The Role of Cancer-Associated Fibroblast Biomechanics on Angiogenesis During tumor development, angiogenesis is upregulated to supply the ever-increasing metabolic demands of the growing tumor. Targeting tumor-associated angiogenesis has long been a therapeutic strategy for cancer patients; however, these techniques demonstrate limited effectiveness in many cancer types, in part due to our limited understanding of the biomechanical environment of the tumor. Recently, carcinoma/cancer-associated fibroblasts (CAFs) have been discovered to be important regulators of the peritumoral environment responsible for secreting factors that control angiogenesis and metastasis. CAFs have been shown to upregulate alpha-smooth muscle actin and the transcription factor Snail1 and have further been shown to have increased contractile forces in 2D. We hypothesized that the CAF-generated increases in biomechanical strains enhance tip cell activation and thus drive angiogenesis in the peritumoral environment. Our lab has developed a 3D in vitro vascularized tumor tissue model that will permit the interrogation of CAF-associated biomechanical factors on angiogenesis. Preliminary data suggests that CAFs but not normal fibroblasts support blood vessel formation in fibrin gels, and that this process is not solely regulated through soluble factors such as vascular endothelial growth factor (VEGF). Therefore, we propose studying CAF-generated biomechanics in tumor-associated angiogenesis in a 3D vascularized tissue model. Using a series of genetic manipulation techniques to elucidate mechano- regulated signaling pathways, this study will leverage the unique design of our 3D tumor tissue model to interrogate the role of CAF generated biomechanical forces on angiogenesis
This research training proposal is driven by the objective of elucidating how carcinoma/cancer- associated fibroblasts (CAFs) modulate the biomechanics of the peritumoral environment specifically to induce angiogenesis. Over 1.5 million Americans have been diagnosed with cancer and current anti-angiogenesis therapies demonstrate only limited efficacy; this is perhaps due, in part, to our limited understanding of biomechanical factors that regulate tumor progression. The results of this proposal could facilitate the design of novel, more effective anti-cancer therapies that target both angiogenesis and CAF-generated biomechanical factors.
Sewell-Loftin, Mary Kathryn; Bayer, Samantha Van Hove; Crist, Elizabeth et al. (2017) Cancer-associated fibroblasts support vascular growth through mechanical force. Sci Rep 7:12574 |