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Abstract
The tumor microenvironment is fundamental to cancer progression, and the influence of its mechanical properties is increasingly being appreciated. Tamoxifen has been used for many years to treat estrogen‐positive breast cancer. Here we report that tamoxifen regulates the level and activity of collagen cross‐linking and degradative enzymes, and hence the organization of the extracellular matrix, via a mechanism involving both the G protein‐coupled estrogen receptor (GPER) and hypoxia‐inducible factor‐1 alpha (HIF‐1A). We show that tamoxifen reduces HIF‐1A levels by suppressing myosin‐dependent contractility and matrix stiffness mechanosensing. Tamoxifen also downregulates hypoxia‐regulated genes and increases vascularization in PDAC tissues. Our findings implicate the GPER/HIF‐1A axis as a master regulator of peri‐tumoral stromal remodeling and the fibrovascular tumor microenvironment and offer a paradigm shift for tamoxifen from a well‐established drug in breast cancer hormonal therapy to an alternative candidate for stromal targeting strategies in PDAC and possibly other cancers.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and one of the leading causes of cancer-related death despite substantial efforts in recent years aimed at optimizing therapies
Given that we observed a significant downregulation of lysyl oxidase (LOX)-L2 after tamoxifen treatment in the analysis of the gene profile of Pancreatic stellate cells (PSCs), and LOX-L2 is elevated in PDAC and regulated by hypoxia-inducible factor-1 alpha (HIF-1A) [23,24], we focused first on this member of the LOX family and tested the LOXL2 levels in PSCs following tamoxifen treatment
We found that tamoxifen promotes multiple changes in PSCs and the microenvironment of pancreatic cancer through a G protein-coupled estrogen receptor (GPER)-dependent mechanism that induces a negative regulation of hypoxia-inducible factor (HIF)-1A by decreasing actomyosindependent PSC contractility and matrix stiffness mechanosensing (Fig 8)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and one of the leading causes of cancer-related death despite substantial efforts in recent years aimed at optimizing therapies. PDAC is distinguished by a strong desmoplasia in the tumor microenvironment or stroma that has been associated with aggressiveness of the disease [1], but has been reported to restrain tumor growth [2,3], suggesting that stromal contribution varies depending on the context. PDAC is one of the stiffest solid carcinomas, which intuitively leads to the idea of disrupted mechanical communication between cancer and stromal cells and unbalanced tissue tension within the extracellular matrix (ECM). A recent study has shown that enhanced mechanosignaling in the tumor epithelia can promote PDAC progression in mouse models, overriding the need for p53 mutation [4], while another study showed that targeting focal adhesion kinase in vivo could reduce fibrosis and sensitize pancreatic cancer cells to immunotherapy [5]
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