title: Extravascular red blood cells and hemoglobin promote tumor growth and therapeutic resistance as endogenous danger signals.
abstract: Hemorrhage is a common clinical manifestation in patients with cancer. Intratumor hemorrhage has been demonstrated to be a poor prognostic factor for cancer patients. In this study, we investigated the role of RBCs and hemoglobin (Hb) in the process of tumor progression and therapeutical response. RBCs and Hb potently promoted tumor cell proliferation and syngenic tumor growth. RBCs and Hb activated the reactive oxygen species-NF-κB pathway in both tumor cells and macrophages. RBCs and Hb also induced chemoresistance mediated, in part, by upregulating ABCB1 gene expression. Tumor growth induced by RBCs was accompanied by an inflammatory signature, increased tumor vasculature, and influx of M2 macrophages. In both the peritoneal cavity and tumor microenvironment, extravascular RBCs rapidly recruited monocyte-macrophages into the lesion sites. In addition, RBCs and Hb increased several nucleotide-binding oligomerization domain-like receptors' expression and induced IL-1β release. Our results provide novel insights into the protumor function of RBCs and Hb as endogenous danger signals, which can promote tumor cell proliferation, macrophage recruitment, and polarization. Hemorrhage may represent a useful prognostic factor for cancer patients because of its role in tumor promotion and chemoresistance.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Tao
authors.initials: T
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Sisi
authors.initials: S
authors.lastname: He
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Tinghong
authors.initials: T
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Yaxiong
authors.initials: Y
authors.lastname: Sang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Chao
authors.initials: C
authors.lastname: Su
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Guobo
authors.initials: G
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Xuelei
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Fuchun
authors.initials: F
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Yanyang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Qiancheng
authors.initials: Q
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China wangys75@gmail.com yqwei@vip.sina.com.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; and Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China wangys75@gmail.com yqwei@vip.sina.com.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004912:Erythrocytes / Q000473:pathology*; D006454:Hemoglobins / Q000494:pharmacology*; D006470:Hemorrhage / Q000473:pathology*; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D009389:Neovascularization, Pathologic; D018384:Oxidative Stress / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D006454:Hemoglobins; C508585:IL1B protein, human; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin