Type of Thesis
Molecular, Cellular, & Developmental Biology
Leslie Leinwand, Ph.D.
Kristi Anseth, Ph.D.
Jennifer Martin, Ph.D.
Lung cancer is a devastating disease that kills more individuals in the United States than any other cancer. The tumor microenvironment is increasingly recognized as playing a major role in the progression of cancer. Thus, studying the interactions among lung cancer cells, non-malignant cells and the surrounding matrix is critical for understanding and treating lung cancer. Three-dimensional in vitro co-culture systems allow for tissue-relevant platforms that better recapitulate the native cell environment. In this work, we employed a cyst templating technique to culture alveolar epithelial cells on photodegradable microspheres and subsequently encapsulated the cell-covered spheres within poly(ethylene glycol) (PEG) hydrogels laden with pulmonary fibroblasts. A healthy fibroblast cell line was co-cultured with either normal mouse alveolar epithelial primary cells or a cancerous alveolar epithelial cell line to probe the influence of tumor-stromal co-culture on cell behavior. We found that cancerous epithelial cells and normal fibroblasts have significantly higher proliferation rates in co-culture, normal fibroblasts migrate significantly faster when co-cultured with cancerous A549 cells, and there is a synergistic increase in matrix metalloproteinase (MMP) activity in this cancer co-culture. None of these changes in cell behavior were observed in a parallel healthy epithelial-cyst/fibroblast co-culture. Further, when MMP activity was reduced via a chemical inhibitor and when cells were cultured in gels with a non-degradable crosslinker, the increase in cancer cell proliferation in co-culture was abrogated and fibroblast migration was dramatically suppressed. The results presented here suggest a nuanced chemical signaling exchange between lung cancer epithelial cells and pulmonary fibroblasts within our 3D hydrogel system and points to potential signaling routes that merit further investigation.
Hall, Jessica Kole, "Epithelial-Mesenchymal Crosstalk Influences Cancer-Related Cell Behavior: A 3D Lung Alveolus-Fibroblast Co-Culture System" (2017). Undergraduate Honors Theses. 1354.