A CCL8 gradient drives breast cancer cell dissemination

Oncogene. 2016 Dec 8;35(49):6309-6318. doi: 10.1038/onc.2016.161. Epub 2016 May 16.

Abstract

The migration of cancer cells towards gradients of chemoattractive factors represents a potential, yet elusive, mechanism that may contribute to cancer cell dissemination. Here we provide evidence for the maintenance of a gradient of increasing CCL8 concentration between the epithelium, the stroma and the periphery that is instrumental for breast cancer cells' dissemination. In response to signals elicited by the neoplastic epithelium, CCL8 production is enhanced in stromal fibroblasts at the tumor margins and in tissues at which breast cancer cells tend to metastasize such as the lungs and the brain. Manipulation of CCL8 activity influences the histology of the tumors and promotes major steps of the metastatic process such as invasion to adjacent stroma, intravasation and ultimately extravasation and seeding. These findings exemplify how gradients of chemoattractive factors such as CCL8, drive metastasis and suggest that interference with their operation may provide means for breast cancer management.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3 Cells
  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Chemokine CCL8 / biosynthesis
  • Chemokine CCL8 / genetics
  • Chemokine CCL8 / metabolism*
  • Female
  • Humans
  • MCF-7 Cells
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RAW 264.7 Cells
  • Transfection

Substances

  • CCL8 protein, human
  • Ccl8 protein, mouse
  • Chemokine CCL8