Chemotherapy-exacerbated cancer cell colonization of the lung is mediated by host-ATF3-dependent and -independent processes.
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Date
2019-03
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Abstract
Even with modern advances in personalized medicine, chemotherapy is still a primary adjunct therapy to treat cancer patients around the world. Emerging evidence indicates that chemotherapy can paradoxically produce a pro-cancer response by triggering tissue repair pathways, inflammation and immune suppression. We have previously shown that chemotherapy exacerbates metastasis in a mouse model of breast cancer, even while shrinking the primary tumor. This effect largely disappeared in mice lacking the gene ATF3, otherwise known as ATF3 knockout (KO) mice. ATF3 is a stress-inducible gene that encodes a transcription factor that regulates hundreds of genes, and is upregulated by chemotherapy. We hypothesized that chemotherapy-derived stress changes the host in an ATF3-dependent manner that produces a better “soil” in which cancer cells can grow. In order to directly test the effects of chemotherapy on the site of metastasis, we developed an experimental metastasis model where wildtype (WT) or ATF3 KO mice are treated with cyclophosphamide or paclitaxel – two widely used chemotherapeutic drugs – four days before breast cancer cells are intravenously injected. By the point that cancer cells are injected, the drugs have been eliminated from the body, ensuring that the chemotherapy has no effect on the cancer cells, only the host. We found that chemotherapy led to an increase in cancer cell colonization of the lungs only in WT mice, indicating that treatment changes the metastatic environment in an ATF3-dependent manner. Using in vitro adhesion experiments, we found that the serum of treated mice increases the adhesion of cancer cells to blood vessel endothelial cells. Additionally, we found an increase in immunosuppressive inflammatory monocytes in the lung, and an increase in myeloid precursors in the bone marrow following chemotherapy, only in WT mice. Finally, we found that depleting ATF3 only in myeloid cells using conditional KO mice resulted in a significant decrease in cancer burden in the lungs, suggesting that myeloid cells are a key component of the chemo-exacerbated metastasis phenotype we observe. Myeloid cells are known to prevent cancer cell death and increase cancer cell proliferation and extravasation—key steps for cancer cells during the colonization process. Future work will attempt to uncover the mechanisms behind this myeloid-regulated increase in colonization, with the overall goal of identifying cellular and molecular targets to inhibit that may improve the efficacy of chemotherapy.
Description
Biological Sciences: 3rd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
Chemotherapy, Metastasis, Stress, ATF3, Cancer