The cancer stem cell theory
Cancer stem cells (CSC) can be difficult to define, even for biologists. In order to understand CSCs, cancer itself must be thought of as highly organized – comprised of cancer cells that have a cellular hierarchy. The cancer stem cell theory is rooted in the scientific discovery that cancer tumors, like normal tissue, contain cells that can both self-renew and give rise to differentiated cells. That is, a subset of cancer cells that can give rise to other cancers. These cells are referred to as CSCs.
The idea of CSCs has been around since 1855, when German pathologist Rudolf Virchow first hypothesized that cancers arise from a type of embryonic-like cell. However, the modern field began with the discoveries published in a 1994 Nature paper, entitled “A cell initiating human acute myeloid leukaemia after transplantation into SCID mice.” In this seminal paper, Lapidot et al. first isolated CSCs in acute myeloid leukemia (AML) patient specimens. In addition, they found that when the cells were transplanted from people with AML into mice with compromised immune systems, human AML was present in the mice. This discovery not only started a field of cancer biology centered around these particular cells, it shifted the paradigm of how cancer is understood.
So, what exactly is a Cancer Stem Cell and how is it different from other cancer cells?
A consensus panel convened by the American Association of Cancer Research has defined a CSC as "a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor."
Dr. Luis Parada, the Director of the Brain Tumor Center and American Cancer Society Research Professor at Memorial Sloan Kettering Cancer Center, adds depth to that definition. His lab works on CSCs in a glioblastoma model and published a landmark study in 2012 showing that deleting the CSC population led to regression of a tumor.
For Dr. Parada, a cell is a cancer stem cell if 1) it sits at the apex of a hierarchy of tumor growth 2) it is responsible for recurrence after therapy and 3) it is responsible for metastasis.
What does that mean in an experimental situation? Dr. Ravi Majeti, an Associate Professor in the Department of Medicine (Hematology) and Member of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University lends some clarity to the question.
Dr. Majeti says, “Let’s fractionate a cancer into two populations. If one fraction of cells generates a tumor when put into a mouse, it contained a CSC. If the fraction of cells did not contain a CSC, it would not generate a tumor in a mouse.” But, he goes on to emphasize that the tumor made from the CSC would be comprised of a heterogenous population of cells - not dissimilar to how a normal stem cell would create a new tissue.
Dr. Majeti’s lab works to identify differences in human acute myeloid leukemia (AML) stem cells and their normal counterparts at the molecular and genetic level. He stresses that the CSC hypothesis hinges on the understanding that cancers are organized as a cellular hierarchy with only a subset of cells being able to give rise to other cancer cells. Therefore, the definition of CSC is operational more than anything else.
The definition of a CSC gets complicated
From the time that the cancer stem cell hypothesis developed 20 years ago, not only has the understanding of CSCs become increasingly complicated, so too have the dynamics of the field as a whole.
Not all cancer stem cell researchers have the same definition of a CSC. In fact, some groups work on cells that others, like Dr. Parada, would not classify as a CSC. This is one area where the CSC field gets murky.
There are vast differences in the experimentation being done in the field with a growing body of work done in cell lines. It’s not that the work is not good – it’s that the assays are imperfect. Dr. Parada states that cells in culture are inherently “screwed up” – and they lack the heterogeneity that exists in tumors because they have adapted to grow in a dish with a particular environment with specific oxygen and serum concentrations, etc. These experiments are not representative of how cells grow in organisms.
Despite these differences in the field, very conclusive work has proven that CSCs play a role in cancers such as liver, skin, basal cell carcinoma, bladder, colon, glioblastoma (brain) and leukemias. The mainstay of this work is through xenografting CSCs into immunocompromised mice.
How do CSCs impact the effectiveness of current therapies?
CSCs have multiple mechanisms that protect them from standard cancer therapies. For example, CSCs are relatively quiescent, making them more recalcitrant to therapies that are effective on rapidly dividing cells. CSCs can also express more multiple drug resistance transporters, deal with more reactive oxygen species, have enhanced DNA repair capacity, and can be more resistant to radiation.
Many anti-cancer therapies are evaluated based on their ability to shrink tumors. However, unless the CSCs are killed along with the other cells, the tumor will grow back, making the role of CSCs particularly important when considering therapies.
CSCs and cancer treatments
There have been no major clinical successes to come out of the CSC field as of yet. Despite the gains the field has made in the overall understanding of cancer, there are challenges in therapeutic development. Perhaps most challenging is how similar CSCs are to normal tissue stem cells. The pathways that have emerged as important in CSC self-renewal are also key pathways in normal stem cell self-renewal. If targeted, it would be incredibly toxic to the normal stem cells. Not only that, but, the possibilities for treatment that were the hope of CSC researchers about a decade ago have been eclipsed by the incredibly exciting strides made by the cancer immunotherapy field.
However, the advances made by the CSC field are incredibly valuable, despite not having a drug to their name. The work done in this field has changed how we think about cancer and given us a more accurate view of the complexities of cancer and how it should be combated. As described by Dr. Majeti, “people used to think about a cancer as a uniform ball.” However, the field of CSCs has shifted that view by showing that there is heterogeneity in cancers, at the single cell level. The gene expression, cell surface markers, epigenetics, mutations, and metabolic states of the cancer cells are vastly different from one another, leading to a much more sophisticated understanding of cancer. Regarding the heterogeneity within the field itself and the lack of a CSC treatment, Dr. Parada adds, “The field is alive and well, even if it is frequently misrepresented.”