Cancer-associated fibroblasts enhance tumor <sup>18</sup>F-FDG uptake and contribute to the intratumor heterogeneity of PET-CT

Shangguan, Chengfang; Gan, Guifang; Zhang, Jieying; Wu, Jiahui; Miao, Ying; Zhang, Miao; Li, Biao; Mi, Jun

doi:10.7150/thno.22717

Cited by 46 publications

(40 citation statements)

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“…This finding was further supported by the MeRIP assay, RNA stabilization assay, and qRT-PCR in control and METTL3-knockout or METTL3-knockdown CRC cells. Our data and previous studies [38,39] demonstrate that HK2 and SLC2A1 may act as oncogenes to promote cell glycolysis metabolism. Here, we also firstly reveal that HK2 and GLUT1 participate in METTL3-mediated biological function in CRC.…”

Section: Discussionsupporting

confidence: 81%

“…HK2 and SLC2A1 (GLUT1) are functionally essential target genes of METTL3 in CRC Hexokinase 2 (HK2) is a pivotal kinase in the glycolytic pathway [37]. Previous studies have demonstrated that HK2 activity is remarkably increased in various malignant neoplasms, as well as in CRC [38,39]. Glucose transporter 1 (GLUT1), encoded by SLC2A1, is the predominant glucose transporter expressed on colonic epithelial cells [40].…”

Section: Transcriptome-wide M 6 A-seq and Rna-seq Assays Identified Pmentioning

confidence: 99%

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m6A-dependent glycolysis enhances colorectal cancer progression

et al. 2020

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Background: Epigenetic alterations are involved in various aspects of colorectal carcinogenesis. N 6methyladenosine (m 6 A) modifications of RNAs are emerging as a new layer of epigenetic regulation. As the most abundant chemical modification of eukaryotic mRNA, m 6 A is essential for the regulation of mRNA stability, splicing, and translation. Alterations of m 6 A regulatory genes play important roles in the pathogenesis of a variety of human diseases. However, whether this mRNA modification participates in the glucose metabolism of colorectal cancer (CRC) remains uncharacterized. Methods: Transcriptome-sequencing and liquid chromatography-tandem mass spectrometry (LC-MS) were performed to evaluate the correlation between m 6 A modifications and glucose metabolism in CRC. Mass spectrometric metabolomics analysis, in vitro and in vivo experiments were conducted to investigate the effects of METTL3 on CRC glycolysis and tumorigenesis. RNA MeRIP-sequencing, immunoprecipitation and RNA stability assay were used to explore the molecular mechanism of METTL3 in CRC. Results: A strong correlation between METTL3 and 18 F-FDG uptake was observed in CRC patients from Xuzhou Central Hospital. METTL3 induced-CRC tumorigenesis depends on cell glycolysis in multiple CRC models. Mechanistically, METTL3 directly interacted with the 5′/3'UTR regions of HK2, and the 3'UTR region of SLC2A1 (GLUT1), then further stabilized these two genes and activated the glycolysis pathway. M 6 A-mediated HK2 and SLC2A1 (GLUT1) stabilization relied on the m 6 A reader IGF2BP2 or IGF2BP2/3, respectively. Conclusions: METTL3 is a functional and clinical oncogene in CRC. METTL3 stabilizes HK2 and SLC2A1 (GLUT1) expression in CRC through an m 6 A-IGF2BP2/3-dependent mechanism. Targeting METTL3 and its pathway offer alternative rational therapeutic targets in CRC patients with high glucose metabolism.

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Section: Discussionsupporting

confidence: 81%

Section: Transcriptome-wide M 6 A-seq and Rna-seq Assays Identified Pmentioning

confidence: 99%

m6A-dependent glycolysis enhances colorectal cancer progression

et al. 2020

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“…High temporal resolution is on the wish list of many systems biologists who study metastasis but is difficult to obtain in mammalian models except through the incorporation of imaging windows that facilitate multiple rounds of high-resolution intravital imaging (Entenberg et al, 2017;Suijkerbuijk and van Rheenen, 2017). Rapid advancement in functional imaging of metabolic or signaling state of tissues in vivo could be used to contextualize metastatic steps with the tissue microenvironment (Herzog et al, 2013;Knox et al, 2018;Miloushev et al, 2018;Shangguan et al, 2018). Zebrafish have emerged as an alternative system to study aspects of cancer metastasis at high temporal and spatial resolution (Heilmann et al, 2015), allowing for quantification of cell-cell or cell-stroma interactions and relatively easy genetic manipulation.…”

Section: Whole-organism Experimental Systems For Metastasis Researchmentioning

confidence: 99%

Systems Biology of Cancer Metastasis

et al. 2019

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Cancer metastasis is no longer viewed as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as successfully metastasizing cells assume new phenotypes while jettisoning older behaviors. The lack of a systemic understanding of this complex phenomenon has limited progress in developing treatments for metastatic disease. Because metastasis has traditionally been investigated in distinct physiological compartments, the integration of these complex and interlinked aspects remains a challenge for both systems-level experimental and computational modeling of metastasis. Here, we present some of the current perspectives on the complexity of cancer metastasis, the multiscale nature of its progression, and a systems-level view of the processes underlying the invasive spread of cancer cells. We also highlight the gaps in our current understanding of cancer metastasis as well as insights emerging from interdisciplinary systems biology approaches to understand this complex phenomenon.

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“…In addition, PnV tumors did not uptake detectable amounts of 18 F-FDG, suggesting impairment of the metabolism of tumor cells. High glucose uptake is a hallmark of cancer; FDG uptake was thought to indicate the aggressiveness of tumors and SUV is a well-known measure for FDG uptake in PET/CT 24 . Therefore, the lower uptake of FDG may indicate that the tumors of PnV treated animals were less aggressive compared to control.…”

Section: Discussionmentioning

confidence: 99%

Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model

Bonfanti

Barreto

Munhoz

et al. 2020

Sci Rep

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Molecules from animal venoms are promising candidates for the development of new drugs. previous in vitro studies have shown that the venom of the spider Phoneutria nigriventer (pnV) is a potential source of antineoplastic components with activity in glioblastoma (GB) cell lines. In the present work, the effects of PnV on tumor development were established in vivo using a xenogeneic model. Human GB (NG97, the most responsive line in the previous study) cells were inoculated (s.c.) on the back of RAG −/− mice. PnV (100 µg/Kg) was administrated every 48 h (i.p.) for 14 days and several endpoints were evaluated: tumor growth and metabolism (by microPET/CT, using 18 F-FDG), tumor weight and volume, histopathology, blood analysis, percentage and profile of macrophages, neutrophils and NK cells isolated from the spleen (by flow cytometry) and the presence of macrophages (Iba-1 positive) within/surrounding the tumor. The effect of venom was also evaluated on macrophages in vitro. tumors from pnV-treated animals were smaller and did not uptake detectable amounts of 18 F-FDG, compared to control (untreated). PnV-tumor was necrotic, lacking the histopathological characteristics typical of GB. Since in classic chemotherapies it is observed a decrease in immune response, methotrexate (MTX) was used only to compare the PnV effects on innate immune cells with a highly immunosuppressive antineoplastic drug. The venom increased monocytes, neutrophils and NK cells, and this effect was the opposite of that observed in the animals treated with MTX. PnV increased the number of macrophages in the tumor, while did not increase in the spleen, suggesting that PnV-activated macrophages were led preferentially to the tumor. Macrophages were activated in vitro by the venom, becoming more phagocytic; these results confirm that this cell is a target of PnV components. Spleen and in vitro PnV-activated macrophages were different of M1, since they did not produce pro-and antiinflammatory cytokines. Studies in progress are selecting the venom molecules with antitumor and immunomodulatory effects and trying to better understand their mechanisms. The identification, optimization and synthesis of antineoplastic drugs from pnV molecules may lead to a new multitarget chemotherapy. Glioblastoma is associated with high morbidity and mortality; therefore, research to develop new treatments has great social relevance. natural products and their derivatives represent over one-third of all new molecular entities approved by FDA. However, arthropod venoms are underexploited, although they are a rich source of new molecules. A recent in vitro screening of the Phoneutria nigriventer spider venom (PnV) antitumor effects by our group has shown that the venom significantly affected glioblastoma cell lines. Therefore, it would be relevant to establish the effects of pnV on tumor development in vivo, considering the complex neoplastic microenvironment. The

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Cancer-associated fibroblasts enhance tumor ¹⁸F-FDG uptake and contribute to the intratumor heterogeneity of PET-CT

Cited by 46 publications

References 46 publications

m6A-dependent glycolysis enhances colorectal cancer progression

m6A-dependent glycolysis enhances colorectal cancer progression

Systems Biology of Cancer Metastasis

Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model

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Cancer-associated fibroblasts enhance tumor 18F-FDG uptake and contribute to the intratumor heterogeneity of PET-CT

Cited by 46 publications

References 46 publications

m6A-dependent glycolysis enhances colorectal cancer progression

m6A-dependent glycolysis enhances colorectal cancer progression

Systems Biology of Cancer Metastasis

Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model

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Cancer-associated fibroblasts enhance tumor ¹⁸F-FDG uptake and contribute to the intratumor heterogeneity of PET-CT