![]() ![]() In physiological settings, inflammatory and anti-inflammatory properties of macrophages can be directed and mediated by cellular metabolism programs ( Van den Bossche et al., 2017). TAM abundance correlates with a worse response to therapy in PDA ( Di Caro et al., 2016), and systemic TAM depletion can block pancreatic tumorigenesis and regress established PDA tumors ( Mitchem et al., 2013 Zhang et al., 2017a). TAMs constitute a large proportion of the overall cellularity and are important regulators of the tumor microenvironment ( Di Caro et al., 2016). Nutrient acquisition and metabolic pathways are rewired in PDA cells to support survival and growth in this environment ( Halbrook and Lyssiotis, 2017 Perera and Bardeesy, 2015). Patients respond poorly to current treatments, where the degree of therapeutic resistance correlates with the fibroinflammatory response ( Koay et al., 2014) and the composition is predictive of survival ( Mahajan et al., 2018). This inhibits vascularization and/or vessel function and thus presumably delivery of therapeutic agents ( Feig et al., 2012 Olive et al., 2009 Provenzano et al., 2012 Rhim et al., 2014). ![]() It is characterized by a dense matrix rich with activated fibroblasts and tumor-associated macrophages (TAMs). Pancreatic ductal adenocarcinoma (PDA) has emerged as one of the most lethal human cancers ( Siegel et al., 2018). Additionally, we report that pyrimidine release is a general function of alternatively activated macrophage cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells. Together, these findings provide insights into the role of macrophages in pancreatic cancer therapy and have potential to inform the design of future treatments. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Profiling metabolite exchange, we demonstrate that macrophages programmed by PDA cells release a spectrum of pyrimidine species. TAMs have been reported to drive resistance to gemcitabine, a frontline chemotherapy in PDA, though the mechanism of this resistance remains unclear. Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant infiltration of tumor-associated macrophages (TAMs).
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |