth of breast tumors. Their findings were published in Cell Reports on June 2, and an image from their study was featured on the cover of the journal issue.
Raghu Kalluri, M.D., Ph.D., professor and chair of Cancer Biology and senior author for this study, explains, “Tumors are made of many more non-cancer cells than cancer cells. One such cell type is fibroblasts. Here, we show that cancer subjugates the fibroblasts that arrive into the tumor to support the growth and spread of breast cancer.”
Study reveals distinct metabolic profile of cancer-associated fibroblasts
Using mouse models, the researchers found that cancer-associated fibroblasts that express α-Smooth muscle actin (αSMA) promote tumor growth. Depleting αSMA+ CAFs in established tumors in various mouse models significantly decreased primary tumor growth and angiogenesis but did not affect mouse body weight. Targeting the αSMA+ CAFs increased hypoxia in the primary tumor. However, genetically depleting αSMA+ CAFs did not affect metastatic growth and, in some cases, increased metastasis.
The researchers also created a catalogue of fibroblasts from patient-derived biopsy samples of tumor tissue, and benign tissue. They found that cancer-associated fibroblasts have a distinct metabolic profile with increased glycolysis and increased lactate production compared to fibroblasts from benign tissue.
In both mouse models and patient samples, the researchers found that lactate and metabolites produced by cancer-associated fibroblasts are transferred to cancer cells and fuel cancer growth, specifically nucleic acid metabolism. Cancer cells hijack metabolites from the tumor microenvironment.
The researchers found that hypoxia induces epigenetic modification and metabolic reprogramming of normal fibroblasts to a CAF-like phenotype via hypoxia-inducible factor 1-alpha (HIF-1α). Lisa Becker, Ph.D., a graduate student in Kalluri’s lab and first author of the study, explains, “As tumors grow and the oxygen supply is limited, fibroblasts undergo epigenetic reprogramming to increase glycolysis and other metabolic pathways and produce more metabolites, which in turn fuels tumor growth.”
The researchers identified several deregulated metabolic pathways in cancer-associated fibroblasts, and these pathways could be novel therapeutic targets. For example, Food and Drug Administration-approved drugs that interfere with glycolysis could be used to target cancer-associated fibroblasts and thus impair tumor growth. Becker says, “Our findings are really exciting because this therapeutic strategy might be available for all patients with breast cancer, regardless of subtype, because we are targeting fibroblasts, not cancer cells.”
Cover image used in Cell Reports, which shows fibroblasts undergoing
epigenetic reprogramming to increase glycolysis and other metabolic
pathways and produce more metabolites, which in turn fuels breast tumor
growth: the green stain shows Carboxic anhydrase levels (hypoxia), the
fibroblasts are stained red (αSMA), and cell nuclei are stained blue.
We show that cancer subjugates the fibroblasts that arrive into the
tumor to support the growth and spread of breast cancer.