ZFIN ID: ZDB-PUB-130712-6
Carcinoma cells misuse the host tissue damage response to invade the brain
Chuang, H.N., van Rossum, D., Sieger, D., Siam, L., Klemm, F., Bleckmann, A., Bayerlová, M., Farhat, K., Scheffel, J., Schulz, M., Dehghani, F., Stadelmann, C., Hanisch, U.K., Binder, C., and Pukrop, T.
Date: 2013
Source: Glia   61(8): 1331-46 (Journal)
Registered Authors: Sieger, Dirk
Keywords: astrocytes, brain metastasis, damage response, glia, invasion, microglia
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Apoptosis/genetics
  • Brain/immunology
  • Brain/pathology*
  • Brain Neoplasms/genetics
  • Brain Neoplasms/immunology
  • Brain Neoplasms/pathology*
  • Carcinoma/genetics
  • Carcinoma/immunology
  • Carcinoma/pathology
  • Coculture Techniques
  • Dogs
  • Humans
  • MCF-7 Cells
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Invasiveness/genetics
  • Neoplasm Invasiveness/immunology
  • Neoplasm Invasiveness/pathology*
  • Organ Culture Techniques
  • Zebrafish
PubMed: 23832647 Full text @ Glia

The metastatic colonization of the brain by carcinoma cells is still barely understood, in particular when considering interactions with the host tissue. The colonization comes with a substantial destruction of the surrounding host tissue. This leads to activation of damage responses by resident innate immune cells to protect, repair, and organize the wound healing, but may distract from tumoricidal actions. We recently demonstrated that microglia, innate immune cells of the CNS, assist carcinoma cell invasion. Here we report that this is a fatal side effect of a physiological damage response of the brain tissue. In a brain slice coculture model, contact with both benign and malignant epithelial cells induced a response by microglia and astrocytes comparable to that seen at the interface of human cerebral metastases. While the glial damage response intended to protect the brain from intrusion of benign epithelial cells by inducing apoptosis, it proved ineffective against various malignant cell types. They did not undergo apoptosis and actually exploited the local tissue reaction to invade instead. Gene expression and functional analyses revealed that the C-X-C chemokine receptor type 4 (CXCR4) and WNT signaling were involved in this process. Furthermore, CXCR4-regulated microglia were recruited to sites of brain injury in a zebrafish model and CXCR4 was expressed in human stroke patients, suggesting a conserved role in damage responses to various types of brain injuries. Together, our findings point to a detrimental misuse of the glial damage response program by carcinoma cells resistant to glia-induced apoptosis.