title: High mobility group box 1 released from necrotic cells enhances regrowth and metastasis of cancer cells that have survived chemotherapy.
abstract: The role of the high mobility group box 1 (HMGB1) protein in chemotherapy-induced cell death was examined. CT26 mouse colon cancer cells were treated with trichostatin A (TSA; apoptosis inducer) or doxorubicin (DXR; necrosis inducer). DXR increased HMGB1 concentration in CT26 cell culture medium, whereas TSA did not. In a CT26 bilateral subcutaneous tumour model, DXR or TSA was injected in a single tumour. After injection, serum HMGB1 concentration in DXR-treated mice was 10 times higher than that in TSA-treated mice. After DXR treatment, the contralateral and remnant tumours showed more pronounced growth than did those treated with TSA. In mouse models, lung and liver metastasis was enhanced by DXR but not by TSA. DXR-enhanced metastasis was abrogated by anti-HMGB1 antibody treatment. In a cancer dormancy model, DXR induced regrowth of quiescent CT26 cells. HMGB1 induced tumour necrosis factor-α secretion via Toll-like receptor (TLR)4 in U937 monocytes; however, HMGB1 decreased the number of U937 cells, resulting in restriction of immune activation via receptor for advanced glycation endproducts (RAGE). RAGE showed a more pronounced effect on nuclear factor kappa B activation than did TLR4 in CT26 cells. These findings suggest that HMGB1 released from necrotic cancer cells treated with a necrosis inducer enhances regrowth and metastasis of remnant cancer cells via RAGE activation.
authors.affiliation: Department of Molecular Pathology, Nara Medical University, Kashihara, Japan.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Chihara
authors.forename: Kiyohide
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Tomonori
authors.initials: T
authors.lastname: Sasahira
authors.forename: Masaomi
authors.initials: M
authors.lastname: Kuwada
authors.forename: Rina
authors.initials: R
authors.lastname: Fujiwara
authors.forename: Kiyomu
authors.initials: K
authors.lastname: Fujii
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohmori
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kuniyasu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000627:therapeutic use; D024243:HMGB1 Protein / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009362:Neoplasm Metastasis; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology; D020298:U937 Cells
chemical_list: D024243:HMGB1 Protein; D006877:Hydroxamic Acids; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C012589:trichostatin A; D004317:Doxorubicin