Editors' ChoiceTUMOR MICROENVIRONMENT

Antidepressants protect bones from metastatic prostate cancer

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Sci. Signal.  28 Mar 2017:
Vol. 10, Issue 472, eaan2866
DOI: 10.1126/scisignal.aan2866

Monoamine oxidase A–targeted antidepressants inhibit a tumor-stroma loop and could delay the metastatic outgrowth of prostate cancer.

Monoamine oxidase A inhibitors (MAOIs) are used to treat patients with depression or Parkinson’s disease. They work by increasing the amount of the neurotransmitters norepinephrine, serotonin and dopamine in the brain. Wu et al. discovered that MAOIs might be repurposed for patients with advanced prostate cancer (PCa) because of their effects in the metastatic tumor microenvironment (see also Nyquist and Nelson). MAOA abundance was associated with metastasis in a cohort of prostate cancer patients. In cell culture models, MAOA stimulated Sonic hedgehog (Shh) production in tumor cells through the transcription factor TWIST. Secreted Shh then transcriptionally activated target genes in stromal cells. Consequently, increased secretion of interleukin-6 and nuclear factor κB ligand (RANKL) from stromal osteoblasts caused bone destruction, which facilitates metastatic colonization of the bone. Bone destruction released growth factors that then stimulated more Shh production from tumor cells. Treating mouse models of disseminated prostate cancer with the MAOI clorgyline delayed bone and visceral colonization, potentially by suppressing this self-amplifying tumor-stroma loop. Thus, MAOIs might be a new therapeutic strategy for patients with advanced prostate cancer.

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