BRAIN CANCER STEM CELLS AND BEYOND
LAY REVIEW

What are Stem Cells?
Stems cells are what all cells from all organs, tissues etc. existed as in the very beginning of their lives.  There are diverse array of stem cells including embryonic stem cells, which have the total potential to become an entire organism.  Hypothetically embryonic stem cells are the derivatives of every single cell type in the body, whether it be a heart cell (cardiomyocyte), a liver cell (hepatocyte), a brain cell (neuron or glial cell), or a blood cell (red and white blood cells), all of these cells at the earliest stage of development originated as what scientists call a totipotent embryonic stem cell.  Beyond this point, there are more compartmentalized stem cells like a hematopoietic stem cell, which eventually evolves into red blood cells, platelets, macrophages, T and B cells for “learned, adaptive” immunity, granulocytic leukocytes like neutrophils, basophils, and eosinophils for your “automatic” immunity.  Another type of stem cell is the adult stem cell, which is still a stem cell but possesses some bias as to what cell it will form and it tends to replenish mature specialized cells of organs and tissues in which itself resides in. 

Besides all of these varying capabilities of stem cells, they have some hallmark qualities in common.  Stem cells can self-renew, meaning during cell division it creates a copy of itself which is identical in every aspect and is a primitive, undifferentiated stem cell just like the one it arose from.  The other cell progeny is a daughter cell that has the genes to code for proliferation, meaning it will grow and mature until it becomes the specialized cell that it is destined to become.  For example, a hematopoietic stem cell will produce two progeny cells; one being identical to the mother stem cell and relatively inactive, the other being a daughter cell that after it has finished evolving into various progenitors and precursors it will terminally differentiate and ultimately become that functional, mature red blood cell, or platelet.  Another characteristic quality of stem cells is that of asymmetric division.  It divides this way because of that single self-renewed progeny cell, which does not divide or give rise to differentiated cells.  The figure below helps explain the phenomenon.

Cancer Stem Cells and Brain Cancer Stem Cells
Cancer stem cells are essentially the primitive cells that the rapidly, out of control dividing cancer cells derive from.  Everyone knows the tremendous effect cancer has on peoples’ lives each year and the countless number of dollars spend on healthcare and research for this disease.  Unlike stem cells, which have been studied for over 50 years, cancer stem cells are relatively new on the field. Originally, scientists believed that tumors and cancers were composed of a homogenous population of cancer cells, meaning all the cells were relatively the same and behaved the same way.  It has been known that cancer cells could divide rapidly, and relatively out of control with the apoptotic (cell death) mechanism in disarray, unable to tell the defective cells to essentially “kill” themselves to ensure the message (DNA code) was not passed on to the next progeny cell and inevitably recapitulate the dysfunction.  It was accepted than any one particular cell in a tumor can cause cancer in much the same way that the next cancer cell of the tumor can.  In other words, all the cells of the tumor were equally carcinogenic and able to cause pathology.  This is known as the “old cancer model.”  Recent studies have strongly contradicted this notion.  Now it is known and widely accepted by many that cancer stem cells are a small population of cells within the realm of the cancer or tumor, that are absolutely essential in the tumor’s growth and survival.  They make up a small percentage of the total number of cells, while the largest percentage consists of the non-tumorigenic cancer cells.  This is known as the “new cancer model.”  With this knowledge, doctors are better able to devise treatments and therapies against tumors like for example, glioblastoma multiforme, which is a brain tumor.  They should no longer be looking to destroy the cancer cells and shrink the tumor, because with the cancer stem cells undamaged the cancer remains in possession of the blueprint for causing disease and ultimately its goal of death.  With the cancer stem cells still intact the tumor will just grow back and perhaps be even more adaptive and armed to survive longer.  So what should doctors do?

Brain cancer stem cells are very similar in purpose and importance to cancer stem cells.  The mere difference being brain cancer stem cells apply to the many different types of cancer and tumors of the brain.  The most common type of brain tumor is known as a glioma.  Within the glioma class of brain tumors, there are other specific names of brain tumors that reflect the origin and cells/tissues affected; there are astrocytomas which are derived from glial cells known as astrocytes, and another very important brain tumor in the astrocytoma family is called glioblastoma multiforme.  This brain tumor is actually the most malignant of all brain tumors and it has an extremely poor prognosis.  Some other important brain tumors are medulloblastomas, oligodendrogliomas and ependymoma.

Scientific Evidence of Existence
In studies conducted over the past three years, it was found that brain cancer stem cells have a neurological origin.  It is quite possible that brain cancer stem cells arose from mutations in specialized adult cells like oligodendrocytes, and astrocytes.  The mutations could have caused these slow dividing mature cells to revert back to the stem cell phenotype (dedifferentiation) and regain the stem cell property of self renewal thus making them neural stem cells again and no longer specialized.

Another possible scenario for the origin of these brain cancer stem cells is maybe something went wrong during the life cycle of the mature neural cells; acquired oncogenic mutations, or received some extraneous cell-signal that caused it to lose its functional capability and convert into a brain cancer stem cell.  After all, the majority of brain tumors involve the differentiated cells that result from neural stem cells (neurons, astrocytes, and oligodendrocytes).  There is a lot of research going on now bridging the gap between the central nervous system, brain tumors, and brain cancer stem cells.  The discovery of neural stem cells however has changed the way brain cancer has been studied.  It is now widely thought these neural stem cells take the brunt of these mutations and subsequently cause abnormal behavior of the specialized cells they give rise to.  Some evidence of this is that most deadly brain tumors such as medulloblastoma and glioblastoma multiforme.  There have been studies that have shown these brain tumors share specific properties with neural stem cells, and this aides the argument that brain tumors are stem cell derived.  A group of scientists at the University of Toronto were able to put forward some solid evidence that shows brain cancer stem cells exist and have close ties with neural stem cells.  These scientists were able to isolate “cancer stem cells” from medulloblastoma and glioblastoma multiforme, two of the most common brain tumors.  After breaking up the tumor samples and adding media and some growth factors amongst other things, they were able to observe floating aggregates known as neurospheres.  These neurospheres are usually formed by neural stem cells when subjected to the same conditions.  These “brain tumor” derived aggregates exhibited self-renewal in culture and expressed neural stem cell markers such as Nestin, CD133, Notch and some other important tell-tale differentiation markers, that in layman’s terms should not have been present on those tumor cells if they did not have some stem cell properties.  But what if they really did have stem cell properties because there were brain cancer stem cells within them?  Eventually, the scientists found that these aggregates they developed from the two separate brain tumors were able to generate their characteristic malignancies in an in vivo animal model.  They concluded that medulloblastomas and glioblastomas contained “cancer-initiating neural stem cell-like cells.”  Later on they were able to use an anti-CD133 antibody and purify their brain cancer stem cells from the two brain tumors.  They concluded by suggesting that CD133 is an excellent marker of brain cancer stem cells along with normal stem cells.

With the recognition of cancer stem cells and brain cancer stem cells now, the way in which scientists and doctors collaborate to come up with new therapies to fight brain cancer and tumors is evolving each and every day.  The way in which drug companies develop anti-cancer drugs inevitably has to change now because of the new cancer model, and they can no longer appease the general population by putting drugs out there that they know shrink tumors and lower cancer threat levels, but do not fully eradicated the disease.  People understand we are leaps and bounds away from the cure for cancer and brain tumors, but they still expect diligence and hard work.  There are numerous aspects of oncology that we can focus on to better attack these brain cancer stem cells.  We can take a closer look at the genes responsible for self-renewal (Wnt, Notch, Sonic Hedgehog etc.), we can dive into the realm of cytokines/chemokines and growth factors: what makes a cell differentiated and migrate the way it does?  Any one of these things are a good start and I feel that it is necessary to get the basic biology of it all understood before we can progress forward into the 21st Century with the best cancer and brain tumor therapies science has to offer.

Acknowledgements

This review was prepared by Michael J. Poynton III, a graduate student in the Stem Cell Biology Class, Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey:

Teaching Assistant: Kathy Trzaska