Internal environment in cancer patients and proposal that carcinogenesis is adaptive response of glycolysis to overcome adverse internal conditions

doi:10.4236/health.2010.27118

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Vol.2, No.7, 781-788 (2010)

doi:10.4236/health.2010.27118

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.

ABSTRACT

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

1. INTRODUCTION

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

hyperglycemia.

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

782

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. MATERIALS AND METHODS

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,

USA).

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

t-test.

3. RESULTS

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

783

(a)

(b)

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.

4. DISCUSSION

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

784

(a)

(b)

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

785

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

Cells

white muscle cells many other ce lls

M. Watanabe et al. / HEALTH 2 (2010) 781-788

786

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

ultraviolet

food additives

radiation

air pollution

Carcinogens

other carcinogens

mutation of proto-

oncogenes or other

genes by

carcinogens

Less

hypothermia

hypoxia

Stress from

lifestyle

hyperglycemia

mutation of proto-

oncogenes or other

genes as adaptation

to “living beings of

glycolysis”

High

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

[42,43].

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

787

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

5. ACKNOWLEDGEMENTS

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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