Publication Date
5-2023
Date of Final Oral Examination (Defense)
3-17-2023
Type of Culminating Activity
Dissertation
Degree Title
Doctor of Philosophy in Biomolecular Sciences
Department
Biology
Major Advisor
Cheryl L. Jorcyk, Ph.D.
Advisor
Daniel Fologea, Ph.D.
Advisor
Richard S. Beard, Ph.D.
Advisor
Julie Oxford, Ph.D.
Abstract
Breast cancer has the highest prevalence of cancers in women in the USA; approximately 1 in 8 women will receive a diagnosis in their lifetime. Invasive ductal carcinoma (IDC) is the most commonly diagnosed breast cancer and presents a serious problem if it metastasizes, decreasing 5-year patient survival from ~98% to ~29%. Tumor cells grow in an environment that is known as the tumor microenvironment (TME). Due to inflammation, the TME of IDC is often saturated with neutrophil- and macrophage-derived proinflammatory cytokines including oncostatin M (OSM) and interleukin-1beta (IL-1β), both of which promote favorable conditions for metastasis. Modifications in the organization, density, and alignment of collagen I fibers present in extracellular matrix (ECM) of the TME directly impact IDC cell motility and invasiveness, both factors in metastasis. Lysyl oxidase like-2 (LOXL2) is an enzymatic protein secreted by fibroblast and IDC cells that catalyzes the crosslinking of collagen I fibers in the ECM. Increased collagen crosslinking alters the characteristics mentioned above, worsening patient prognosis and promoting metastasis. Proposed is a novel mechanism for proinflammatory cytokine-promoted ECM remodeling and subsequent metastasis in IDC. OSM signaling induces enzymatically active LOXL2 expression and extracellular secretion, leading to significant remodeling of ECM collagen I fibers that promotes significantly increased invasion, tumor growth, and metastasis. LOXL2-mediated ECM remodeling is also critical for OSM promoted IDC tumor growth and metastatic progression. Combined, these results demonstrate that OSM-induced LOXL2 has serious implications for IDC tumor progression and metastasis. Further studies and understanding of the mechanisms at play in this association will hopefully lead to better therapeutic discoveries to prevent metastases.
DOI
https://doi.org/10.18122/td.2054.boisestate
Recommended Citation
Dinca, Simion C., "Mechanics for Inflammatory Cytokine-Promoted Breast Cancer Progression: OSM-Induced LOXL2 Leads to Extracellular Matrix Remodeling of Collagen I and Subsequent Metastasis" (2023). Boise State University Theses and Dissertations. 2054.
https://doi.org/10.18122/td.2054.boisestate