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52 ALTERNATIVE THERAPIES, mar/apr 2010, VOL. 16, NO. 2 Defi ning the Cancer Domain
Jeffrey Bland, PhD, FAC N, FAC B, is cofounder of the Institute for
Functional Medicine, Gig Harbor, Washington. (Altern Ther
Health Med. 2009;16(2):52-54.)
Cancer represents a very different disease than other
chronic diseases in the minds of both health profes-
sionals and patients. Even though heart disease is the
cause of death for many more people than cancer, it
engenders less signifi cant fear and social stigma than
cancer does. This is undoubtedly because it is generally felt that we
know much less about the origin and treatment of cancer than
heart disease and that there is some sense of “personal responsibili-
ty” for cancer. Over the past decade, the understanding of the etiol-
ogy of cancer has started to emerge as in part a systemic functional
disorder associated with alteration in cellular biology associated
with dedifferentiation, proliferation, angiogenesis, and metastasis.
In the broadest sense, it is now recognized that cancer is really
“cancers.” Each person’s cancer has a slightly different molecular
and cellular biology associated with it. This makes treatment of
cancer via a “one size fi ts all” therapy virtually impossible, and in a
sense, each cancer patient becomes his or her own clinical experi-
ment without a control. To manage cancer more effectively, there-
fore, it is important to identify common functional characteristics
that different cancers share. In this two-part series of articles, the
concept of cancer as a systemic functional disorder will be devel-
oped, and a general framework of managing disorders associated
with malignant cellular proliferation will be described based upon
this model. In part 1 of this series, the establishment of a cellular
milieu characteristic of cancers will be developed, and in part 2, a
clinical approach based on the functional medicine concept of the
diathesis of cancer derived from the understanding of its anteced-
ents, triggers, mediators, signs, and symptoms will be described.
There are several systemic functional changes associated
with the genesis of cancers, including
• increased DNA damage,
• decreased DNA repair,
• altered epigenetic marks,
• alteration in cell cycle check point integrity,
• alteration in intercellular signal transduction,
• reduced patency of immune surveillance, and
• increased hormonal and chemokine stimulation of
mitotic activity.
From this list, which will be discussed in detail in part 2 of
this series, it can be seen that cancers are a disturbance of molec-
ular genetics and biology as well as systemic changes in immune
defense mechanisms. Historically, it has been thought that can-
cer goes through several steps, including initiation, propagation,
angiogenesis, invasion, and metastasis. The initiating step has
been thought to be the result of a mutagenic or carcinogenic cel-
lular insult that can come from either an external or internal ini-
tiating event.1 The recognition that cancer can be initiated by
external exposure to a chemical carcinogen goes back to the
19th-century discovery of the correlation between the soot expo-
sure of chimney sweeps and scrotal cancer by Sir Percival Pott.
During the early 1900s, it was recognized that exposure to ioniz-
ing radiation induced cancers. Later in the 20th century, Denis
Parsons Burkitt noted that a form of lymphoma was associated
with a specific viral infection, thereby broadening the list of
external environmental cancer-inducing agents to include chemi-
cals, radiation, and specifi c infectious organisms. More recently,
Mary-Claire King discovered the BRCA1 and BRCA2 genetic
polymorphisms associated with a high prevalence of breast can-
cer, heralding in the era of cancer genetics.2
From these observations, subsequent research developed
the approach to cancer prevention that is now advocated, which
is focused on reducing the exposure to known carcinogens in the
diet and environment, such as charred meat and polynuclear
aromatic hydrocarbons and other chemicals from smoking,
respectively. The approach also advocates reducing exposure to
radiation from x-rays and to ultraviolet light associated with
excess sun exposure as well as limiting activities that would
increase the risk for chronic viral, bacterial, and helminth infec-
tions.3 The recommendations also include positive behaviors
such as regular exercise and appropriate body mass indices;
increased intake of dietary fi bers, fruits, and vegetables; adequate
intake of B-vitamins and minerals and omega-3–containing oils;
and inclusion of soy products in the diet.4
But beyond these recommendations, there is evidence that
other systemic functional factors contribute to the initiation,
propagation, tissue invasion, and metastasis of cancers. There is
now increasing evidence that the cellular and animal models of
carcinogen-induced cancer are not suffi cient for understanding
the origin of human cancers.5 In human cancer, there seems to be
no simple relationship between carcinogen exposure and cancer
incidence, suggesting that there is more complex interplay
CANCERS AS SYSTEMIC FUNCTIONAL DISEASES,
PART 1: DEFINING THE CANCER DOMAIN
Jeffrey Bland, PhD, FACN, FAC B
perspectives
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ALTERNATIVE THERAPIES, mar/apr 2010, VOL. 16, NO. 2 53
Defi ning the Cancer Domain
between the exposure to the carcinogen and a several-step pro-
cess associated with the development of a cancer. This has been
called the “two-hit” mechanism and implies that multiple factors
must work in combination to convert a normal cell into the sys-
temic disease of cancer. This newer understanding of carcinogen-
esis raises the opportunity for intervention at several stages
along the cascade of cellular and organismic events associated
with the development of cancer, including the stage of initiation,
the stage of altered intercellular signaling, the propagation of the
altered cell, the angiogenic process that is necessary to support
the nutrient needs of a growing malignant cellular mass, the
invasive process whereby the malignant cells vie for “real estate”
in a tissue, and the metastatic events that result in spread of the
cancer to distant sites. This multiple-hit progression has resulted
in the development of a much more diverse set of therapeutic
tools to block cancer growth and progression throughout the
various stages of its development.
It is now recognized that every person probably develops a
protocancer several times during his or her life but that in most
instances, the altered cells are arrested at one of the several check
points along the development of the cancer by inherent physio-
logical processes that are cytotoxic to the transformed cells.6 This
concept opens the door to recognition that certain functional
physiological states associated with disturbed metabolism are
more conducive to cancer development and progression. The
clinical application of this model focuses on the assessment and
management of physiological functional states that are associat-
ed with increased oncogenic potential.7
Common contributors to increased oncogenic potential
include but are not limited to
• disturbances in insulin signaling,
• states of chronic infl ammation,
• increases in messages triggering cellular cycling,
• increased genomic instability,
• altered mitochondrial bioenergetics associated with oxi-
dant stress,
• altered nucleosome epigenetic methylation patterns, and
• cellular hypoxia.
There is still substantial belief that cancer is predominantly
inherited, and therefore, there is little an individual can do to
reduce his or her risk of cancer, suggesting that this list of agents
that infl uence oncogenic potential is irrelevant. In 2000, The New
England Journal of Medicine published a landmark article from a
group at the Karolinska Institute in Sweden evaluating the herita-
bility of cancer.8 The study of 44
788 pairs of identical twins con-
cluded that “inherited genetic factors make a minor contribution
to susceptibility to most types of neoplasms. This fi nding indi-
cates that the environment has the principal role in causing spo-
radic cancer.”8 Genetics are not a modifiable factor, but the
environmental causes of cancer certainly are modifi able if they
are recognized and managed. The common contributors to
increased oncogenic potential are potentially modifi able factors
in cancer etiology. This observation has a direct relationship to
the importance of recognizing in the individual early-stage bio-
markers that are indicative of a systemic functional state that is
associated with an alteration in cellular function favoring onco-
genesis and tumor progression.
There is also the belief that specifi c therapeutic agents will
be discovered to personalize the treatment of cancer based upon
the cancer genetics of the tumor. Certainly some progress has
been made in this regard with the development of new chemo-
therapeutic agents that target specifi c mutated kinases associated
with specifi c tumor types. The problem is that as they advance,
cancers change their genetics and undergo monoclonal to poly-
clonal conversion, which results in “single-hit” drug resistance.9
There is now evidence emerging that targeted cancer therapy in
advanced disease has not worked for this reason, and the future
of chemotherapy is to develop agents whose mechanisms of
action have a broader range of activities cutting across many
interrelated regulatory steps in cellular signaling.10 The medical
community now more fully recognizes that lifestyle and diet
modifi cations can have this “multi-hit” impact on the processes
associated with oncogenesis and thereby slow progression and
improve patient outcome. A 2008 controlled clinical trial dem-
onstrated the infl uence of improving functional physiology in
prostate cancer patients by altering the host environment
through diet and lifestyle—not by targeting a specifi c regulatory
process, but rather by supporting multiple cellular processes
related to the reduction of oncogenic potential.11
It is becoming more clear that many steps along the process
are modifi able through changes in the host environment in nego-
tiating the complex path of cancer from the genotype of suscepti-
bility to the phenotype of cancer.12 In 1983, Bruce Ames pointed
out that a complex, minimally processed diet rich in plant-
derived nutrients promoted anticarcinogenic outcome by modu-
lation of multiple processes associated with cancer development
and progression.13 He indicated that our natural diets contain
potentially cancer-causing substances, but in their natural state,
they also have high levels of anticancer properties. It is the bal-
ance between carcinogens and anticarcinogens that determines
the potential influence of the environment on susceptibility
genes. It is now understood that diet and specifi c nutrients play
important roles in the risk of specifi c types of cancer.14 These fac-
tors are modifi able and modulate the systemic functional status
of the individual, thereby infl uencing oncogenic potential at all
the diverse stages throughout the cancer development process.
The Mishio Kushi Macrobiotic Diet is one dietary approach that
has been studied for the reduction in oncogenic potential.15 This
approach has developed compelling evidence for the nutritional
factors associated with the macrobiotic diet as important in can-
cer survival and therefore may be of value in the improvement in
systemic functional states associated with the development of
cancer and its treatment.
It appears that within the various medical subspecialties,
the primary care provider (PCP) might be best suited to recom-
mend therapeutic diet and lifestyle programs for patients with
altered systemic functional status associated with oncogenic
potential. It is most often the PCP that best understands the life-
styles of patients and provides consultation on factors associated
with both disease prevention and management of chronic condi-
tions.16 Studies on home-based diet and exercise programs in
cancer survivors that are having their disease managed as a
chronic disease have found that PCP-administered functional
lifestyle programs resulted in a reduced rate of decline of health.17
It has also been reported that the impact of PCP-administered
prognostic assessment and intervention programs focused on
improving systemic functional physiology had a marked positive
effect on survival in cancer patients.18
This article promotes the concept of cancers as systemic
functional diseases that can be recognized early through the
application of a functional medicine assessment approach and
adjunctively managed through a PCP-administered diet, lifestyle,
and environment intervention program. The second article in
this series will offer a discussion of the prognostic markers to
identify systemic functional imbalances associated with onco-
genic potential and interventions designed to reduce it.
REFERENCES
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Oxford, United Kingdom: Oxford University Press; 2005.
2. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited
mutations in BRCA1 and BRCA2. Science. 2003;302(5645):643-646.
3. Greaves M. Cancer: The Evolutionary Legacy. Oxford, United Kingdom: Oxford University
Press; 2001.
4. Milner J. Incorporating basic nutrition science into health interventions in cancer pre-
vention. J Nutr. 2003;133(11 Suppl 1):3820S-3826S.
5. Brash D, Cairns J. The mysterious steps in carcinogenesis. Br J Cancer. 2009;101(3):
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6. Chiang AC, Massague J. Molecular basis of metastasis. N Engl J Med. 2008;359(26):
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7. Cohen AA, Geva-Zatorsky N, Eden E, et al. Dynamic proteomics of individual cancer
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10. Sawyers CL, Hochhaus A, Feldman E. Imatinib induces hematologic and cytogenetic
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11. Ornish D, Magbanua MK, Weidner G, et al. Changes in prostate gene expression in
men undergoing an intensive nutrition and lifestyle intervention. Proc Natl Acad Sci U
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12. Strohman R. Maneuvering the complex path from genotype to phenotype. Science.
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13. Ames B. Dietary carcinogens and anticarcinogens. Oxygen radicals and degenerative
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14. Key TJ, Allen NE, Spencer EA, Travis RC. The effect of diet on risk of cancer. Lancet.
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15. Kushi LH, Cunningham JE, Herbert JR, Lerman RH, Teas J. The macrobiotic diet in
cancer. J Nutr. 2001;131(11 Suppl):3056S-364S.
16. Ballard-Barbash R, Neuhouser ML. Challenges in design and interpretation of observa-
tional research on health behaviors and cancer survival. JAMA. 2009;302(22):2483-2484.
17. Morey MC, Snyder DC, Sloane R, et al. Effects of home-based diet and exercise on
functional outcomes among older, overweight long-term cancer survivors: RENEW: a
randomized, controlled trial. JAMA. 2009;301(18):1883-1891.
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