I have updated this paper, originally published in December 2017, see http://www.natpernick.com/HowCancerArises.pdf. I plan to present it at a cancer research conference in Spring 2020. The Abstract and Executive Summary are below. I am happy to answer questions about this paper or cancer in general, but cannot answer patient specific questions.
Abstract
Background: The War on Cancer has failed, due in part to its reliance on reductionist thinking to understand how cancer arises.
Methods: We reviewed prominent cancer risk factors at major sites and categorized them based on a complexity theory approach that focuses on early changes to network behavior instead of later changes to oncogenes.
Results: Cancer is caused by nine sources of chronic cellular stress that often interact to provide the multiple “hits” that produce malignancy. They are: chronic inflammation (due to infection, infestation, autoimmune disorders, trauma, overweight, diabetes and other causes); exposure to carcinogens; reproductive hormones; Western diet (high fat, low fiber, vegetable and fruit consumption); aging; radiation; immune system dysfunction; germ line changes and random chronic stress or bad luck.
Conclusions: Cancer is an inevitable tradeoff of human biologic design that will always be with us, particularly as life expectancy increases. However, we can often prevent it, we can detect it earlier and we can treat it more effectively. Most cancer is caused by chronic cellular stress that disturbs the delicate balance of our interconnected biologic networks. Malignancy arises due to a buildup of dysfunctional hierarchical structures, in which combination of agents (biomarkers and networks) at one level become agents at the next level. These dysfunctional structures are identifiable by patterns of network changes, molecular changes or possibly histologic changes. New treatment approaches include targeting multiple tumor features to overcome tumor heterogeneity, targeting the chaotic nature of some tumors, moving tumor cells into less lethal network states by emulating physiologic mechanisms and reducing chronic stressors.
Executive summary
1. Cancer is an inevitable tradeoff of human biologic design. It will always be with us, particularly as life expectancy increases. However, we can often prevent it, we can detect it earlier and we can treat it more effectively.
2. Most cancer is caused by chronic cellular stress, which disturbs the delicate balance that exists in our interconnected biologic networks. In the correct microenvironment, it pushes susceptible stem or progenitor cells into increasingly dysregulated and unstable network trajectories that are ultimately associated with uncontrolled cell growth. It is foreseeable that some chronic cellular stressors will cause cancer but which stressors will be important, where the cancers will arise and what their molecular and histologic features will be is not predictable due to the nonlinear nature of complex systems.
3. There are nine important sources of chronic cellular stress that cause cancer and often interact to provide the multiple “hits” (genetic or network aberrations) that produce malignancy:
* Chronic inflammation (due to infection, infestation, autoimmune disorders, trauma, overweight, diabetes and other causes)
* Exposure to carcinogens
* Reproductive hormones
* Western diet (high fat, low fiber, vegetable and fruit consumption)
* Aging
* Radiation
* Immune system dysfunction
* Germ line changes
* Random chronic stress or bad luck
These chronic stressors typically create a field effect; i.e., large areas are affected by a single aberration.
4. Complexity theory helps us better understand how cancer arises:
A. To understand cancer, it is important to think about how life arose from cellular networks because the same principles guide the pathophysiology of cancer. Focusing too much on specific details of the networks, such as characteristics of individual molecules in the network, ignores the overriding theme that the emergence and disturbance of generic network features is independent of these details.
B. Living systems require fine tuning of cellular networks to enable rapid transitions during fertilization, embryogenesis and repair of external or internal damage via inflammation, as well as slower transitions during fetal growth, childhood growth, puberty and response to environmental changes. Living systems must also have enough flexibility to promote and tolerate evolutionary change. Robust control mechanisms prevent these transitions from being activated inappropriately, but the chronic stressors may disrupt these control mechanisms.
C. Malignancy arises due to a build up of hierarchical structures, in which combination of agents (biomarkers and networks) at one level become agents at the next level. Hierarchical structures may be identifiable by patterns of network changes, molecular changes or histologic changes.
D. We can acquire new insights about malignancy by analyzing patterns of network behavior (such as the creation of new hierarchical structures or increasing instability) that are more uniform than changes to downstream oncogenes.
E. Self-organized criticality describes how enormous transformations (“catastrophes”) occur in living and nonliving systems. Similarly, malignant change does not occur through gradualism but by bursts of activity.
5. Treatment approaches based on complexity theory focus on interacting cellular networks, not just killing tumor cells where they exist. Curative treatment must combine multiple strategies that target existing tumors, prevent future tumors from arising and optimize the overall health of the patient:
* Cytotoxic cancer therapy should kill as many tumor cells as possible.
* Curative treatment for adult tumors must address tumor heterogeneity to a greater extent than curable childhood tumors.
* It may be useful to move cancer networks into less lethal states using biomolecules that influence malignant-type behavior or that alter pathways that promote malignant-type behavior.
* Reducing the chronic stressors is important because current knowledge is often inadequate to reverse network changes caused by even the simplest carcinogens.
* Novel treatments may take advantage of the sophistication present in physiologic cells but lost in the somewhat chaotic cells of advanced and aggressive cancers.
* Targeting the microenvironment that nurtures the tumor cells may have therapeutic value.
* More effective screening is important, both for premalignant and malignant lesions.
* Promoting rational medical care is important at the individual and societal level to more easily detect signs and symptoms associated with malignancy and to increase the range of possible treatments.
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