Jonathan W. Uhr & Klaus Pantel (2011). Controversies in clinical cancer dormancy Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1106613108
| Common medical and immunological assumptions of cancer dormancy should be re-evaluated in order to render it a viable therapeutic approach. |
However, there is an alternative and possibly more realistic method of achieving essentially the same result. Inducing cancer dormancy, in which cancer cells remain in low levels without triggering a recurrence of the disease, is worthy of consideration.
HIV/AIDS treatment faces a similar challenge. Some important research focuses on completely eliminating the virus from the body, but the far more common treatment option of reducing viral levels to the asymptomatic level is surely a reasonable alternative.
Towards this cancer therapy goal, Jonathan Uhr (University of Texas Southwestern Medical Center, United States) and Klaus Pantel (University Medical Center Hamburg-Eppendorf, Germany) have questioned several common hypotheses of cancer dormancy. Such re-evaluations are very important in order to fully understand cancer biology and develop effective medical treatments based on this knowledge.
The physical origin of recurring cancer.
Growing tumors shed cancerous cells, and some of these cells (for many biochemical reasons) are in a growth-arrested state (do not divide). Such cells readily evade chemotherapy.
This is because many chemotherapy agents target highly proliferative cells (a hallmark of cancer). Many cancer scientists think that dormant cancer cells that are shed at an early stage of tumor development eventually come out of dormancy to re-establish the cancer.
This might not be an accurate presumption. Recently-shed cancer cells don't remain in circulation for very long, suggesting to Uhr and Pantel that they may not be the origin of recurring cancer from a long-gone tumor.
The origin of recurring cancer may instead be a secondary tumor that established iself elsewhere in the body and is itself slowly shedding non-proliferative cells. Uhr and Pantel propose that biochemically interrogating two batches of non-proliferative cells, one known to be from the original tumor (easily identified) and the other from this hypothesized secondary tumor (e.g. from bone marrow, long after the original tumor is gone), may help scientists understand cancer dormancy and the molecular basis of cancer cell re-activation.
Cancer and the immune response.
Many studies in mice suggest that the immune system plays important roles in preventing cancer, and a failing immune system facilitates cancer progression. One would therefore think that human cancer patients who have an organ replaced and are put on immunosuppresant drugs (to prevent organ rejection) would be at greater risk of recurring cancer.
However, there is little convincing evidence of this outcome. For example, Uhr and Pantel report on a large-scale study published in 2000 that showed no elevated risk of non-viral cancer after renal transplants.
What about the results in mice? These studies indicate that a hindered immune response is correlated only with a local cancer recurrence, suggesting to Uhr and Pantel that genetic or other changes (specific to the location of the original tumor) are the fundamental causes of recurring cancer, as opposed to general immune response failures.
A specifically-activated immune response may nevertheless be a general approach to eradicating cancer. Uhr and Pantel are cautiously optimistic about this approach, but they also stress that model systems which more closely mimic human cancer are needed, instead of the typical mouse model that may not readily translate to human medicine.
Cellular life-death balance and cancer.
Cell division in your body is generally in balance with cell death. Given that recurring cancer favors dividing rather than dying cells, understanding how to induce a tumor back into a balanced life-death (dormant) state may be a viable therapeutic direction.
Many genetic, hormonal, immunological, and other biochemical mechanisms have been proposed for the origin of cancer dormancy. In their article, Uhr and Pantel summarize evidence that the "Hippo" biochemical signaling pathway, which controls organ size, may be important to cancer progression.
To date, such research efforts have generally focused on mice and flies. Testing in humans is needed to unravel the biochemical possible relationship between organ size maintenance and cancer dormancy in human medicine.
Implications.
Scientists have not conclusively identified the physical origin of recurring cancer. They have not conclusively shown that the immune response is important to non-viral cancer recurrence.
Neither have they conclusively uncovered how the cellular life-death balance is related to cancer recurrence. Uhr and Pantel are urging scientists to tackle these questions in order to render cancer permanently dormant, serving as a practical cure as opposed to one of fundamental eradication.
NOTE: The scientists' research was funded by the Raymond and Ellen Willie Distinguished Chair in Cancer Research, the National Cancer Institute, as well as the Deutsche Forschungsgemeinschaft.
Jonathan W. Uhr & Klaus Pantel (2011). Controversies in clinical cancer dormancy Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1106613108