Pretreatment tumor-related leukocytosis misleads positron emission tomography-computed tomography during lymph node staging in gynecological malignancies

Mabuchi, Seiji; Komura, Naoko; Sasano, Tomoyuki; Shimura, Kentaro; Yokoi, Eriko; Kozasa, Katsumi; Kuroda, Hiromasa; Takahashi, Ryoko; Kawano, Mahiru; Kato, Hirohisa; Hatazawa, Jun; Kimura, Tadashi

doi:10.1038/s41467-020-15186-z

Cited by 27 publications

(42 citation statements)

References 33 publications

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“…These studies support a model where myeloid cells including TAM consume the most glucose in the TME. Consistent with our findings, myeloid infiltration is known to drive FDG avidity in nontumor bearing lymph nodes in human and mouse gynecological malignancies 24 . Our data extend these findings directly to the solid TME.…”

Section: Tme Myeloid Cells Uptake More Glucose Than Other Cell Types supporting

confidence: 92%

Cell Programmed Nutrient Partitioning in the Tumor Microenvironment

Reinfeld

Madden

Wolf

et al. 2020

Preprint

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The tumor microenvironment (TME) includes transformed cancer and infiltrating immune cells. Cancer cells can consume large quantities of glucose through Warburg metabolism that can be visualized with positron emission tomography (PET). While infiltrating immune cells also rely on glucose, disruptions to metabolism can contribute to tumor immunological evasion. How immune cell metabolism is programmed or restrained by competition with cancer cells for nutrients, remains uncertain. Here we used PET tracers to measure the accessibility of glucose and glutamine to cell subsets in the TME. Surprisingly, myeloid cells including macrophages were the greatest consumers of intra-tumoral glucose, followed by T cells and cancer cells. Cancer cells, in contrast, had the highest glutamine uptake. This distinct nutrient partitioning was programmed through selective mTORC1 signaling and glucose or glutamine-related gene expression. Inhibition of glutamine uptake enhanced glucose uptake across tumor resident cell types and shifted macrophage phenotype, demonstrating glucose is not limiting in the TME. Thus, cancer cells are not the only cells in tumors which exhibit high glucose uptake in vivo and instead preferentially utilize glutamine over other cell types. We observe that intrinsic cellular programs can play a major role in the use of some nutrients. Together, these data argue cell selective partitioning of glucose and glutamine can be exploited to develop therapies and imaging strategies to alter the metabolic programs of specific cell populations in the TME.

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Section: Tme Myeloid Cells Uptake More Glucose Than Other Cell Types supporting

confidence: 92%

Cell Programmed Nutrient Partitioning in the Tumor Microenvironment

Reinfeld

Madden

Wolf

et al. 2020

Preprint

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“…Immunocompetent C57BL/6 mice were subcutaneously inoculated with 1.0 × 10 6 ID-8 cells/mouse. Fourteen days after inoculation, mice were randomized into 2 groups that were administered either Gr-1 antibody (n = 5) or PBS (n = 5), every other day (day 14,16,18,20). Kaplan-Meier estimates of survival is shown.…”

Section: Discussionmentioning

confidence: 99%

“…Sixty minutes after injection, PET measurements were performed in an abdominal position using a small-animal FDG-PET/CT scanner (Inveon MM; Siemens Medical Solutions, Knoxville, USA). The image data acquired from the small-animal FGD-PET/CT scanner were displayed and analyzed with RadiAnt DICOM 4.6.9 Viewer (Medixant, Poznan—Poland), as reported previously 16 .…”

Section: Methodsmentioning

confidence: 99%

Prognostic significance of bone marrow FDG uptake in patients with gynecological cancer

Shimura

Mabuchi

Komura

et al. 2021

Sci Rep

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We investigated the prognostic significance and the underlying mechanism of increased bone marrow (BM) 2-(18F) fluoro-2-deoxy-D-glucose as a tracer (FDG)-uptake in patients with gynecological cancer. A list of patients diagnosed with cervical, endometrial, and ovarian cancer from January 2008 to December 2014 were identified. Then, through chart reviews, 559 patients who underwent staging by FDG-positron emission tomography (PET)/computed tomography (CT) and subsequent surgical resection were identified, and their clinical data were reviewed retrospectively. BM FDG-uptake was evaluated using maximum standardized uptake value (SUVmax) and BM-to-aorta uptake ratio (BAR). As a result, we have found that increased BAR was observed in 20 (8.7%), 21 (13.0%), 21 (12.6%) of cervical, endometrial, and ovarian cancer, respectively, and was associated with significantly shorter survival. Increased BAR was also closely associated with increased granulopoiesis. In vitro and in vivo experiments revealed that tumor-derived granulocyte colony-stimulating factor (G-CSF) was involved in the underlying causative mechanism of increased BM FDG-uptake, and that immune suppression mediated by G-CSF-induced myeloid-derived suppressor cells (MDSCs) is responsible for the poor prognosis of this type of cancer. In conclusion, increased BM FDG-uptake, as represented by increased BAR, is an indicator of poor prognosis in patients with gynecological cancer.

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“…These processes are regulated by MDSC-derived mediators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), Bv8, and matrix metalloproteinase (MMP)-9, all of which are essential for tumor angiogenesis and cancer cell invasion [11,14]. Moreover, recent reports suggested that MDSCs stimulate the metastatic activity of cancer cells by facilitating epithelial-to-mesenchymal transition (EMT) or by creating "premetastatic niches" [15,16]. Importantly, the evidence has indicated that MDSCs induce "stemness," which might be associated with resistance to existing anticancer treatments including chemotherapy or radiotherapy [17].…”

Section: Nonimmune Activities Of Mdscmentioning

confidence: 99%

Targeting Myeloid-Derived Suppressor Cells in Ovarian Cancer

Mabuchi

Sasano

Komura

2021

Cells

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Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that exhibit immunosuppressive activity. They also directly stimulate tumor cell proliferation, metastasis, and angiogenesis. In ovarian cancer, there are increased numbers of circulating or tumor-infiltrating MDSCs, and increased frequencies of MDSCs are associated with a poor prognosis or an advanced clinical stage. Moreover, in murine models of ovarian cancer, MDSC depletion has shown significant growth-inhibitory effects and enhanced the therapeutic efficacy of existing anticancer therapies. In this review, we summarize the current knowledge on MDSC biology, clinical significance of MDSC, and potential MDSC-targeting strategies in ovarian cancer.

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Pretreatment tumor-related leukocytosis misleads positron emission tomography-computed tomography during lymph node staging in gynecological malignancies

Cited by 27 publications

References 33 publications

Cell Programmed Nutrient Partitioning in the Tumor Microenvironment

Cell Programmed Nutrient Partitioning in the Tumor Microenvironment

Prognostic significance of bone marrow FDG uptake in patients with gynecological cancer

Targeting Myeloid-Derived Suppressor Cells in Ovarian Cancer

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