Three new studies of cancer in the brain, skin and gut, appear to support the controversial idea that cancer may have its own stem cells that drive the regrowth of tumors. If confirmed with more evidence, the idea may transform our understanding of cancer and how it should be treated.
Papers on all three studies appeared online on Wednesday, two in Nature and one in Science.
In all three studies, the teams used genetic cell-marking techniques to track cell lineage and show that a restricted cell population appears to be the source of new tumor cells, in much the same way as stem cells are the “master builders” of new healthy cells.
In one of the Nature studies, researchers from the University of Texas (UT) Southwestern Medical Center in Dallas, examined the regrowth of glioblastoma multiforme (GBM) tumors in the brain after chemotherapy. The study leader was Luis Parada, chairman of developmental biology and director of the Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration.
GBM is a type of brain cancer that is currently considered incurable. It is a fast-growing tumor with a median survival of about 15 months. Although initially it responds to chemotherapy, the cancer nearly always comes back.
In their study, Parada and colleagues used genetically engineered mice bred to develop GBM and found that the resting tumor cells act more like stem cells.
They used a genetic marker that labels healthy adult neural stem cells, but not their more specialized descendants, to see if it would do the same for cancer stem cells in GBM. When they did so, they found all the tumors contained at least a few labelled cells, which they presumed to be stem cells.
The tumors also contained unlabelled cells, which could be killed with standard chemotherapy, but then the tumors came back soon afterwards. When they tested them again, they found the tumors contained unlabelled cells that came from labelled predecessors.
When they applied chemotherapy with a technique that suppressed the labelled cells, the researchers found the tumors shrank back to what Parada described to Nature NEWS as “residual vestiges” that bore no resemblance to GBM.
In a separate statement to the press, Parada said:
“We identified a subset of brain tumor cells that are slower growing or remain at rest, and appear to be the source of cancer recurrence after standard therapy in which the drug temozolomide is given to stop the tumor’s growth.”
There is still a lot of work to do, but the UT researchers believe they have found a new therapeutic target for treating GBM.
In the second Nature study, Cédric Blanpain, a stem cell researcher at the Université Libre de Bruxelles in Belgium, and colleagues, report how in mouse papilloma tumors, a precursor to skin cancer, most of the tumor growth came from a few cells, which were similar to the stem cells that make healthy skin cells.
For that study, the team labelled individual tumor cells, without specifically targeting stem cells. They found the cells had two ways of dividing: either they made a few cells then no more, or they went on to produce a vast number.
As in the GBM study, they discovered a distinct subset of cells drove tumor growth.
However, they also found that as tumors became more aggressive they were more likely to produce these new stem-like cells, which like stem cells, can keep dividing ad infinitum.
This is quite different to the idea that tumors only produce differentiated cells, which can only divide a limited number of times. The finding may provide a key to stopping the early growth of tumors, says Blanpain, according to a report in Science NOW.
In the Science study, Hans Clevers, a stem-cell biologist at the Hubrecht Institute in Utrecht, the Netherlands, and colleagues, examined what kinds of cell form intestinal tumors, using mice bred to develop differently coloured intestines.
In previous work, they showed you can use a genetic marker that labels healthy gut stem cells to label stem cells in benign gut tumors, which are precursors of cancer.
In this latest study, they engineered mice to carry a gene that when activated with a drug, causes labelled cells to fluoresce in one of four colours.
They found, even though tumors had many cell types, each tumor had a single colour, suggesting it arose from a single stem cell.
To double-check this, and show the stem cells continued to fuel tumor growth, the Clevers team added a second, low dose of the drug, which causes the stem cells to change colour. The effect was to produce lots of cells in the new colour, showing that the stem cells were generating the other types of cell.
The team also found that the tumors grow from cells that express a gene called Lgr5+, which is also active in normal gut stem cells.
“The tumor is really like a caricature of normal tissue,” says co-author Hugo Snippert in a report by Science NOW.
Parada said the concept of cancer stem cells in solid tumors remains controversial: some experts take the idea for granted while others reject it outright. Plus the definition of a cancer stem cell is somewhat of a “moving target”, which is why they prefer to use the term “stem-like cell” in their study.
If tumor regrowth really is driven by stem cells, then we may have to rethink how we treat them. As Parada explains:
“Current therapy targets fast-growing tumor cells but not those responsible for new tumors. To the best of our knowledge, this is the first identification of a cancer stem-like cell in a spontaneously forming tumor inside a mammal.”
If cancer really is driven by stem cells, then the focus of research would have to shift from testing whether a treatment shrinks tumors to testing whether it is killing the right kind of cell.
The discovery that the Blanplain team made, may trigger another shift in thinking about cancer treatment: instead of trying to kill the stem cells, perhaps coaxing them to differentiate into non-dividing cells could halt tumor development early.
Parada says that as we get to know these cells better, then the obstacles become technial ones rather than conceptual ones.
Written by Catharine Paddock PhD