Abstract
Cancer associated fibroblasts (CAF) play a key role in cancer progression and metastasis. Diminished TGFβ response on CAF correlates with poor outcome and recurrence in cancer patients. Mechanisms behind lost TGFβ signaling on CAF are poorly understood, but, utilizing MMTV-PyMT mouse model, we have previously demonstrated that in tumor microenvironment myeloid cells, producing adenosine, contribute to downregulated TGFβ signaling on CAFs. In the current work, we performed serial in vitro studies to investigate the role of adenosine/TGFβ axis in mouse mammary fibroblast functions, i.e., proliferation, protein expression, migration, and contractility. We found that adenosine analog NECA diminished TGFβ-induced CCL5 and MMP9 expression. Additionally, we discovered that NECA completely inhibited effect of TGFβ to upregulate αSMA, key protein of cytoskeletal rearrangements, necessary for migration and contractility of fibroblasts. Our results show that TGFβ increases contractility of mouse mammary fibroblasts and human fibroblast cell lines, and NECA attenuates theses effects. Using pharmacological approach and genetically modified animals, we determined that NECA effects on TGFβ pathway occur via A2A/A2B adenosine receptor—AC—PKA dependent manner. Using isolated CD11b+ cells from tumor tissue of CD73-KO and CD39-KO animals in co-culture experiments with ATP and AMP, we confirmed that myeloid cells can affect functions of mammary fibroblasts through adenosine signaling. Our data suggest a novel mechanism of interaction between adenosine and TGFβ signaling pathways that can impact phenotype of fibroblasts in a tumor microenvironment.
Highlights
It is recognized that the tumor microenvironment (TME), comprising of different cell types and extracellular matrix (ECM), can determine the tumor fate [1, 2]
In our recently published work, in MMTV-PyMT mouse tumor model, we have determined that impact of TGFβ on CD73 expression on myeloid cells associates with the ability of adenosine to regulate TGFβ signaling on mammary fibroblasts [22]
We reported that this paracrine two-cell type negative feedback loop mechanism may contribute to a novel adenosinergic mechanism of TGFβ regulation in the tumor microenvironment and represents a potential therapeutic target
Summary
It is recognized that the tumor microenvironment (TME), comprising of different cell types and extracellular matrix (ECM), can determine the tumor fate [1, 2]. Fibroblasts play a key role in the formation and remodeling of ECM structures in TME [13,14,15]. In addition to this well-defined function, in recent years it was recognized that fibroblasts contribution to TME is more complex and dynamic with evidences for both tumor-promoting and tumor-suppressive actions [16]. These actions are mediated both by cell-cell contacts as well as by secreted factors [3]
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