Investigations into cancer’s ultimate origins bring to mind the “want of a nail” proverb, a reminder that a small initial dysfunction can trigger a chain of increasingly serious problems that culminate in disaster. Yet these investigations have had difficulty nailing down the oncogenic, well, nail. Must cancer originate in a stem cell, or may it originate in a progenitor cell?
An answer to this question comes from scientists based at Université Libre de Bruxelles and the University of Cambridge. They studied a mouse model of basal cell carcinoma, the most frequent cancer in humans, to determine that only stem cells have the capacity to develop into deadly invasive tumors. Progenitor cells, unlike the stem cells, were unable to overcome apoptosis, or programmed cell death. Progenitor cells subjected to oncogenic mutation gave rise to clones that were checked by increasing levels of apoptosis, and so they led to the formation of benign tumors.
These findings appeared July 8 in the journal Nature, in an article entitled, “Defining the Clonal Dynamics Leading to Mouse Skin Tumour Initiation.” The article describes how a transgenic mouse model allowed the scientists to activate oncogenes in stem cells or in both stem cells and progenitor cells.
“We found that only stem cells, and not progenitors, were competent to initiate tumour formation upon oncogenic hedgehog signalling,” wrote the article’s authors. “Interestingly, this difference was due to the hierarchical organization of tumour growth in oncogene-targeted stem cells, characterized by an increase in symmetric self-renewing divisions and a higher p53-dependent resistance to apoptosis, leading to rapid clonal expansion and progression into invasive tumours.”
The article describes how the oncogene was coupled with a fluorescent marker so that cells in which the oncogene was active could be easily identified. Also, as these cells proliferated, the marker allowed the tracking of daughter cells. These related fluorescent cells are known as clones.
By analyzing the number of fluorescently labeled cells per clone using mathematical modeling, the scientists were able to show that only clones derived from mutant stem cells were able to overcome apoptosis and continue to divide and proliferate unchecked.
“It's incredibly rare to identify a cancer cell of origin, and until now no one has been able to track what happens on an individual level to these cells as they mutate and proliferate,” said Cédric Blanpain, M.D., Ph.D., a professor at Université Libre de Bruxelles. “We now know that stem cells are the culprits: when an oncogene in a stem cell becomes active, it triggers a chain reaction of cell division and proliferation that overcomes the cell's safety mechanisms.”
“While this has solved a long-standing scientific argument about which cell types can lead to invasive skin tumors, it is far more than just a piece of esoteric knowledge,” added Ben Simons, Ph.D., a professor at the University of Cambridge. “It suggests to us that targeting the pathways used in regulating cell fate decisions—how stem cells choose between cell proliferation and differentiation—could be a more effective way of halting tumors in their tracks and lead to potential new therapies.”