Study Shows Heterogeneity in Brain Tumor Cells-of-Origin

A new study led by the National Neuroscience Institute (NNI) and Singapore Institute for Clinical Sciences (SICS), A*STAR shows for the first time that primary brain tumors are caused by a minority group of cells that display a genetic profile distinct from that of the tumor bulk.

This minority group of cells has established a method of cryopreservation for these tumorinitiating cells (frequently termed “cancer stem cells”), thus facilitating the development of a brain tumor stem cell repository for future research and drug screening efforts. The findings have been accepted for publication in Stem Cells.

Although malignant tumors are known to be made up of a variety of cell types, this concept of cellular heterogeneity in the study and design of anti-cancer therapeutics has largely been ignored. Emerging evidence in recent years has established key culprit cells within the tumor mass – the cancer stem cells, which are responsible for initiation and propagation of tumor growth.

These cancer stem cells are considered resistant to radiation and chemotherapy. The latter adjuvant therapies, which preferentially target rapidly dividing cells thus end up eliminating the bulk of tumor cells but spare these stem cells that divide at a slower rate.

Primary malignant brain tumors are devastating cancers with poor survival rates despite major advances in surgical technology and adjuvant therapies. The results of this study demonstrate the isolation of brain tumor stem cells from patient tumor samples, which are capable of re-creating tumor masses in mice.

These implanted cells in the mouse brain would eventually form tumors with morphology identical to that seen on the pathological analysis of patient specimens. The tumor cells-of-origin display genetic profiles that are distinct from the tumor bulk.

Researchers have found that different patients with similar tumor tissue pathology on microscopic examination display different genetic profi les in their cells-oforigin, the cancer stem cells. This has major implications as current treatment strategies are largely decided based upon classification systems tailored according to morphological characteristics of the tumor.

The different genetic profiles of such tumor stem cells might explain variability of treatment response and points to the existence of different genetic brain tumor subtypes which one is unable to discern based on current classifi cation systems.

As brain tumor stem cells constitute the minority of the tumor mass, a key challenge has been to create a stable collection of such cells to enable investigative efforts in drug screening. The researchers have established a method of cryopreservation that facilitates the establishment of a brain tumor stem cell repository.

The study is led by senior co-investigators Carol Tang, a NNI research scientist and Christopher Ang Beng Ti, a neurosurgeon at NNI and clinical investigator with SICS, with collaborative efforts from the National University of Singapore, National Cancer Centre, Duke-NUS Graduate Medical School and Genome Institute of Singapore.

Brain tumor-initiating cells are stained for various markers. A) Nestin and Musashi-1 indicate cells with stem cell-like properties.

B) Neurons (marked by TuJ1) are formed by differentiated brain tumor stem-like cells.

C) Brain tumor stem-like cells differentiate to form cells with neuronal and astrocytic properties.