The metastatic microenvironment: Brain-residing melanoma metastasis and dormant micrometastasis

Sivan Izraely, Orit Sagi-Assif, Anat Klein, Tsipi Meshel, Galia Tsarfaty, Metsada Pasmanik-Chor, Clara Nahmias, Pierre Olivier Couraud, Eugene Ateh, Joseph L. Bryant, Dave S.B. Hoon, Isaac P. Witz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Brain metastasis occurs frequently in melanoma patients with advanced disease whereby the prognosis is dismal. The underlying mechanisms of melanoma brain metastasis development are not well understood. We generated a reproducible melanoma brain metastasis model, consisting of brain-metastasizing variants and local, subdermal variants that originate from the same melanomas thus sharing a common genetic background. The brain-metastasizing variants were obtained by intracardiac inoculation. Brain metastasis variants when inoculated subdermally yielded spontaneous brain dormant micrometastasis. Cultured cells from the spontaneous brain micrometastasis grew very well in vitro and generated subdermal tumors after an orthotopic inoculation. Expression analysis assays indicated that the brain metastasis and micrometastasis cells expressed higher levels of angiopoietin-like 4, prostaglandin-synthesizing enzyme cyclooxygenase-2, matrix metalloproteinase-1 and preferentially expressed antigen in melanoma and lower levels of claudin-1 and cysteine-rich protein 61 than the corresponding cutaneous variants. The reproducible models of human melanoma metastasizing experimentally and spontaneously to the brain will facilitate the identification of novel biomarkers and targets for therapy and contribute to the deciphering of mechanisms underlying melanoma metastasis.

Original languageEnglish
Pages (from-to)1071-1082
Number of pages12
JournalInternational Journal of Cancer
Issue number5
StatePublished - 1 Sep 2012


  • Brain metastasis
  • Dormancy
  • Melanoma
  • Micrometastasis
  • Xenograft model


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