Politics aside, we recently lost one of our public servants who dedicated more than 40 years of service to our country. Towards the end of his life, Senator John McCain suffered from glioblastoma, a very aggressive and malignant type of brain cancer. Currently, the standard treatment for glioblastoma relies on surgery, radiation, and chemotherapy using the drug temozolomide. Even with prompt treatment, however, the prognosis is very poor, with less than 5% of patients surviving 5 years after diagnosis (Tamimi and Juweid, 2017). This is because many of these patients experience a recurrence of the cancer from undetected and evasive glioblastoma cells. Although that sounds discouraging, many researchers are working hard to understand the reasons for this relapse.
One research group from Belgium found one possible explanation. They showed that glioblastoma initiating-cancer cells migrate into areas of the brain called neurogenic niches, which are populated with stem cells and progenitor cells that eventually become neurons and other brain cells (Kroneen J, et al. 2011). These neurogenic zones give off cues that signal the stem cells to remain dormant or to divide. The researchers originally suggested that the cancer cells migrate towards these zones to hide and become dormant like the stem cells, where they gain resistance to chemotherapy because a majority of the drugs specifically target rapidly dividing (i.e. active) cancer cells.
The group later discovered that the glioblastoma cells were also able to survive radiation treatment while within these niches (Goffart, et al. 2017). This raises the question: what is in this neurogenic niche that enables them to survive? The answer has yet to be determined, but the research group found a protein called chemokine CXCL12 that may give us some clues. This small protein is secreted by cells in the subventricular zone, one of those niches, to attract the cancer cells. CXCL12 then binds to a receptor on the surface of the cancer cells. This, in turn, causes the cancer cells to become mesenchymal or “connective tissue-like”, where they become resistant to radiation. But how do these cancer cells migrate to those niches in the first place?
To answer that question, the researchers used CXCL12 to stimulate glioblastoma cells and identify proteins that changed. They showed that the protein called Aurora A gets activated in response to CXCL12 (Willems, et al. 2018). This then leads to the reorganization of the cytoskeleton (the network of protein filaments such as actin and vimentin that give shape and structure to the cells), triggering the migration of cancer cells towards those niches in the brain. The researchers therefore concluded that altered levels of CXCL12 interacting with Aurora A could affect the progression of glioblastoma. Together, their work sheds light on the role of CXCL12 in tumor invasion and resistance to treatment.
So there you go! We managed to unravel one way glioblastoma cells can mask themselves and hide from treatments, persisting in the brain undetected. After surgery to remove the visible brain tumor, there can still be some remaining undetected glioblastoma cells. These cancerous cells can hide in regions of the brain where they can become dormant and protected from radiation or chemotherapy. They can then later emerge and begin to grow again more aggressively. It sounds like these cancer cells have built their own Cû Chi tunnels that researchers have yet to fully uncover.
Tamimi AF, Juweid M. Epidemiology and Outcome of Glioblastoma. In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 8. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470003/ doi: 10.15586/codon.glioblastoma.2017.ch8
Kroonen J, et al. Human glioblastoma-initiating cells invade specifically the subventricular zones and olfactory bulbs of mice after striatal injection. Int J Cancer 2011. PMID: 20886597
Goffart N, et al. CXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone. Neuro Oncol 2017. PMID: 27370398
Willems E, et al. Aurora A plays a dual role in migration and survival of human glioblastoma cells according to the CXCL12 concentration. Oncogene 2018. PMID: 30082913
Glioblastoma macro, Sbrandner