Poster abstracts
Poster number 45 submitted by Justin Middleton
Chemotherapy-exacerbated cancer cell colonization and growth is dependent on the stress-inducible gene, Atf3, in non-cancer host cells.
Justin D. Middleton (MCDB), Tsonwin Hai (Biological Chemistry and Pharmacology, College of Medicine)
Abstract:
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 in mice that the stress of chemotherapy exacerbates metastasis, even while shrinking the primary tumor. This chemotherapy-driven effect was much dampened in 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. Our findings suggest that chemotherapy changes the function of myeloid-lineage immune cells through ATF3 to promote metastasis. In order to directly test the effects of chemotherapy on the site of metastasis, we developed an experimental metastasis model where chemotherapy was injected four days before murine breast cancer cells were intravenously injected into mice, which ensures that the chemotherapy would have no effect on the cancer cells themselves. We found that chemotherapy led to an increase in cancer cell colonization of the lungs only in wildtype (WT) mice, indicating that treatment changes the metastatic environment in an ATF3-dependent manner. Using a time-course analysis, we found that chemotherapy increased cancer cell abundance in the first few hours independent of ATF3, but over time, the number of colonies in ATF3 KO mice decreased. Our preliminary results support the hypothesis that chemotherapy increases adhesion to blood vessels in the first few hours after injection, while promoting cancer cells to colonize the lung in an ATF3-dependent manner in the later stages. Using in vitro adhesion experiments, we found that the serum of treated mice increases the adhesion of cancer cells to 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 in WT mice. Myeloid cells are known to decrease cancer cell death but increase cancer cell proliferation and extravasation—keys steps for cancer cells to colonize the tissues. Thus, this myeloid shift may be a contributing factor for the phenotype we observed. Understanding how chemotherapy affects metastasis is incredibly important, as 80% of breast cancer patients receive chemotherapy during their treatment.
Keywords: metastasis, chemotherapy, stress