Abstract
The lysophosphatidic acid receptor 1 (LPAR1) is mechanistically implicated in both tumor metastasis and tissue fibrosis. Previously, metastasis was increased when fulminant fibrosis was first induced in mice, suggesting a direct connection between these processes. The current report examined the extent of metastasis-induced fibrosis in breast cancer model systems, and tested the metastasis preventive efficacy and fibrosis attenuation of antagonists for LPAR1 and Idiopathic Pulmonary Fibrosis (IPF) in breast and ovarian cancer models. Staining analysis demonstrated only focal, low-moderate levels of fibrosis in lungs from eleven metastasis model systems. Two orally available LPAR1 antagonists, SAR100842 and EPGN9878, significantly inhibited breast cancer motility to LPA in vitro. Both compounds were negative for metastasis prevention and failed to reduce fibrosis in the experimental MDA-MB-231T and spontaneous murine 4T1 in vivo breast cancer metastasis models. SAR100842 demonstrated only occasional reductions in invasive metastases in the SKOV3 and OVCAR5 ovarian cancer experimental metastasis models. Two approved drugs for IPF, nintedanib and pirfenidone, were investigated. Both were ineffective at preventing MDA-MB-231T metastasis, with no attenuation of fibrosis. In summary, metastasis-induced fibrosis is only a minor component of metastasis in untreated progressive breast cancer. LPAR1 antagonists, despite in vitro evidence of specificity and efficacy, were ineffective in vivo as oral agents, as were approved IPF drugs. The data argue against LPAR1 and fibrosis as monotherapy targets for metastasis prevention in triple-negative breast cancer and ovarian cancer.
Highlights
Fibrosis is a chronic wound healing response that has lost normal controls
The current report examined the extent of metastasis-induced fibrosis in breast cancer model systems, and tested the metastasis preventive efficacy and fibrosis attenuation of antagonists for lysophosphatidic acid receptor 1 (LPAR1) and Idiopathic Pulmonary Fibrosis (IPF) in breast and ovarian cancer models
We have further explored the potential connection between fibrosis and cancer metastasis using triple-negative breast cancer and ovarian cancer model systems
Summary
Fibrosis is a chronic wound healing response that has lost normal controls. It is well studied in the lungs (as idiopathic pulmonary fibrosis), the liver, the kidney, and the skin (as systemic scleroderma). Shared cell biology characteristics include inflammation, ECM remodeling, proliferation, and the epithelial-mesenchymal transition (EMT). Pathways underlying both processes include TGF-β [5], the receptors to the phospholipid lysophosphatidic acid (LPA) [6], PDGF [7], hedgehog [8], integrins [9], chemokines [4], lysyl oxidase [10], etc. When pulmonary fibrosis was induced in mice by either radiation treatment [12] or bleomycin injection [13, 14], tumor metastasis was significantly accelerated. These data provided the experimental foundation for the hypothesis that fibrosis was a mechanistic contributor to cancer progression and a potential therapeutic target. Other reports have disagreed, suggesting that fibrosis correlated with better outcome based on changes in immunity [17]
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