It can be tough to find the mutations responsible for turning a normal cell cancerous. By the time a tumor has been diagnosed and analyzed, its cells have undergone many, many rounds of DNA replication and division – likely accumulating mutations all the while. But oncogenes (mutated versions of normal genes often associated with cell division) have been identified as the smoking gun in many cancers, some are viewed as attractive targets for cancer therapies because their effects on cell growth appear so pervasive.
Now new research is beginning to suggest a cancer cell’s reliance on oncogenes and other mutations may be much more nuanced than originally believed. Stanford oncologists Ash Alizadeh, MD, PhD, and Michael Green, PhD, study diffuse B-cell lymphoma, which is the most-common aggressive lymphoma in this country. About half of all people diagnosed with the condition will die from the disease. (Stanford’s Lymphoma and Hodgkin’s Disease Research Program treats many patients with this and other blood cancers.)
In 2000, Alizadeh showed that cancer cells from patients with diffuse B-cell lymphoma fall into two subsets when categorized by their gene expression profiles. One, the germinal center B-cell like (or GCB-like) subset has a much better prognosis than the other, which more closely resembles the gene profile seen in activated B-cells (ABC-like). But the basis of the prognostic differences between the two groups has not been known.
In the new study, which was published this week in Nature Communications (subscription required), Alizadeh and Green investigate the role of an oncogene called Bcl6 in diffuse B cell lymphoma. Their research suggests that, in at least one of the subcategories of this type of lymphoma, the reliance on the Bcl6 oncogene is limited to very early stages of development, before the cells themselves had completely matured.
As Green explained in an e-mail to me:
This work adds to growing evidence that the two subtypes of diffuse large B-cell lymphoma, which have very different clinical outcomes, may in fact be two genetically distinct diseases. There were also a number of surprises in this project. In particular, the notion that expression of an oncogene for a limited period in a stem cell is capable of reprogramming those cells towards becoming cancer at a later stage of development is a completely new paradigm. Now we have to ask ourselves whether we should be thinking differently about how lymphoma, and maybe cancer in general, evolves.
This type of hit-and-run hypothesis is different from the traditional view of how oncogenes work, Alizadeh explained in an e-mail:
The results from this study clearly illustrate that, if cancers can result via ”hit-and-run” oncogenesis, oncogenes that initiate tumor formation might be dispensable for tumor cell survival and/or tumor progression. In this context, mutations that activate oncogenes would have a driving role in the tumorigenic process, but may act as passenger mutations thereafter, or may have a secondary role in evolved tumor cell clones. This may provide an explanation for the failure of some modern targeted therapies to clear tumor progenitor cells, despite being effective agents against evolved tumor cells. As a consequence, targeted treatment strategies may need to be altered to accommodate combinations of agents that target oncogenic pathways that are active at both the early and late stages of tumor development.
Their research was conducted in collaboration with researchers in the laboratory of Isidro Sanchez-Garcia, MD, PhD at the Institute of Biomedical Research of Salamanca in Spain.
Previously: Cellular culprit identified for invasive bladder cancer, according to Stanford study, Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers, and Leukemia prognosis and cancer stem cells
Photo by brett jordan