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RANK-mediated signaling network and cancer metastasis

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Abstract

Cancer metastasis is highly inefficient and complex. Common features of metastatic cancer cells have been observed using cancer cell lines and genetically reconstituted mouse and human tumor xenograft models. These include cancer cell interaction with the tumor microenvironment and the ability of cancer cells to sense extracellular stimuli and adapt to adverse growth conditions. This review summarizes the coordinated response of cancer cells to soluble growth factors, such as RANKL, by a unique feed forward mechanism employing coordinated upregulation of RANKL and c-Met with downregulation of androgen receptor. The RANK-mediated signal network was found to drive epithelial to mesenchymal transition in prostate cancer cells, promote osteomimicry and the ability of prostate cancer cells to assume stem cell and neuroendocrine phenotypes, and confer the ability of prostate cancer cells to home to bone. Prostate cancer cells with activated RANK-mediated signal network were observed to recruit and even transform the non-tumorigenic prostate cancer cells to participate in bone and soft tissue colonization. The coordinated regulation of cancer cell invasion and metastasis by the feed forward mechanism involving RANKL, c-Met, transcription factors, and VEGF-neuropilin could offer new therapeutic opportunities to target prostate cancer bone and soft tissue metastases.

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Acknowledgments

This work was supported in part by a NCI PO-1 grant (2P01CA098912), RO-1 grant (1R01CA122602), Board of Governor's Distinguished Cancer Chair and PCF Challenge and 2013 Steve Wynn Young Investigator Awards. We thank Mr. Gary Mawyer from the University of Virginia for editorial assistance, Dr. Ruoxiang Wang from Cedars-Sinai Medical Center for his role in providing critical reading of this manuscript and manuscript processing, and Drs. John Lu and Murali Gururajan from Cedars-Sinai Medical Center for their help in the construction of RANK-mediated signal network in PCa cells.

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  1. Departments of Medicine and Surgery, Samuel Orchin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Gina Chia-Yi Chu & Leland W. K. Chung

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  1. Gina Chia-Yi Chu
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Correspondence to Leland W. K. Chung.

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Chu, G.CY., Chung, L.W.K. RANK-mediated signaling network and cancer metastasis. Cancer Metastasis Rev 33, 497–509 (2014). https://doi.org/10.1007/s10555-013-9488-7

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