Cancer Research Liu Wen/Yang Yunlong collaborated to report a new mechanism for hyperglycemia to promote tumor metastasis through megakaryocytes

Tumor metastasis is the main cause of tumor-related death and is regulated by many factors
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Among them, hyperglycemia is considered to be an important risk factor for tumor metastasis
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Hyperglycemia may be induced by many factors such as diabetes, obesity, pancreatitis, improper diet, and is closely related to the poor prognosis of cancer patients
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Hyperglycemia can increase tumor metastasis, but its molecular mechanism has not been fully elucidated
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Existing reports mostly focus on the effects of hyperglycemia on tumor cell proliferation, apoptosis, epithelial-mesenchymal transition and so on
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Tumor metastasis is a complicated process
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The circulation of tumor cells is restricted by many factors such as anoikis, blood shearing force, and immune cell attack
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Platelets can protect tumor cells and assist their spread by interacting with tumor cells in the circulation [1]
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Glucose regulatory protein 75 (GRP75) belongs to the heat shock protein 70 family, but it does not respond to heat, but to stimuli such as glucose
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Studies have shown that GRP75 is not only a molecular chaperone in the mitochondria, but also a member of the mitochondrial-endoplasmic reticulum interface protein complex, which can control the release of calcium ions and mediate a variety of pathophysiological changes in cells [2]
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Recently, Professor Liu Wen of Fudan University and researcher Yang Yunlong (the first author is Master Wu Biying) published an online article titled Megakaryocytes mediate hyperglycemia-induced tumor metastasis on Cancer Research.
The researchers found that hyperglycemia affects GRP75 in megakaryocytes to make platelets.
Producing the phenotype of tumor metastasis, and verifying the feasibility of related signaling pathways as targets for anti-metastatic therapy
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The researchers used a mouse model of hyperglycemia-induced metastasis and observed that the glucose transporter in tumor cells was related to the size of the metastasis, but not to the rate of metastasis
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It is suggested that glucose may affect the efficiency of metastasis through non-tumor cells
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The authors further found that platelets were significantly activated in hyperglycemic mice, and that the co-injection of platelets from hyperglycemic mice with untreated tumor cells into healthy mice also resulted in an increased metastasis rate, showing that under hyperglycemic conditions The metastasis-promoting phenotype of platelets
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Through the isolation of bone marrow primary megakaryocytes and a series of molecular biology experiments, the authors found that hyperglycemia can significantly up-regulate the expression of GRP75 in megakaryocytes through the transcription factor MYC
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GRP75, as an intracellular calcium ion control protein regulated by glucose, can activate platelets through the Ca2+-PKCα pathway after platelet production, enhance their binding to tumor cells, and promote tumor metastasis efficiency
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Inhibition of platelet activity or inhibition of GRP75 can block the metastasis-promoting effect caused by hyperglycemia
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Finally, in healthy volunteers who drank 5% glucose water, GRP75 in platelets was significantly increased, and platelet activity was significantly enhanced
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These platelets can show a metastasis-promoting phenotype in nude mouse tumor metastasis models
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The authors used a variety of metastasis models to verify the role of the glucose-megakaryocyte-MYC-GRP75-Ca2+-PKCα signaling axis in activating platelets and indirectly promoting tumor metastasis
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This work found for the first time that hyperglycemia promotes platelet activation by affecting megakaryocytes, driving tumor metastasis in an indirect manner
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As a signal regulated by glucose, the GRP75 protein switches platelets to a metastatic phenotype
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This signal axis may be used as a drug target to treat various types of solid tumor metastasis
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This work also suggests that the interaction between the host and the tumor can occur on a larger scale than the tumor microenvironment, increasing our understanding of the complexity of tumor metastasis
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Original link: https://cancerres.
aacrjournals.
org/content/early/2021/09/17/0008-5472.
CAN-21-1180 Platemaker: 11 References 1.
Gay LJ, Felding-Habermann B.
Contribution of platelets to tumour metastasis.
Nat Rev Cancer 2011;11(2):123-34 doi 10.
1038/nrc3004.
2.
Szabadkai G, Bianchi K, Varnai P, De Stefani D, Wieckowski MR, Cavagna D, et al.
Chaperone- mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels.
J Cell Biol 2006;175(6):901-11 doi 10.
1083/jcb.
200608073.
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