This article is more than 5 years old. Information may no longer be current.
Fire and fury in cancer cells and politics
Click Here to Manage Email Alerts
Welcome to 2018 and another opportunity for us to influence our future!
This construct has me thinking about the state of play in U.S. politics and the chaotic and unparalleled year of political confusion we have just witnessed, with the unexpected resurrection of several disgraced political careers. Michael Wolff’s soon-to-be bestseller has added to the drama, attempting to set a new context in his thoughts on the battle between good and evil.
I recognized a curious parallel as I read the report by Spinelli and colleagues, published in October in Science, demonstrating what happens in the tempest of cancer cell breakdown.
Briefly, they showed that recycled ammonia — reflecting the nitrogen breakdown products of cancer cell death — can be utilized by breast cancer cells to maintain survival and even accelerate tumor growth. It seems to me that the concept of degraded excretion products helping an organism to survive is a metaphor of the political scene in which continued survival, and perhaps even growth of influence, can occur despite personal misadventure or degradation.
‘Unanticipated source’ of tumor growth
Now, back to the specific biomedical topic at hand.
The Spinelli work may be of fundamental importance, but requires a little understanding of biochemical cycles to appreciate its full import.
It has been known for more than a decade that ammonia is a ubiquitous product of cellular metabolism, and that bacteria and yeast are able to extract derived nitrogen from their environment to support their own growth.
It has previously been thought that, in the tumor microenvironment, metabolic waste products — such as lactate and ammonia — accumulate and may even be harmful to the tumor. Thus, for the tumor to survive, it has been thought that ammonia and other breakdown products need to be exported, perhaps via urea cycle clearance in the liver or elsewhere.
It is also known that, in the physiological environment, changes in pH will inhibit cellular growth. We have previously shown that, after effective anticancer treatment reflecting a different pattern of microenvironmental cellular perturbation, there is a significant local production of acidity associated with DNA release that may be a biomarker of treatment efficacy. This presumably contributes further to the growth inhibition and/or death of the cancer cells.
In the present series of experiments, Spinelli and colleagues have studied rapidly proliferating breast cancer cells and have shown that a degradation product — glutamine-derived ammonia — is recycled into central amino acid synthesis via reductive amination catalyzed by glutamate dehydrogenase (GDH), with incorporation of the derivative nitrogen into other amino acids, as well. GDH is a bidirectional enzyme, so the investigators carried out experiments that specifically demonstrated that oxidative deamination was not occurring.
Researchers replicated the tissue culture studies in a xenograft model in immunosuppressed mice, including the use of nitrogen radio-labeling to track the flow of ammonia. This demonstrated that metabolic recycling of ammonia waste products actually contributed to acceleration of tumor growth!
It is not yet clear that this is a generically applicable observation, as it appears that local tumor ammonia accumulation should be contingent on the cancer cells being poorly vascularized — thus avoiding breakdown products being carried away from the tumor microenvironment. Further, these investigators did not explore geographical microheterogeneity of function — ie, they did not assess whether there is a differential level of recycling deep within the tumor compared with the pattern at the leading growth edge. By analogy, there is variation of nitrogen metabolism in yeast colonies, with greater recycling occurring at the edge of the yeast colony.
This study emphasizes specifically that the mechanism for nitrogen to be recycled into tumor growth after cellular destruction occurs via the function of GDH and not through the impact of another key enzyme involved in the urea cycle, carbamoyl phosphate synthetase-1 (CPS-1). However, Kim and colleagues studied lung cancer cells and showed that CPS-1 actually does have a similar impact, contributing both to pyrimidine and DNA synthesis. This probably reflects heterogeneity of function in tumors, and merely indicates that there may be different and/or redundant mechanisms for tumor breakdown products to be harnessed for tumor resurrection.
The important issue in this report is the demonstration of a newly discovered similarity between basic biochemistry of yeasts, bacteria and cancer cells, reflecting an unanticipated source of autostimulation of tumor growth and another potential biochemical target for tumor growth inhibition. This pattern contrasts with nitrogen metabolism in normal human cells.
Data-driven choices
However, there may be a more philosophical message associated with this work, with a curious parallel to the political milieu in the United States.
The products of cellular destruction in yeast, bacteria and some tumor cells actually contribute to cellular survival and even increased growth, perhaps via redundant mechanisms. This is not an intuitive concept. Neither is the observation that outrageous actions on both sides in the toxic political domain — despite often being excused as being the product of false reporting — actually do not exist and, thus, should not be considered by the electorate. Sadly, this type of protectionism also seems to occur via redundant mechanisms.
When perceptions do not make sense and challenge reality, they should be ignored or overturned. This opportunity will again present itself in the upcoming midterm elections, and hopefully the electorate will make data-driven choices with respect to its choices for all political parties.
References:
Dang CV. Science. 2017;doi:10.1126/science.aaq1070.
Kim J, et al. Nature. 2017;doi:10.1038/nature22359.
Lindner D and Raghavan D. Br J Cancer. 2009;doi:10.1038/sj.bjc.6605022.
Spinelli JB, et al. Science. 2017;doi:10.1126/science.aam9305.
Zeng A-P and Bi J (2005). Cell culture kinetics and modeling. In Ozturk SS and Hu W-S (Eds.), Cell culture technology for pharmaceutical and cell-based therapies (pp. 299-341). Boca Raton, FL: Taylor & Francis.
For more information:
Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Carolinas HealthCare System. He can be reached at derek.raghavan@carolinashealthcare.org.
Disclosure: Raghavan reports no relevant financial disclosures.