Vol.2, No.7, 781-788 (2010)
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Internal environment in cancer patients and proposal
that carcinogenesis is adaptive response of glycolysis
to overcome adverse internal conditions
Mayumi Watanabe1, Kenya Miyajima2, Ittoku Matsui2, Chikako Tomiyama-Miyaji3,
Eisuke Kainuma1, Masashi Inoue1, Hiroaki Matsumoto1, Yuh Kuwano1, Toru Abo1*
1Department of Immunology, Niigata University School of Medicine, Niigata, Japan;
*Corresponding Aut hor: immunol2@med.niigata-u.ac.jp
2Yushima-Shimizuzaka Clinic, Tokyo, Japan
3School of Health Sciences, Faculty of Medicine, Niigata Univ e rsity, Niigata, Japan
Received 4 March 2010; revised 16 March 2010; accepted 20 March 2010.
In a series of our recent studies, stress was
found to induce simultaneously hypothermia
and hyperglycemia. These conditions are bene-
ficial to obtain prompt force which depends on
the glycolysis pathway and to escape emer-
gency. Since we have noticed that such condi-
tions resemble the internal environment seen in
some cancer patients, it was investigated whe-
ther such conditions were accompanied with
other patients. We selected patients with early
and advanced cancer. Body temperature and
other parameters including blood gas contents
were examined. A difference was seen in body
temperature, namely, many patients showed
hypothermia, irrespective of cancer stages. Fur-
ther characterization of other parameters show-
ed that hypothermia and hyperglycemia existed
in many patients. They had immunosuppressive
state and anemia. Blood gas analysis showed
that oxygen contents were low and carbon di-
oxide contents were high in patients. These re-
sults suggest a possibility that the internal en-
vironment seen in patients is responsible to
induce onset of disease and to maintain their
cell growth, because cancer cells have an en-
ergy system of predominant glycolysis. Al-
though hypothermia, hypoxia and hyperglyce-
mia are important to activate the glycolysis
pathway and to escape from emergency, such
responses suppress the mitochondrial pathway
for long span and may result in carcinogenesis.
Keywor ds: Cancer; Hypothermia; Hypoxia;
Hyper glycemia; Glycolysis; Mitochondria
Many investigators and clinicians have felt that cancer
might be a systemic disease although tumor masses are
primarily present at local sites. If this is the case, we
have to consider specific, common internal environment
in cancer patients. In the course of the analysis of many
parameters in cancer patients, we noticed that many
cancer patients showed simultaneous hypothermia and
In light of these findings, we then investigated the in-
ternal environment in relation to stress-associated re-
sponses [1,2 ]. Of interest was that both hypother mia and
hyperglycemia were induced by stress. Such an internal
environment might be beneficial for humans and animals
to escape emergencies [3]. Namely, prompt output of
force by white muscle fibers depends on the energy
production system of glycolysis. Although the efficiency
of energy production is low (2 ATP/glucose) in the gly-
colysis pathway, the ATP synthesis in this system is
much quicker (× 100) than that of the mitochondrial sys-
tem (× 1) [4].
In a short span of time, hypothermia and hyperglyce-
mia are therefore good conditions for escape from stress
or emergencies. However, these conditions are not ap-
propriate for energy production of the mitochondrial
pathway (i.e., oxidative phosphorylation). Many patients
with hypothermia and hyperglycemia suffer from gen-
eral fatigue, emaciated conditions, diabetic disease, etc.
In the present study, we investigated the internal en-
vironment in cancer patients in detail and herein propose
on adaptation theory, namely, that the onset of cancer is
a phenomenon of a glycolytic adaptation response by
living beings to overcome deteriorated internal condi-
tions in the body. Cumulative evidence has shown that
M. Watanabe et al. / HEALTH 2 (2010) 781-788
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cancer cells have a shift of glucose metabolism from
oxidative phosphorylation to glycolysis, eventually re-
sulting in few or defective mitochondria in the cyto-
plasm [5-7]. Although many investigators have consid-
ered that carcinogens such as ultrav iolet rays, food addi-
tives, air pollution, etc. [8-12], induce multiple mutation
steps in proto-oncogenes, there is an alternative possib il-
ity that such mutation is a process of glycolytic adapta-
tion by living beings, namely, cancer cells. Hypothermia,
hypoxia and hyperglycemia, which are induced by con-
tinuous stress (due to the lifestyle in patients), might be
important factors which induce the adaptive response.
2.1. Subjects
Patients with early or advanced cancer were first exam-
ined as to body temperature (n = 28). They were 54.3 ±
8.0 years old. Age-matched healthy controls (n = 27),
45.8 ± 11.0 years of age, were also examined.
For detailed analysis of many parameters other than
body temperature, patients with advanced cancer (n = 13)
were then selected (Ta bl e 1 ). Details of the cancer pa-
tients are listed in the table, including sex and age (52.1
± 8.7 years old). At the time of analysis, these patients
were receiving neither chemotherapy nor irradiation
therapy. Age-matched healthy controls (n = 11), 46.7 ±
10.0 of age, were also examined.
Table 1. Patients with Advanced Cancer.
Case Type of Cancer Sex Age
1 chronic myelogenic leukemia F 68
2 ovarian cancer F 56
3 brain cancer M 50
4 stomach cancer F 63
5 parotid gland cance F 48
6 rectum cancer, metastasis to lung M 58
7 uterus cervical cancer F 36
8 rectum cancer, metastasis to lung M 45
9 bladder cancer M 52
10 lung cancer M 48
11 breast cancer F 56
12 malignant lymphoma M 42
13 stomach cancer M 55
Informed consent was obtained from all subjects.
2.2. Parameters Tested
Blood for the analysis was obtained from a vein. Blood
glucose was measured by Precision Xtra TM (Abott Ja-
pan Co., Ltd., Chiba, Japan). Venous blood analysis of
lactate and of the levels of pH, O2 and CO2 was also
performed using i-STAT 300F (i-STAT Corporation, NJ,
To analyze the hematological parameters, leukocyte
counts of fresh venous blood were determined by hem-
ocytemeter and were stained by the Giemsa method. The
contents of hemoglobin (Hb) and others in the blood
were measured by Sodium Lauryl Sulfate (SLS)-Hb
methods and hematocytemeter, respectively.
2.3. Statistical Analysis
The difference between the values was determined by
Student’s t-test, Mann-Whitney’s U test and Welch’s
3.1. Hypothermia and Hyperglycemia Seen
in Cancer Patients
Twenty-eight patients with early or advanc ed cancer and
twenty-seven healthy subjects were examined as to body
temperature (Figure 1(a)). It was found that there were
many persons with hypothermia (36.1 ± 0.5˚C) among
cancer patients in comparison with healthy persons (36.6
± 0.4˚C), the difference being statistically significant (p
< 0.01).
We then analyzed many parameters in patients with
advanced cancer (n = 13) and age-matched controls (n =
11) (Figure 1(b)). Hypothermia was confirmed in these
patients with advanced cancer (35.9 ± 0.5˚C) in com-
parison with controls (36.5 ± 0.3˚C). In addition to hy-
pothermia, hyperglycemia was also detected in cancer
patients (125.3 ± 28.5 mg/dL) in comparison with con-
trols (106.3 ± 1 1.1 mg/dL).
Since stress-associated responses simultaneously in-
duce hypothermia and hyperglycemia, other stress-as-
sociated parameters were also examined in this experi-
ment (Figure 1(b), bottom). Although there was a ten-
dency that some patients with advanced cancer had a
high pulse rate (sympathetic nerve activ ation) and a high
level of lactate, these were not common to all p atients (p
> 0.05 in both pulse and lactate).
3.2. Immunosuppressive States and Anemia
in Cancer Patients
Immunoparameters were examined in cancer patients and
M. Watanabe et al. / HEALTH 2 (2010) 781-788
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Figure 1. (a) Comparison of body temperature and other pa-
rameters between healthy controls and cancer patients. (a).
Body temperature, (b). Further analysis of body temperature
and others. In experiment (a), healthy controls (n = 27) and
cancer patients (n = 28) were examined. In experiment (b),
healthy controls (n = 11) and patients with advanced cancer (n
= 13) were examined. In addition to body temperature, the
levels of glucose and lactate and the pulse rate were examined
in this experiment. Body temperature was measured in the
axilla for 3 min. **p < 0.01.
healthy controls (Figure 2(a)). The total number of
white blood cells (WBC) was lower in patients (4691 ±
1769 /L) than in controls (619 0 ± 1088 /L) (p < 0.05).
When the ratio of WBC (leukocyte) subsets was enu-
merated, the ratio of granulocytes was found to be high,
while that of lymphocytes was low (p < 0.01). The ratio
of monocytes was comparable in patients and controls.
By calculation, the abso lute number of leukocyte subs ets
was determined. It was found that the most prominent
distinction was in lymphocytes, namely, the number of
lymphocytes in patients (1334 ± 476 /L) was extremely
low in comparison with the number in controls (2387 ±
538 /L) (p < 0.01). The decrease in the number of leu-
kocytes seen in patients was found to be due to the de-
crease in the number of lymphocytes. The ratio and
number of monocytes were comparable in controls and
cancer patients.
The level of red blood cells (RBC) and related pa-
rameters was then examined (Figure 2(b)). In addition
to the decrease in the number of WBC, the number of
RBC was found to decrease in cancer patients (407 ± 47
× 104/L) in comparison with controls (446 ± 39×104 /L)
(p < 0.05). The level of Hb was lower in patients (11.9 ±
1.7 g/dL) than in controls (13.9 ± 1.3 g/dL). The level of
hematocrit (Ht) was also lower in patients (37.6 ± 4.1%)
than in controls (42.0 ± 3.5%) (p < 0.01). Other parame-
ters of RBC, namely, mean red cell volume (MCV),
mean corpuscular hemoglobin (MCH) and mean cor-
puscular hemoglobin concentration (MCHC) were all
comparable between controls and patients (p > 0.05).
This was also the case for the number of platelets.
3.3. Blood Gas Analysis in Cancer Patients
It is conceivable that hypothermia and anemia seen in
patients with advanced cancer may influence the pa-
rameters as shown by blood gas analysis. Therefore,
such analysis using venous blood was conducted (Fig-
ure 3). It was demonstrated that blood pH was lower in
patients (7.36 ± 0.03 ) than in controls (7.40 ± 0.03) (p <
0.05). The major factors influencing blood pH are
known to be the levels of O2 and CO2 contents. Indeed,
the levels of PO2 (mmHg) and SO2 (%) were found to be
extremely low in patients (p < 0.01, p < 0.05, respec-
tively). On the other hand, the levels TCO2 (mmol/L)
and PCO2 (mmHg) tended to be high in patients. BEecf
(mmol/L), which shows a base excess in extracellular
fluids, was slightly high in cancer patients.
We herein demonstrated that many cancer patients had
hypothermia, hypoxia and hyperglycemia simultaneously.
Immunosuppressive states, showing granulocytosis and
M. Watanabe et al. / HEALTH 2 (2010) 781-788
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Figure 2. Blood cell analysis. (a) Immunoparameters. (b) Analysis of the number of RBC and the levels of Hb
and other parameters. In experiment (a), the absolute number of leukocyte subsets was calculated from the
data on the number of WBC and the ratio of leukocy te subsets. In experi ment (b), Number of RBC a nd leve l s o f
b, Ht, MCV, MCH and MCHC, including the number of platelets, were examined * p < 0.05, ** p < 0.01. H
Openly accessible at
M. Watanabe et al. / HEALTH 2 (2010) 781-788
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Figure 3. pH and blood gas analysis in healthy controls and
cancer patients. Venous blood was used for the analysis. * p <
0.05, ** p < 0.01.
lymphocytopenia, were also present. Although clinicians
are empirically aware of the deteriorated conditions such
as hypoxia, immunosuppression and anemia in cancer
patients [13-20], as shown by a review of the literature,
few studies have been done on the simultaneous identi-
fication of all these conditions. We propose the possibil-
ity that hypothermia, hypoxia and hyperglycemia are
beneficial for stress-exposed persons to escape from
emergencies inducing stress for short periods of time,
but that such internal environment might become can-
cer-inducing over a longer period of time. This proposal
is based on an understanding of the energy production
system comprising the glycolysis and mitochondria path-
ways [3,4].
It has been speculated that the ancestors of eukaryo-
cytes were generated by a connection between living
beings with glycolysis and those with mitochondria at
approximately 2 billion years ago [21,22]. Under such
situation, eukaryocytes had two energy production
methods, namely, the glycolysis and mitochondria path-
ways (Ta b l e 2 ). As shown in this table, the functioning
conditions, usage and other characteristics between two
pathways are quite different. If we consider the internal
environment (i.e., hypoxia and hyperglycemia) seen in
cancer patients, these conditions are rather appropriate
for the function of glycolysis.
In a recent study, we analyzed in detail the stress-as-
sociated conditions in mice exposed to restraint stress
[1,2]. Of interest was that such conditio ns were revealed
to be hypothermia and hyperglycemia. In addition, the
administration of catecholamines or glycocorticoids also
directly induced hypothermia and hyperglycemia [2]. In
a short span of time, such internal conditions are benefi-
cial for humans and animals to obtain the prompt force
of white muscle fibers via activation of the glycolysis
Table 2. Energ y prod uctio n system.
Glycolysis Pathway Mitochondrial Pathway
Site cytoplasm mitochondria
Oxgen – or ± ++
glucose pyruvic acid (lactate)
Source ketone bodies
Temperature 32-36 > 37
cell division suppression of cell division
Usage prompt force continuous force
ATP productionquick (× 100) slow (× 1)
Efficiency low (2ATP/gl ucos e) high (36ATP/glucose)
sperms cardiac muscle cells
cancer cells neurons
skin cells hepatocytes
bone marrow cells red muscle cells
white muscle cells many other ce lls
M. Watanabe et al. / HEALTH 2 (2010) 781-788
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pathway [3]. As a result, such conditions realize the
power needed to escape from stressful conditions such as
those in emergencies. In other words, the internal condi-
tions of hypothermia and hyperglycemia do not seem to
be a failure of our body r es po nses.
If a certain person is exposed to stress for a long time,
the internal conditions of hypothermia and hyperglyce-
mia then suppress the mitochondria pathway which pro-
duces continuous force and energy for protein synthesis.
Such a person might be suffering from general fatigue,
emaciated conditions, diabetic disease and other difficul-
ties. This notion seems to be important for understanding
the mechanisms involved in the onset of many diseases.
In addition, we propose another possibility of hypo-
thermia, hypoxia and hyperglycemia which may be as-
sociated with the onset of malignancy. As shown in Ta-
ble 3, many investigators and clinicians have believed
that carcinogens are key factors which induce cancer via
the multiple mutation steps of proto-oncogenes [23-27].
However, such carcinogens do not seem to be always
present in actual cases. Given this fact, such cases may
be rather rare. We propose herein the possibility th at the
internal environment (i.e., hypoxia and hyperglycemia)
induced by continuous stress results in an adaptation
response in which normally dividing cells become can-
cer cells (i.e., living beings with glycolysis). In such
cases, stress may be caused by overwork, mental stress,
obesity, etc., namely, their lifestyle. We consider that
these cases are of higher frequency than those due to
carcinogens in carcinogenesis. Immunosuppression and
anemia in cancer patients as revealed in the present
study might result from such stress via the activation of
sympathetic nerves [28]. Interaction of leukocyte sub sets
with catecholamines or glucocorticoids (hypothalamic-
pituitary-adrenal axis) was reported previously [29].
Table 3. Transformation to Cancer Cells.
Direct Cause Secondary Response Frequency
food additives
air pollution
other carcinogens
mutation of proto-
oncogenes or other
genes by
Stress from
mutation of proto-
oncogenes or other
genes as adaptation
to “living beings of
O. Warlburg has reported that cancer cells contained a
few mitochondria in the cytoplasma and produce energy
mainly by the g lycolysis p athway [7]. Recent cu mulativ e
evidence also supports this earlier observation [30-35].
The functions of oncog enes are eventually related to not
only the system of cell-proliferation but also to the sys-
tem of energy production. The nature of the predominant
function of glycolysis in cancer cells is utilized by PET
scans [36,37]. The energy produced by glycolysis is used
not only to obtain prompt elicitation but also for cell
dividing energy (see Table 2 again). In other words, the
initial stress-associated response of hypothermia, hy-
poxia and hyperglycemia is estimated as allostasis (i.e.,
change of the internal environment to overcome stress).
However, continuous stress then turns to allostatic load
and induces the carcinogenesis as adaptation responses
(i.e., break of “homeostasis” in our body). These con-
cepts on “allostasis” were proposed by B. S. McEwen, F.
S. Dhabhar and their colleagues [38-41]. Stressful life
events were reported to be related to such allostatic load
In our recent study using hyperthermia equipment [44,
45], many cancer patients could live in good conditions
without further tumor enlargement when they exposed to
mild hyperthermia (i.e., the maximum rectum tempera-
ture is 38.0ºC for 15-30 min). In some cases, tumor re-
gression resulted from mild hyperthermia [45]. At this
time, the values of pH, PO2, PCO2 and other factors im-
proved. Immunosuppression and anemia seen in cancer
patients were also alleviated. These results suggest that a
slight shift of glucose metabolism from the glycolysis
pathway to the mitochondria pathway (i.e., oxidative
phosphorylation) might be important to cure malignancy.
Local, strong hyperthermia (e.g., 42ºC) was not effective
and rather acted as severe stress in cancer patients. In
other words, systemic improvement of the internal envi-
ronment is critical to cure malignancies. However, we do
not recommend patients to use expensive equipment for
hyperthermia. The most important things for spontane-
ous regression of cancer are as follow: changing harmful
lifestyle (e.g., overwork), using hot-water bottle at
sleeping time, taking a deep breath several times a day,
dietary consideration and control of the fear.
We have herein proposed the possibility that stress-
associated conditions are beneficial for humans to es-
cape from emergencies in a short span of time, but that
the resulting hypothermia and hyperglycemia act as fac-
tors which induce the generation of cancer cells. In other
words, the onset of malignancy might be a return to
“living beings with glycolysis at 2 billion years ago”.
Cancer cells eventually contain only a few mitochondria
in the cytoplasm. However, we could not neglect a mi-
tochondrial function in tumor cell growth [46,47].
M. Watanabe et al. / HEALTH 2 (2010) 781-788
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A hypothesis by J. S. Fang, R. J. Gillies and R. A.
Gaten was proposed that evolution of carcinogenesis is
an adaptation response to hypoxia and acidosis, showing
the interaction of cancer cells and microenvironments in
the surrounding tissu es [48,49]. At that time, a paracrine
signaling between epithelial and stromal cells is known
to be important for tumor initiatio n and prog ression [50].
We were also able to reveal the systemic, internal envi-
ronment of hypoxia, acidosis and other conditions in
actual cancer patients. However, a further research is
required to support our proposal definitely. Such re-
search includes an animal experiment using mice with
cancer and a cancer cell culture experiment under condi-
tions of hypothermia, hypoxia and hyperglycemia
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science and Culture, Japan. The au-
thors thank Mrs Yuko Kaneko for preparation of the manuscript and
Mr Taiki Hashimoto and Ms Kaori Yamamoto (Yushima-Shimizuzaka
clinic) for arrangement of the clinical research.
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