Abstract
Solid tumors are often challenged by hypoxic and nutrient-deprived tumor microenvironments (TME) as tumors progress, due to limited perfusion and rapid nutrient consumption. While cancer cells can demonstrate the ability to survive in nutrient-deprived conditions through multiple intrinsic alterations, it is poorly understood how nutrient-deprived cancer cells co-opt the TME to promote cancer cell survival and tumor progression. In the present study, we found that glutamine deprivation markedly potentiated the expression of G-CSF and GM-CSF in mouse mammary cancer cells. The IRE1α-JNK pathway, which is activated by glutamine starvation, was found to be important for the upregulation of these cytokines. G-CSF and GM-CSF are well-known facilitators of myelopoiesis and mobilization of hematopoietic progenitor cells (HPC). Consistently, as tumors progressed, we found that several myeloid HPC compartments were gradually decreased in the bone marrow but were significantly increased in the spleen. Mechanistically, the HPC-maintaining capacity of the bone marrow was significantly impaired in tumor-bearing mice, with lower expression of HPC maintaining genes (i.e., CXCL12, SCF, ANGPT1, and VCAM1), and reduced levels of mesenchymal stem cells and CXCL12-producing cells. Furthermore, the mobilized HPCs that displayed the capacity for myelopoiesis were also found to accumulate in tumor tissue. Tumor-infiltrating HPCs were highly proliferative and served as important sources of immunosuppressive myeloid-derived suppressor cells (MDSCs) in the TME. Our work has identified an important role for glutamine starvation in regulating the expression of G-CSF and GM-CSF, and in facilitating the generation of immunosuppressive MDSCs in breast cancer.
Highlights
Proliferative cancer cells exhibit a strong demand for nutrients to maintain energy supplies and for biosynthesis [1,2,3]
To elucidate the metabolic processes involved in regulating the expression of granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF), multiple selective inhibitors and metabolic products were introduced into 4T1 culture medium
In contrast to DON, BPTES and aminooxyacetic acid (AOA) treatment did not phenocopy the effects of glutamine deprivation, indicating that glutaminolysis is not involved in regulating the expression of G-CSF and GM-CSF (Figure 1B)
Summary
Proliferative cancer cells exhibit a strong demand for nutrients to maintain energy supplies and for biosynthesis [1,2,3]. Solid tumors are often challenged by hypoxic and nutrient-deprived conditions in the tumor microenvironment (TME) due to inadequate vascular perfusion and rapid nutrient consumption as the tumor grows [4,5,6,7]. When challenged with metabolic stress, cancer cells can still survive in a nutrient-poor TME through the action of multiple cancer cell-intrinsic alterations [8,9,10]. Cancer cells can adapt to nutrient starvation conditions by utilizing alternative nutrients or through epigenetic modification [7, 10]. In addition to cancer cell evolution, components of the TME are influential accomplices of tumor survival and progression. It is critical to explore the impact of nutrient starvation on remodeling the TME, to better understand how the TME contributes to tumor progression
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