title: The tumor-educated-macrophage increase of malignancy of human pancreatic cancer is prevented by zoledronic acid.
abstract: We previously defined macrophages harvested from the peritoneal cavity of nude mice with subcutaneous human pancreatic tumors as "tumor-educated-macrophages" (Edu) and macrophages harvested from mice without tumors as "naïve-macrophages" (Naïve), and demonstrated that Edu-macrophages promoted tumor growth and metastasis. In this study, Edu- and Naïve-macrophages were compared for their ability to enhance pancreatic cancer malignancy at the cellular level in vitro and in vivo. The inhibitory efficacy of Zoledronic acid (ZA) on Edu-macrophage-enhanced metastasis was also determined. XPA1 human pancreatic cancer cells in Gelfoam co-cultured with Edu-macrophages proliferated to a greater extent compared to XPA1 cells cultured with Naïve-macrophages (P = 0.014). XPA1 cells exposed to conditioned medium harvested from Edu culture significantly increased proliferation (P = 0.016) and had more migration stimulation capability (P<0.001) compared to cultured cancer cells treated with the conditioned medium from Naïve. The mitotic index of the XPA1 cells, expressing GFP in the nucleus and RFP in the cytoplasm, significantly increased in vivo in the presence of Edu- compared to Naïve-macrophages (P = 0.001). Zoledronic acid (ZA) killed both Edu and Naïve in vitro. Edu promoted tumor growth and metastasis in an orthotopic mouse model of the XPA1 human pancreatic cancer cell line. ZA reduced primary tumor growth (P = 0.006) and prevented metastasis (P = 0.025) promoted by Edu-macrophages. These results indicate that ZA inhibits enhanced primary tumor growth and metastasis of human pancreatic cancer induced by Edu-macrophages.
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America; Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hiroshima
authors.affiliation: Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Ali
authors.initials: A
authors.lastname: Maawy
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Mohamed K
authors.initials: MK
authors.lastname: Hassanein
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America.
authors.forename: Rhiana
authors.initials: R
authors.lastname: Menen
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Momiyama
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Shinji
authors.initials: S
authors.lastname: Miwa
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Mako
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Fuminari
authors.initials: F
authors.lastname: Uehara
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Shuya
authors.initials: S
authors.lastname: Yano
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Mori
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Ryusei
authors.initials: R
authors.lastname: Matsuyama
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Chishima
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kuniya
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ichikawa
authors.affiliation: Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.affiliation: Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Endo
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D064593:Heterografts; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008938:Mitosis; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology*; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid