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What Makes Healthy Food Healthy: From a Stress Perspective

Is Cancer Random? Or can “bad luck” be defined by Stress Mechanisms?

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Several articles have popped up in major News, Medical and University sites about Cancer with headlines such as “Random gene mutations primary cause of cancer” and “Bad luck, not genes or the environment, cause for many cancers, researchers find“.

The most provocative aspect of the study by Tomasetti and Vogelstein is not what is causing cancer, we know that certain environmental carcinogens like smoking can be responsible for cancer. Rather its that we just learned definitively that most cancers are not coming from direct and linear impacts.  The either/or argument that cancer is either “just genetic” or “just a single environmental impact” has been officially squashed. What does that leave? Well according to the lead researcher: Only pure chance.

CRISTIAN TOMASETTI: We know that cancer is due to three main factors: the environment — things like smoking, environmental factors; those that are genetically inherited; and then the third factor is just pure chance.

But that is not necessarily true….. The third factor might be that the mutations, or what they mean by “luck” is rather Stress Dynamics or Epigenetics: The Gene-Environment Interaction So, instead of “random chance”,  we’d refer to the workings of  “epigenetics” or the canalization (a disruption in one’s particular balanced state) into disease states. (What is Canalization?) Clearly Vogelstein, a cancer expert is familiar with epigenetics.  In fact, I believe, it is through epigenetic research that Vogelstein hopes to utilize early intervention techniques. (Unraveling the Cancer Code) Their research seems perfectly sound: “Overall, they determined that 65% of the variation in the risk of different cancer types can be attributed to how frequently stem cells make copies of themselves.”

This suggests that random errors occurring during DNA replication in normal stem cells are a major contributing factor in cancer development. Remarkably, this “bad luck” component explains a far greater number of cancers than do hereditary and environmental factors.

Its the conclusions, assumptions and I think the media may be leaping to what they think is the logical conclusion: That it’s just random luck and nothing but living is creating cancer, unless you smoke or go out in the sun. Beyond healthy living and preventing obesity (from over-eating I would presume), cancer, it seems to be surmised, is out of our control and beyond our understanding. I may be taking too much liberty here, but I’m not certain from what I’m reading that is what they (or what they should) mean. From Wikipedia:

Theory on the evolution of mutation rates identifies three principal forces involved: the generation of more deleterious mutations with higher mutation, the generation of more advantageous mutations with higher mutation, and the metabolic costs and reduced replication rates that are required to prevent mutations.

Epigenetics is where the environment “speaks” to the gene altering its and the multitude of other genes and functional pathways attached to it in a response to the environment. The method in which the environment speaks to genes is through various and multiple stress channels and activation pathways.

Previous studies have shown a wide variety of environmental toxicants and abnormal nutrition can promote the epigenetic transgenerational inheritance of disease. More recently a number of studies have indicated environmental stress can also promote epigenetic alterations that are transmitted to subsequent generations to induce pathologies. http://www.biomedcentral.com/1741-7015/12/153

If an outcome like cancer doesn’t have a single cause or an absolute cause, then by default many believe it to be random luck. What they miss is that there is a scientific framework that is not utilized in the equation: Deterministic Chaos. In medicine this means systems models which incorporates epigenetics. How the gene and the environment interact to create not absolute patterns, but probabilistic patterns.

It’s the true incorporation of the stochastic or probabilistic science that medicine is missing and assuming is “random luck”. However, that “luck” may be how we individually handle, our susceptibility to, and our attempts to adapt to stress. While Chaos principles may appear to be “chance” or “luck”, Chaos or Complexity is a science we can utilize to take something that appears to be random to see that it is not as random as it appears.

Chaos science utilizes nonlinear probabilistic influences. I refer to them as Stress Dynamics because I feel that we can best delineate these probabilistic patterns with the science of stress pathways, vulnerabilities and mechanisms. And I use the word stress because it is our means of adapting, evolving and compensating from environmental inputs in an individual (or phenotype) manner.

This means that somewhere between “random” and “deterministic” is a science of probability patterns we aren’t using yet.

Taking a stress perspective

Mutations may occur on a variety of levels and for a variety of reasons.  In one sense be random; heads or tails, yin or yang. Or a mutation may be random because its creating mistakes in the replication of the genetic code G for an A. I’m not going to pretend to know everything about mutations.  My limited view does see that there is an avenue for changing some of these assumptions and seeing how stress influences these outcomes.  The rate or a heavy influence of these mutations may manifest from factors of stress. Epigenetics and stress balancing on one level are “random” and appear random, however in larger scope, the combination of all those random dials become order. An order that is attempting to balance the system in a predictable manner. This isn’t an outlandish theory. It’s a theory based on the actual pathways that regulate such matters and the idea that our current framework of medicine has a blind spot when it comes to stress mechanisms, systems models and the use of complexity dynamics.

—->Stress from a linear perspective is good/bad, or, on/off. A linear perspective looks at stress as damage. Whereas stress from a nonlinear perspective is about the complex communication, dance, adaptation and balances.  Stress isn’t just about having too much stress (and therefore wanting to “lower” it, which can backfire), rather, it’s about what too much “stress” (or too much to do) communicates to the system about its environment and the adaptations that occur to accommodate the stress.  It’s not that we hope stress doesn’t happen, but rather that stresses communicate what is happening in the environment accurately. Also that stress occurs within proper accommodations through adequate resources and resource management and not having to “downregulate” or shut other functions down to compensate.

So it’s a logical conclusion that if the researchers in the study see that cancer coordinates and correlates with stem cell replication, then cancer would be caused by these mutations. And since a stress model isn’t yet realized into their paradigm (yet), it is very logical that they would come to their conclusions that cancer is caused by “bad luck”.  It becomes “bad luck” because the scope of addressing it go far and beyond a single cause or a linear model. It goes into a stress model. This then switches into a nonlinear scientific model.  Stress in a linear model means something quite different from what the word stress means in a nonlinear model. In a linear model it’s just another variable, in a nonlinear model it becomes the rules and “ether” that all the other variables exist in.

Epigenetics and Stem Cells: Epigenetic alterations involved in cancer stem cell reprogramming: Current hypotheses suggest that tumors originate from cells that carry out a process of “malignant reprogramming” driven by genetic and epigenetic alterations. (Munoz, 2012)

Stem Cells and Oxidative Stress

Role of Oxidative Stress in Stem Cell and Cancer : The term ‘‘oxidative stress” refers to a cell’s state characterized by excessive  production of reactive oxygen species (ROS) and oxidative stress is one of the most important regulatory mechanisms for stem, cancer, and cancer stem cells.  This review elucidates the effect and the mechanism of the oxidative stress on the regulation of stem, cancer, and cancer stem cells and focuses on the cell signaling cascades stimulated by oxidative stress and their mechanism in cancer stem cell formation, as very little is known about the redox status in cancer stem cells. (Dayem, 2012)

Regulation of reactive oxygen species in stem cells and cancer stem cells: Until recently, the focus in stem cell biology has been on the adverse effects of ROS, particularly the damaging effects of ROS accumulation on tissue aging and the development of cancer, and various anti-oxidative and anti-stress mechanisms of stem cells have been characterized. However, it has become increasingly clear that, in some cases, redox status plays an important role in stem cell maintenance, i.e., regulation of the cell cycle. An active area of current research is redox regulation in various cancer stem cells, the malignant counterparts of normal stem cells that are viewed as good targets of cancer therapy. In contrast to cancer cells, in which ROS levels are increased, some cancer stem cells maintain low ROS levels, exhibiting redox patterns that are similar to the corresponding normal stem cell. (Kobayashi, 2011)

In Stress Dynamics, as in Systems Dynamics, the outside force isn’t in technical terms “the cause” because its the system that is its own cause. The “causes” are merely inputs. This is why “smoking causes lung cancer” is true from a linear perspective, where 90% of lung cancers are caused by smoking. However, from a nonlinear perspective the “truth” becomes a bit more fuzzy, because only 10% of smokers get cancer. Whether something turns out to be good or bad depends on the system and the context of that system. Rules for how stress causes a system to be it’s own cause that “allows” an input to lead to an outcome. When it comes to cancer we might think that when a system gets stressed enough it produces mutations for that system in an attempt to self-correct. However, the weight of the compensations get out of hand and it starts misprogramming for the environment its in. The “good attempts” at adaptation gets out of hand.  Those attempts at adaptation create what we know of as cancer. Some cancer systems even work “better” than the surrounding cells (sometimes creating its own antioxidant pathways) and subsequently takes over.  This may be one reason why cancer is so difficult to treat. Cancer in a way is a mistaken attempt during genomic instability to make cells better and is wildly not making the larger organism better.

Since its description by Cairns and Nowell8, 9, the evolutionary concept of cancer has become widely accepted; this concept has recently been updated in an excellent review10, and the molecular mechanisms of metastasis have been reviewed and conceptualized in detail11, 12, 13. (Klein, 2013)

So from my point of view, my “Stress Perspective” view.  A model which I have also applied to obesity and Autism (See my Kickstarter Campaign as of Jan. 26th “When Mayonnaise was a Health Food and Autism just a Whisper“). This perspective, in theory, is that when we take a scientific model, like a linear model and apply it we got rid of “things” or singular causes to solve problems. That approach can have some inherent issues. Namely, that if you take important things that appear to be problematic out of an ecosystem, you run the risk of disrupting that ecosystem. I theoretically wonder if that is what is currently happening with our epidemic of chronic diseases and disorders.

There are three major mistakes that I found during my research into past decisions that may have destabilized our ability to handle stress. Mainly because these three things are major contributors to our foundational (for example our “innate immune”) systems’ ability and resiliency to stress. We evolved along with or even because these “things” were available to us; fats, microbes and sunlight. Disturbing the availability or relationship with them may have disturbed our equilibrium and balance.

Fats. The introduction of transfats as replacement to saturated fats and our being oblivious to the balance of omega-3 fatty acids to the other fats.
Germs or Microbes. Our war on germs and under-appreciation for the microbiome, from the medical model and logic this set up; the over-use of antibiotics, pasteurization and missing the impact foods can have on our gut microbes.
Sunlight. That the continued advice to “slather on sunscreen” neglects that from single cell micro-organisms the sun and its energy has been one of the single most important energy resources we have ever had.

These three, among others, are major contributors to our stress foundations. And I feel to have fruitful discussions of causes and solutions they, and a stress perspective of adaptation and epigenetics, need to be part of the conversation.

While better screening, pills and potential cures are helpful in our fight against cancer, and maybe my theory here is green and underdeveloped… but I think its enough to challenge the “just random luck” philosophy of our current medical paradigm. While “random” is a correct way to describe what is happening when we don’t have all the variables, it is also wildly misleading if that “random” label means to scientists and the public that it is beyond our control or understanding… I don’t believe it is. I believe its only beyond the scope of our current paradigm.

I believe in a new “stress” paradigm we will find intervention programs and treatment protocols to “hack” this misprogramming and mis-adaptations, but we all also discover that to solve our current health crisis; is to discover how to live in balance with our ecosystems… and that it’s time to change our scientific paradigm and medical framework for understanding and changing our “luck”.

References: (one current example of each for fat, germs and sunlight):
Fat
Omega-3 fatty acids reduce obesity-induced tumor progression independent of GPR120 in a mouse model of postmenopausal breast cancer. Chung H, Lee YS, Mayoral R, Oncogene. 2014 Sep 15. doi: 10.1038/onc.2014.283.  LINK
Germs/Microbes
The microbiome and cancer, Schwabe, R.F, Jobin, C. Nature Reviews CancerVolume:13,Pages:800–812Year published:(2013  LINK
Microbiota and host form a complex ‘super-organism’ in which symbiotic relationships confer benefits to the host in many key aspects of life. However, defects in the regulatory circuits of the host that control bacterial sensing and homeostasis, or alterations of the microbiome, through environmental changes (infection, diet or lifestyle), may disturb this symbiotic relationship and promote disease. Increasing evidence indicates a key role for the bacterial microbiota in carcinogenesis. In this Opinion article, we discuss links between the bacterial microbiota and cancer, with a particular focus on immune responses, dysbiosis, genotoxicity, metabolism and strategies to target the microbiome for cancer prevention.
Changes in Abundance of Oral Microbiota Associated with Oral Cancer. PLoS ONE 9(8): e106297. doi: 10.1371/journal.pone.0106297 LINK
Sunlight
Is prevention of cancer by sun exposure more than just the effect of vitamin D? A systematic review of epidemiological studies. van der Rhee H1, Coebergh JW, de Vries E. Eur J Cancer. 2013 Apr;49(6):1422-36. doi: 10.1016/j.ejca.2012.11.001. Epub 2012 Dec 10.  LINK
Other Stress
Stress (social)
Impact of stress on cancer metastasis. Moreno-Smith, M., Lutgendorf, S. K., & Sood, A. K. (2010). Future Oncology (London, England), 6(12), 1863–1881. doi:10.2217/fon.10.142 LINK
Fat cells in breast may connect social stress to breast cancer By John Easton June 20, 2013
Psychosocial stress and inflammation in cancer.
Powell ND1, Tarr AJ, Sheridan JF. Brain Behav Immun. 2013 Mar;30 Suppl:S41-7. doi: 10.1016/j.bbi.2012.06.015. Epub 2012 Jul 9. LINK
Stress (oxidative)
Oxidative Stress and Oxidative Damage in Carcinogenesis. Toxicol Pathol James E. Klaunig,
Lisa M. Kamendulis, and Barbara A. Hocevar. January 2010 38: 96-109
Interleukin 6 Alters Localization of hMSH3, Leading to DNA Mismatch Repair Defects in Colorectal Cancer Cells.
Tseng-Rogenski SS1, Hamaya Y1, Choi DY1, Carethers JM2.Gastroenterology. 2014 Nov 20. pii: S0016-5085(14)01459-0. doi: 10.1053/j.gastro.2014.11.027 LINK
Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer.
Khansari N1, Shakiba Y, Mahmoudi M.Recent Pat Inflamm Allergy Drug Discov. 2009 Jan;3(1):73-80. LINK
Modulation of oxidative stress as an anticancer strategy.
Gorrini C1, Harris IS, Mak TW.Nat Rev Drug Discov. 2013 Dec;12(12):931-47. doi: 10.1038/nrd4002.
Oxidative stress, inflammation, and cancer: how are they linked?
Reuter S1, Gupta SC, Chaturvedi MM, Aggarwal BB. Free Radic Biol Med. 2010 Dec 1;49(11):1603-16. doi: 10.1016/j.freeradbiomed.2010.09.006. Epub 2010 Sep 16 LINK
Epigenetics, Mutation and Stress
Mutation as a Stress Response and the Regulation of Evolvability. Critical Reviews in Biochemistry and Molecular Biology, Galhardo, R. S., Hastings, P. J., & Rosenberg, S. M. (2007).  42(5), 399–435. doi:10.1080/10409230701648502 LINK
Are mutations truly random? On Mutation “Hot Spots”
Endogenous DNA damage in humans: a review of quantitative data. LINK
Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer – See more at: http://elifesciences.org/content/early/2014/09/30/eLife.02935#sthash.5xkZti1s.dpuf
Mitochondrial Apoptosis Reduces Mutagenesis Regardless Oxidative Stress. J Carcinog Mutagen S3:005. doi: 10.4172/2157-2518.S3-005. Giorgio M, Ruggiero A, Pelicci PG (2014) LINK
Oxidative stress-induced mutagenesis in single-strand DNA occurs primarily at cytosines and is DNA polymerase zeta-dependent only for adenines and guanines. Degtyareva NP, Heyburn L, Sterling J, Resnick MA, Gordenin DA, Doetsch PW. Nucleic Acids Research 2013;41(19):8995-9005. doi:10.1093/nar/gkt671. LINK
Cancer genetics and epigenetics: two sides of the same coin? You JS1, Jones PA. Cancer Cell. 2012 Jul 10;22(1):9-20. doi: 10.1016/j.ccr.2012.06.008. LINK
Epigenetic and genetic alterations have long been thought of as two separate mechanisms participating in carcinogenesis. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disrupt DNA methylation patterns, histone modifications, and nucleosome positioning and hence, gene expression. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. This crosstalk between the genome and the epigenome offers new possibilities for therapy.
Cancer epigenetics: an introduction. Kanwal R1, Gupta K, Gupta S. Methods Mol Biol. 2015;1238:3-25. doi: 10.1007/978-1-4939-1804-1_1. LINK
Evidence of non-random mutation rates suggests an evolutionary risk management strategy. Iñigo Martincorena, Aswin S. N. Seshasayee, & Nicholas M. Luscombe. NatureVolume:485, Pages:95–98, (03 May 2012) DOI:doi:10.1038/nature10995 LINK
Importantly, the variation is not random: we detect a lower rate in highly expressed genes and in those undergoing stronger purifying selection. Our observations suggest that the mutation rate has been evolutionarily optimized to reduce the risk of deleterious mutations. Current knowledge of factors influencing the mutation rate—including transcription-coupled repair and context-dependent mutagenesis—do not explain these observations, indicating that additional mechanisms must be involved. The findings have important implications for our understanding of evolution and the control of mutations.
Oxidants, antioxidants and the current incurability of metastatic cancers. by Jim Watson
Physics of cancer propagation: A game theory perspective. Chris Cleveland, David Liao, and Robert Austin, AIP Adv. Mar 2012; 2(1): 011202. doi:  10.1063/1.3699043 LINK
Predictive genomics: A cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data. Wang E1, Zaman N2, Mcgee S3, Milanese J4, Masoudi-Nejad A5, O’Connor-McCourt M6.Semin Cancer Biol. 2015 Feb;30C:4-12. doi: 10.1016/j.semcancer.2014.04.002. Epub 2014 Apr 18. LINK
Adaptation and learning of molecular networks as a description of cancer development at the systems-level: Potential use in anti-cancer therapies Authors: David M. Gyurko, Daniel V. Veres, Dezso Modos, Katalin Lenti, Tamas Korcsmaros, Peter Csermely http://arxiv.org/abs/1306.3371
Our hypotheses presented here underlie the need for patient-specific multi-target therapies applying the correct ratio of central hits and network influences — in an optimized sequence
“Oxidative Stress, Tumor Microenvironment, and Metabolic Reprogramming: A Diabolic Liaison,” Tania Fiaschi and Paola Chiarugi,I nternational Journal of Cell Biology, vol. 2012, Article ID 762825, 8 pages, 2012. doi:10.1155/2012/762825
Conversely to normal cells, where deregulated oxidative stress drives the activation of death pathways, malignant cells exploit oxidative milieu for its advantage. Cancer cells are located in a very complex microenvironment together with stromal components that participate to enhance oxidative stress to promote tumor progression. Indeed, convincing experimental and clinical evidence underline the key role of oxidative stress in several tumor aspects thus affecting several characteristics of cancer cells. Oxidants influence the DNA mutational potential, intracellular signaling pathways controlling cell proliferation and survival and cell motility and invasiveness as well as control the reactivity of stromal components that is fundamental for cancer development and dissemination, inflammation, tissue repair, and de novo angiogenesis. This paper is focused on the role of oxidant species in the acquisition of two mandatory features for aggressive neoplastic cells, recently defined by Hanahan and Weinberg as new “hallmarks of cancer”: tumor microenvironment and metabolic reprogramming of cancer cells.
A systems biology approach to invasive behavior: comparing cancer metastasis and suburban sprawl development. John J Ryan12*, Benjamin L Dows1, Michael V Kirk1, Xueming Chen3, Jeffrey R Eastman4, Rodney J Dyer12 and Lemont B Kier. BMC Research Notes 2010, 3:36  doi:10.1186/1756-0500-3-36
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Author: Lori Hogenkamp

Lori's passion is for food, the brain, science and stress shifting perspectives .

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