Abstract
Increased collagen expression in tumors is associated with increased risk of metastasis, and triple-negative breast cancer (TNBC) has the highest propensity to develop distant metastases when there is evidence of central fibrosis. Transforming growth factor-β (TGF-β) ligands regulated by cancer-associated fibroblasts (CAFs) promote accumulation of fibrosis and cancer progression. In the present study, we have evaluated TNBC tumors with enhanced collagen to determine whether we can reduce metastasis by targeting the CAFs with Pirfenidone (PFD), an anti-fibrotic agent as well as a TGF-β antagonist. In patient-derived xenograft models, TNBC tumors exhibited accumulated collagen and activated TGF-β signaling, and developed lung metastasis. Next, primary CAFs were established from 4T1 TNBC homograft tumors, TNBC xenograft tumors and tumor specimens of breast cancer patients. CAFs promoted primary tumor growth with more fibrosis and TGF-β activation and lung metastasis in 4T1 mouse model. We then examined the effects of PFD in vitro and in vivo. We found that PFD had inhibitory effects on cell viability and collagen production of CAFs in 2D culture. Furthermore, CAFs enhanced tumor growth and PFD inhibited the tumor growth induced by CAFs by causing apoptosis in the 3D co-culture assay of 4T1 tumor cells and CAFs. In vivo, PFD alone inhibited tumor fibrosis and TGF-β signaling but did not inhibit tumor growth and lung metastasis. However, PFD inhibited tumor growth and lung metastasis synergistically in combination with doxorubicin. Thus, PFD has great potential for a novel clinically applicable TNBC therapy that targets tumor-stromal interaction.
Highlights
Collagen, mainly produced by fibroblasts, is the most abundant extracellular matrix (ECM) protein in the stroma
To determine fibrosis and Transforming growth factor-β (TGF-β) activation in triple-negative breast cancer (TNBC) as a model, we used patient-derived xenograft (PDX) models that retain the essential features of the original patient tumors and metastasis to specific sites (HCI-001 and HCI-002) [19, 20], and are authentic experimental systems for studying human cancer metastasis
We showed that PFD inhibited tumor growth of TNBC in vitro by targeting cancer-associated fibroblasts (CAFs)
Summary
Mainly produced by fibroblasts, is the most abundant extracellular matrix (ECM) protein in the stroma. Increased type I collagen expression and desmoplasia/fibrosis in tumors are associated with increased risk of metastasis [2,3,4]. An increasing body of evidence suggests that activated cancer-associated fibroblasts (CAFs) can promote cancer fibrosis and progression [1, 5,6,7,8,9,10]. TGF-β ligands are often enriched in the TNBC tumor microenvironment [13,14,15,16] This suggests that targeting the desmoplasia/fibrosis and TGF-β signaling in TNBC could be of value. We have evaluated TNBC tumors that have enhanced collagen expression to determine whether we can reduce metastasis by targeting the CAFs with Pirfenidone (PFD). PFD is an orally administered pyridine (5-methyl-1-phenyl-2-[1H]pyridone) that exhibits antifibrotic properties in a variety of in vitro and animal models of fibrosis as a TGF-β antagonist, and has been clinically developed for the treatment of idiopathic pulmonary fibrosis (IPF) [17, 18]
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