title: Blocking IL1β Pathway Following Paclitaxel Chemotherapy Slightly Inhibits Primary Tumor Growth but Promotes Spontaneous Metastasis.
abstract: Acquired resistance to therapy is a major obstacle in clinical oncology, and little is known about the contributing mechanisms of the host response to therapy. Here, we show that the proinflammatory cytokine IL1β is overexpressed in response to paclitaxel chemotherapy in macrophages, subsequently promoting the invasive properties of malignant cells. In accordance, blocking IL1β, or its receptor, using either genetic or pharmacologic approach, results in slight retardation of primary tumor growth; however, it accelerates metastasis spread. Tumors from mice treated with combined therapy of paclitaxel and the IL1 receptor antagonist anakinra exhibit increased number of M2 macrophages and vessel leakiness when compared with paclitaxel monotherapy-treated mice, indicating a prometastatic role of M2 macrophages in the IL1β-deprived microenvironment. Taken together, these findings demonstrate the dual effects of blocking the IL1 pathway on tumor growth. Accordingly, treatments using "add-on" drugs to conventional therapy should be investigated in appropriate tumor models consisting of primary tumors and their metastases.
authors.affiliation: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Tali
authors.initials: T
authors.lastname: Voloshin
authors.affiliation: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Alishekevitz
authors.affiliation: Faculty of Biotechnology, Technion, Haifa, Israel.
authors.forename: Limor
authors.initials: L
authors.lastname: Kaneti
authors.affiliation: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Valeria
authors.initials: V
authors.lastname: Miller
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Elina
authors.initials: E
authors.lastname: Isakov
authors.affiliation: The Shraga Segal Department of Microbiology, Immunonology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Irena
authors.initials: I
authors.lastname: Kaplanov
authors.affiliation: The Shraga Segal Department of Microbiology, Immunonology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Voronov
authors.affiliation: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Fremder
authors.affiliation: Department of Biochemistry, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Benhar
authors.affiliation: Faculty of Biotechnology, Technion, Haifa, Israel.
authors.forename: Marcelle
authors.initials: M
authors.lastname: Machluf
authors.affiliation: The Shraga Segal Department of Microbiology, Immunonology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Ron N
authors.initials: RN
authors.lastname: Apte
authors.affiliation: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel. yshaked@tx.technion.ac.il.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D017239:Paclitaxel / Q000008:administration & dosage; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D017239:Paclitaxel