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Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD.
Ma, Chi; Fu, Qiong; Diggs, Laurence P; McVey, John C; McCallen, Justin; Wabitsch, Simon; Ruf, Benjamin; Brown, Zachary; Heinrich, Bernd; Zhang, Qianfei; Rosato, Umberto; Wang, Sophie; Cui, Linda; Berzofsky, Jay A; Kleiner, David E; Bosco, Dale B; Wu, Long-Jun; Lai, Chunwei Walter; Rotman, Yaron; Xie, Changqing; Korangy, Firouzeh; Greten, Tim F.
Affiliation
  • Ma C; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Fu Q; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Diggs LP; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • McVey JC; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44106, USA.
  • McCallen J; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Wabitsch S; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Ruf B; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Brown Z; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Heinrich B; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany.
  • Zhang Q; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Rosato U; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Wang S; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Cui L; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Berzofsky JA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Kleiner DE; Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Bosco DB; Department of Neurology, Mayo Clinic, Rochester, MN, USA.
  • Wu LJ; Department of Neurology, Mayo Clinic, Rochester, MN, USA.
  • Lai CW; Liver and Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • Rotman Y; Liver and Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • Xie C; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Korangy F; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Greten TF; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: tim.greten@nih.gov.
Cancer Cell ; 40(9): 986-998.e5, 2022 09 12.
Article in En | MEDLINE | ID: mdl-36055226
ABSTRACT
Platelets, the often-overlooked component of the immune system, have been shown to promote tumor growth. Non-alcoholic fatty liver disease (NAFLD) is a common disease in the Western world and rising risk for hepatocellular carcinoma (HCC). Unexpectedly, we observed that platelets can inhibit the growth of established HCC in NAFLD mice. Through pharmacological inhibition and genetic depletion of P2Y12 as well as in vivo transfusion of wild-type (WT) or CD40L-/- platelets, we demonstrate that the anti-tumor function of platelets is mediated through P2Y12-dependent CD40L release, which leads to CD8+ T cell activation by the CD40 receptor. Unlike P2Y12 inhibition, blocking platelets with aspirin does not prevent platelet CD40L release nor accelerate HCC in NAFLD mice. Similar findings were observed in liver metastasis models. All together, our study reveals a complex role of platelets in tumor regulation. Anti-platelet treatment without inhibiting CD40L release could be considered for liver cancer patients with NAFLD.
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Full text: 1 Database: MEDLINE Main subject: Blood Platelets / Carcinoma, Hepatocellular / Receptors, Purinergic P2Y12 / Non-alcoholic Fatty Liver Disease / Liver Neoplasms Type of study: Prognostic_studies Limits: Animals Language: En Year: 2022 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Blood Platelets / Carcinoma, Hepatocellular / Receptors, Purinergic P2Y12 / Non-alcoholic Fatty Liver Disease / Liver Neoplasms Type of study: Prognostic_studies Limits: Animals Language: En Year: 2022 Type: Article