A collective route to metastasis: Seeding by tumor cell clusters

Kevin J. Cheung and Andrew J. Ewald (April 7, 2016) Science 352 (6282), 167-169. [doi: 10.1126/science.aaf6546]

Summary & Highlights

  • “Although conventional models suggest that metastases are seeded by single cells from the primary tumor, there is growing evidence that seeding requires the collective action of tumor cells traveling together in clusters.”
  • Carcinomas typically arise from polarized, nonmotile epithelial cells… striking difference from original state!
  • Tumor clusters first observed in 1950s in blood… tumors more efficient at producing metastases than single cells when injected intravenously!
  • If metastatic seed is single cancer cell, resulting tumor = clonal; if seed is cicrulating tumor cells (CTC) cluser, then metastasis can be polyclonal from the start
  • A breast cancer study in mice showed that >97% of metastases arose from clusters
  • Clusters exhibited superior survival & colony-forming potential in culture and in vivo
  • A recent 3D dimensional analysis of stromal border of human breast tumors detected frequent collective invasion and basically no single cancer cells! [P. Bronsert et al., J. Pathol. 234, 410–422 (2014).]
  • Cancer cells leading collective invasion have common molecular properties across subtypes of breast cancer
    • Markers of basal epithelial differentiation, including cytokeratin14 (K14), K5, P-cadherin, p63
    • K14+ invasive state observed in all stages of disseminative spread (collective in- vasion, local dissemination, CTC cluster, and micrometastasis), but rare in primary tumor and micrometastases
  • Previously, it was thought that intercellular adhesion complexes impede motility, so metastasis = transient/permanent loss of epithelial features (via EMT)
    • HOWEVER, show that epithelial adhesion complexes play important role! Breast cancer cells retain the expression of epithelial cytoskeletal and adhesion genes (K5, K8, K14, E-cad, P-cad)
    • Seems like you need these to allow for cancer cell clusters to stick

Future Questions

  • How do tumor cell clusters escape from primary tumor?
  • What are their molecular properties as the clusters transit to the distant site?
  • How does the budding off of small clusters of cancer cells actually happen?
  • Do cancer cells exhibit migratory advances during metastasis or are they more metastatic simply because they can survive better?
  • “It remains an important future challenge to distin- guish the relative frequencywithwhich epithelial- phenotype versus mesenchymal-phenotype tumor cell clusters function asmetastatic seeds.”
  • “What is the biological basis of metastatic seeding by tumor cell clusters?”
    • Need to understand mechanisms that drive enhanced metastatic efficiency of clusters relative to single cells
    • Also understand how cell clusters coordinate their migration/differentiation
    • How do clusters interface with stromal population?
  • What causes single cells to pop out, versus a whole cell pulling??
  • What are the cell/molecular properties of metastatic seed across different tumor types/sites?

Personal Thoughts

  • K14 stuff pretty interesting. Could use this as marker for in vitro studies.
  • Seems like there’s still a lot not known about this topic. Lots of room for research– this paper is more focused on the genetics aspect, but what about the mechanical strengths of these clusters? How well do they stay together?
  • At what points on the spheroids do the cells choose to migrate out?
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