title: Cyclophosphamide creates a receptive microenvironment for prostate cancer skeletal metastasis.
abstract: A number of cancers predominantly metastasize to bone, due to its complex microenvironment and multiple types of constitutive cells. Prostate cancer especially has been shown to localize preferentially to bones with higher marrow cellularity. Using an experimental prostate cancer metastasis model, we investigated the effects of cyclophosphamide, a bone marrow-suppressive chemotherapeutic drug, on the development and growth of metastatic tumors in bone. Priming the murine host with cyclophosphamide before intracardiac tumor cell inoculation was found to significantly promote tumor localization and subsequent growth in bone. Shortly after cyclophosphamide treatment, there was an abrupt expansion of myeloid lineage cells in the bone marrow and the peripheral blood, associated with increases in cytokines with myelogenic potential such as C-C chemokine ligand (CCL)2, interleukin (IL)-6, and VEGF-A. More importantly, neutralizing host-derived murine CCL2, but not IL-6, in the premetastatic murine host significantly reduced the prometastatic effects of cyclophosphamide. Together, our findings suggest that bone marrow perturbation by cytotoxic chemotherapy can contribute to bone metastasis via a transient increase in bone marrow myeloid cells and myelogenic cytokines. These changes can be reversed by inhibition of CCL2.
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Serk In
authors.initials: SI
authors.lastname: Park
authors.forename: Jinhui
authors.initials: J
authors.lastname: Liao
authors.forename: Janice E
authors.initials: JE
authors.lastname: Berry
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Koh
authors.forename: Megan E
authors.initials: ME
authors.lastname: Michalski
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Eber
authors.forename: Fabiana N
authors.initials: FN
authors.lastname: Soki
authors.forename: David
authors.initials: D
authors.lastname: Sadler
authors.forename: Sudha
authors.initials: S
authors.lastname: Sud
authors.forename: Sandra
authors.initials: S
authors.lastname: Tisdelle
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Daignault
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Nemeth
authors.forename: Linda A
authors.initials: LA
authors.lastname: Snyder
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wronski
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Laurie K
authors.initials: LK
authors.lastname: McCauley
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects; D001859:Bone Neoplasms / Q000556:secondary*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000494:pharmacology; D003520:Cyclophosphamide / Q000009:adverse effects / Q000494:pharmacology*; D000077143:Docetaxel; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000473:pathology*; D043823:Taxoids / Q000494:pharmacology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018932:Chemokine CCL2; D015850:Interleukin-6; D043823:Taxoids; D000077143:Docetaxel; D003520:Cyclophosphamide