A recent study, led by Itay Tirosh of Broad Institute Massachusetts and in collaboration with Massachusetts General Hospital, has reported the involvement of cancer stem cells (CSCs) in shaping the fate of tumor cells progeny. By utilizing the knowledge of genomics related to brain tumors, it became evident to the researchers that CSCs do exist and play a vital role in the proliferation of oligodendroglioma – an incurable brain tumor.
Glioblastoma, the tumor of supportive tissue of the brain, has been a point of focus of extensive research in the past few years. The conclusive remarks of those studies agreed upon the importance of stem cells like cells in the aggressiveness of brain tumors e.g., glioblastoma. In the previously reported studies, animal models (mice) were induced with brain tumors and then the test subjects were analyzed; which raised questions regarding the relevance of these studies with that of human cancer cells.
In the present study, six samples were taken from human brain tumors (oligodendrogliomas from both IDH1 and IDH2 or both mutations) at an early stage and cells were isolated at single-cell state for RNA sequencing in order to better understand the mechanism involved in the proliferation of oligodendroglioma.
Oligodendroglioma comes under the umbrella of glioma, having an origin in either the glial (precursor) cells or the oligodendrocytes. The oligodendroglioma accounts for 9.4% of total brain tumors in adults and 4% of total brain tumors in children.
Mario Suva of Department of Pathology at Massachusetts General Hospital, a senior author of the study, highlighted the importance of CSCs by saying, “Our work strongly supports that cancer stem cells are the main source of growth in these tumors and, as such, should be considered promising targets for treatment.”
Do We Really Know Cancer Cells That Well?
A total of 4,347 single cell brain cancer cells were analyzed individually, making this study the most expansive of its kind to date. This helped the researchers classify the cancer cells into three categories depending on their development; the first category had a striking resemblance to neural stem cells while the other two categories had genes pointing them towards their respective differentiation spells.
The research unearthed that there was a particular subset of cells – cancer stem cells – which specifically showed proliferation in all the six samples while the remaining cancer cells did not show any such indication. While the cancer cells in majority follow the same process of maturation before differentiation and so on, these subsets of cells have their own gene expression signals similar to that of neural stem cells.
The three signs of development of proliferation were only shown by a particular set of tumor cells which shared identical genetic material (genetic clones). All of the proliferating cancer cells had an association with these cancer stem cells across six samples. Even in the case of tumor cells possessing and occurring because of different genetic mutations, they had similar stem cells as observed in the case of normal neural stem cells giving rise to neural cells.
About this particular finding Mario Suva said, “Finding that different subclones within tumors show the same developmental patterns suggests that developmental programs – whether in stem cells or differentiated cancer cells – set the context within which genetic evolution of oligodendroglioma occurs, which is key to supporting the cancer stem cell model.”
“Trying to understand as much as we can about genetic versus non-genetic determinants of tumor organization is key to our understanding of tumor propagation and to the design of new therapies. Our work suggests that targeting a specific stem cell phenotype, for example with immunotherapies, could be beneficial in patients with oligodendroglioma,” she also added.
A Breakthrough To Beat Cancer At Its Roots
When the copy number variation (CNV) of the tumor subclones was done, it was noticed that they shared same hierarchical structure of their cellular components which leads to the assumption of the presence of pre-determined developmental programs that dictate the overall proliferation span of oligodendroglioma.
If the point-mutations — that cause a single nucleotide insertion, deletion or substitution — are considered for the cancer subclones, even then it supports the cancer stem cell model. There is a need to consider extensive phylogenetic studies in order to assess the effect of genetic evolution on these developmental programs in the long run. This study firmly suggests that after carefully examining oligodendrogliomas at single cell level utilizing the precise single cell analysis techniques, there is a presence of stem cell model for cancers as well which operates and signals in accordance with the hierarchies followed by neural stem cell.
The extensive study clearly suggests that a therapy – targeting cancer stem cells – can help in restricting the growth of the tumor and this approach can be equally applied to all aggressive brain tumors. Moreover, this strategy can also be utilized to manage the progression and resistance towards the treatment of other emerging cancers e.g., leukemia that predominately presents as the tumor of the blood system.