Making Connections between Stem Cells and Cancer
The striking similarities between stem cells in normal tissue that are responsible for continuously replacing adult tissues and a very small subset of cells found in growing tumors have sparked considerable interest in the research community. As a result, there is perhaps no better time for cancer biologists to draw on the considerable knowledge of our colleagues in embryology and developmental biology to explore questions about the initiation and progression of cancer—and potentially to understand how it develops resistance to therapies and how it metastasizes.
Indeed, future strategies for treating the disease may be informed by insights drawn from knowledge of embryonic stem cell biology and the intricate genetic processes that lead to the formation of organs. Against this backdrop, President Barack Obama’s Executive Order lifting restrictions on federal funding for research on embryonic stem cells will greatly impact cancer research in the years ahead.
There is a growing body of evidence that some tumors are driven by a small number of cells that have properties similar to embryonic stem cells. According to the cancer stem cell hypothesis, these rare cells are the only cells within a tumor that can self-renew and give rise to diverse progeny, much like stem cells in the embryonic setting and in adult tissues. These cells are therefore known as cancer stem cells or tumor-initiating cells.
Unlike the bulk of tumor cells, tumor-initiating cells may be able to endure hostile environments by entering a state of dormancy. This hypothesis, if confirmed, could help explain why many patients with cancer unfortunately relapse after apparently successful treatments.
The elucidation of early events in the transformation of normal cells into malignant cells is essential if we are to advance research on cancer stem cells. Recent studies have revealed that the genetic signatures of some poorly defined high-grade tumors are similar to those of embryonic stem cells. In particular, genes associated with self renewal appear to be active in both the normal and the tumor stem cells. This tells us that the activation of an embryonic stem cell-like genetic program in certain adult cells may induce self-renewal characteristics and trigger a progression to tumor-initiating cells.
We also know that normal human embryonic stem cells themselves can transform to become malignant cells. Thus, to define the genetic regulatory networks and cell signals that drive normal embryonic stem cells toward malignancy, it may be necessary to profile gene expression patterns of normal and transformed embryonic stem cells. Such experiments could provide clues to the most important regulatory genes that are altered in the events leading to cancer.
In theory, the availability of a larger spectrum of normal, stable human embryonic stem cell lines should make it easier to define such signatures and associate them with the earliest events in malignancy for human disease.
My own lab has been focused on identifying stem cells within the NCI 60 cell lines through the use of surface markers identified in the literature that are associated with tumor stem cells. In another project, we are investigating whether viruses that cause cancer need to infect the adult tissue stem cells in order to trigger a transformation of these cells. We hypothesize that if non-stem cells are infected, these cells would simply die and cancer would not develop. Stem cells, by contrast, live a long time and through their ability to self-renew would be able to perpetuate the genetic changes initiated by a virus.
What is hampering these investigations—indeed, hampering all research into cancer stem cells—is the inability to clearly identify the adult epithelial stem cell. The availability of new embryonic stem cell lines in research would facilitate studies of the genetic program associated with the maturation, or differentiation, of a stem cell. This could lead to markers that would allow us to truly identify adult tissue stem cells for the first time.
Once that hurdle is passed, experiments such as those with the NCI 60 cell lines and the viral oncogenesis studies could proceed with the knowledge that the targeted cell is in fact a stem cell.
In the area of treatment, a central question is whether cancer stem cells can be made vulnerable to therapies by identifying and disrupting critical cell-signaling pathways. Promising work in this area has come recently from the laboratory of Dr. Mary J.C. Hendrix at the Northwestern University School of Medicine. Her team has identified an embryological signaling pathway that is improperly activated in metastatic melanoma and that could be targeted for the reprogramming of aggressive tumor cells.
This research, which was done using federally approved embryonic stem cell lines, confirms previous studies showing that the embryonic environment can reprogram cancer cells, in effect “taming” aggressive melanoma cells under experimental conditions. As a next step, Dr. Hendrix has shown that the microenvironment of embryonic stem cells therefore may be a previously unexplored therapeutic entity for controlling abnormally expressed embryonic factors in aggressive tumor cells.
Such unexpected connections and opportunities for therapies are likely to emerge as more researchers focus on the mechanisms of embryogenesis and developmental biology.
Dr. John E. Niederhuber
Director, National Cancer Institute