Cyclophosphamide creates a receptive microenvironment for prostate cancer skeletal metastasis

Serk In Park, Jinhui Liao, Janice E. Berry, Xin Li, Amy J. Koh, Megan E. Michalski, Matthew R. Eber, Fabiana N. Soki, David Sadler, Ha Sud, Sandra Tisdelle, Stephanie D. Daignault, Jeffrey A. Nemeth, Linda A. Snyder, Thomas J. Wronski, Kenneth J. Pienta, Laurie K. McCauley

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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.

Original languageEnglish
Pages (from-to)2522-2532
Number of pages11
JournalCancer Research
Volume72
Issue number10
DOIs
Publication statusPublished - 2012 May 15

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Park, S. I., Liao, J., Berry, J. E., Li, X., Koh, A. J., Michalski, M. E., Eber, M. R., Soki, F. N., Sadler, D., Sud, H., Tisdelle, S., Daignault, S. D., Nemeth, J. A., Snyder, L. A., Wronski, T. J., Pienta, K. J., & McCauley, L. K. (2012). Cyclophosphamide creates a receptive microenvironment for prostate cancer skeletal metastasis. Cancer Research, 72(10), 2522-2532. https://doi.org/10.1158/0008-5472.CAN-11-2928