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YC Thesis Final for Graduate school.pdf (6.08 MB)

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ATF3 in non-Cancer Host Cells Contributes to Stress-Enhanced Cancer Progression

Chang, Yi Seok
http://rave.ohiolink.edu/etdc/view?acc_num=osu1460485983

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Cancer is one of the leading causes of death in the U.S. Among them, metastatic cancer is almost impossible to cure due to its highly aggressive nature and resistance to established therapeutic intervention. Consequently, metastasis is a cause of more than 90% of cancer death. Although recent effort of many investigators has improved our understanding of the metastatic cascade, a large portion of the cellular and molecular mechanisms of metastasis remains elusive. Non-cancer host cells, such as macrophages/myeloid cells, have been shown as key cell types to promote cancer progression and metastasis. Recently, we demonstrated that activating transcription factor 3 (ATF3), a hub of the cellular adaptive-response network, in the non-cancer host cells (host-ATF3) plays a role to enhance breast cancer metastasis. Our data indicated that macrophages/myeloid cells are important for the pro-metastatic function of ATF3. The expression of this bZip transcription factor gene can be induced by various stress signals that disturb the cellular homeostasis. In addition, ATF3 has been demonstrated to be an important regulator of immune responses and inflammation. Thus, ATF3 could be a molecular hub connecting stress response, inflammation, and cancer progression. iii The work presented in this dissertation focused on the function of ATF3 in cancer progression under stress paradigms. We used two mouse models of metastasis: (a) a spontaneous metastasis model with orthotopic injection of cancer cells, a model that tests the ability of cancer cells to metastasize from the primary tumor at its orthotopic site to a distant site—a true metastasis model; (b) a lung colonization model with intravenous injection of cancer cells, a model that tests the ability of cancer cells in circulation to colonize the lung—the late steps of metastasis. We examined whether stress has an effect on cancer progression. If so, does ATF3 play a role? With a loss-of-function approach, we examined two stress paradigms that cancer patients often experience: chemotherapy (Chapter 2) and behavioral stress (Chapter 3). The data presented in Chapter 2 demonstrated that paclitaxel (PTX) treatment exacerbates breast cancer metastasis and host-ATF3 plays an important role in this PTX-effect. My data from analyzing the metastatic lungs indicated that PTX enhances cancer cell seeding and modulates immune components in the lung to generate a more permissive tissue microenvironment for cancer cells—in a manner dependent on the host-ATF. Analyses of gene expression in the mouse model, combined with analyses of publicly available human microarray datasets, supported the notion that our findings from the mouse models have relevance to human cancer. For behavioral stress (presented in Chapter 3), we collaborated with Dr. John Sheridan and Dr. Seoungho Jung to test the effect of repeated social defeat (RSD) stress on lung colonization by cancer cells. The data presented in Chapter 3 support that RSD stress enhanced lung colonization and host-ATF3 plays an important role in this RSD effect. iv Taken together, the data presented in this dissertation address the pro-metastatic function of ATF3 in the non-cancer host cells, under two stress paradigms: chemotherapy and behavioral stress. My data suggest that a key mechanism by which ATF3 functions is through modulating immune cells and generating a more conducive microenvironment in the lung for cancer cells.
Tsonwin Hai, PhD (Advisor)
Denis Guttridge, PhD (Committee Member)
Sissy Jhiang, PhD (Committee Member)
Mariano Viapiano, PhD (Committee Member)
207 p.
Biology; Biomedical Research
ATF3; cancer; metastasis; chemotherapy; behavioral stress; cellular stress response;

Recommended Citations

Citations

  • Chang, Y. S. (2016). ATF3 in non-Cancer Host Cells Contributes to Stress-Enhanced Cancer Progression [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460485983

    APA Style (7th edition)

  • Chang, Yi Seok. ATF3 in non-Cancer Host Cells Contributes to Stress-Enhanced Cancer Progression. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1460485983.

    MLA Style (8th edition)

  • Chang, Yi Seok. "ATF3 in non-Cancer Host Cells Contributes to Stress-Enhanced Cancer Progression." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460485983

    Chicago Manual of Style (17th edition)

osu1460485983
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This open access ETD is published by The Ohio State University and OhioLINK.