Activated Fibroblasts: Gluttonous for Glutamine.
Ontology highlight
ABSTRACT:
SUBMITTER: Nieweld C
PROVIDER: S-EPMC6827061 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
Publications
Activated Fibroblasts: Gluttonous for Glutamine.
American journal of respiratory cell and molecular biology 20191101 5
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Project description:Like in an ecosystem, cancer and other cells residing in the tumor microenvironment engage in various modes of interactions to buffer the negative effects of environmental changes. One such change is the consumption of common nutrients (such as glutamine/Gln) and the consequent accumulation of toxic metabolic byproducts (such as ammonium/NH4). Ammonium is a waste product of cellular metabolism whose accumulation causes cell stress. In tumors, it is known that it can be recycled into nutrients by cancer associated fibroblasts (CAFs). Here we present monoculture and coculture growth of cancer cells and CAFs on different substrates: glutamine and ammonium. We propose a mathematical model to aid our understanding. We find that cancer cells are able to survive on ammonium and recycle it to glutamine for limited periods of time. CAFs are able to even grow on ammonium. In coculture, the presence of CAFs results in an improved survival of cancer cells compared to their monoculture when exposed to ammonium. Interestingly, the ratio between the two cell populations is maintained under various concentrations of NH4, suggesting the ability of the mixed cell system to survive temporary metabolic stress and sustain the size and cell composition as a stable entity.
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Project description:Women diagnosed with breast cancer within 5 years of childbirth have poorer prognosis than nulliparous or pregnant women. Weaning-induced breast involution is implicated, as the collagen-rich, immunosuppressive microenvironment of the involuting mammary gland is tumor promotional in mice. To investigate the role of mammary fibroblasts, isolated mammary PDGFRα+ cells from nulliparous and postweaning mice were assessed for activation phenotype and protumorigenic function. Fibroblast activation during involution was evident by increased expression of fibrillar collagens, lysyl oxidase, Tgfb1, and Cxcl12 genes. The ability of mammary tumors to grow in an isogenic, orthotopic transplant model was increased when tumor cells were coinjected with involution-derived compared with nulliparous-derived mammary fibroblasts. Mammary tumors in the involution-fibroblast group had increased Ly6C+ monocytes at the tumor border, and decreased CD8+ T cell infiltration and tumor cell death. Ibuprofen treatment suppressed involution-fibroblast activation and tumor promotional capacity, concurrent with decreases in tumor Ly6C+ monocytes, and increases in intratumoral CD8+ T cell infiltration, granzyme levels, and tumor cell death. In total, our data identify a COX/prostaglandin E2 (PGE2)-dependent activated mammary fibroblast within the involuting mammary gland that displays protumorigenic, immunosuppressive activity, identifying fibroblasts as potential targets for the prevention and treatment of postpartum breast cancer.
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Project description:Activated cancer-associated fibroblasts (CAFs) play a major role in the poor outcome in many diseases including pancreatic cancer. Normally quiescent with high lipid content and low proliferative capacity, CAFs receiving cues from cancer cells in the tumor microenvironment become activated and transformed into a lipid-deprived and highly proliferative myofibroblast type phenotype. Therefore, reversal of activated fibroblasts to the quiescence state is an important area of investigation that may help the therapeutic management of a number of diseases including pancreatic cancer. Here, we describe a unique biological function of gold nanoparticles (GNPs) and demonstrate that GNPs may be used to transform activated CAFs to quiescence and provide insights into the underlying molecular mechanisms. Using immortalized and primary patient derived CAFs, we demonstrate that GNPs enhanced lipid content in the cells by inducing expression of lipogenesis genes such as FASN, SREBP2, and FABP3. Using pharmacological inhibitors of lipolysis, lipophagy, and fatty acid oxidation, we further demonstrate that CAFs utilized a GNP-induced endogenously synthesized lipid to maintain the quiescent phenotype. Consequently, treatment with GNP sensitizes CAF to FASN inhibitor or FASN siRNA. Hence, GNPs may be used as a tool to probe mechanisms of quiescence in CAFs and help device strategies to target the stromal compartment exploiting the mechanisms of lipid utilization.
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