n-3 PUFAs in cancer

[Guest guest]

Hi All,

The below pdf-available review appears to suggest

that n-3 polyunsaturated fatty acids play a role in cancer

incidence, progression and treatment. For my interest,

the incidence seems more important.

For CRON, this may be significant. In CR, cancer occurs

less frequently. For our optimal nutrition to go with our

CR, healthy fats are recommended in our community of

CRers.

http://www.andypryke.com/pub/EssentialFattyAcids

suggests fatty acid choices to derive the best cancer

reductions.

Nutr Res Rev (2004),17 ,177–192

n -3 Polyunsaturated fatty acids throughout the cancer trajectory:

in & #64258;uence on disease incidence,progression,response to therapy and

cancer-associated cachexia

Evidence from epidemiological studies suggests that diets rich in

n -3 PUFA may be associated

with reduced cancer risk.These observations have formed the rationale

for exploring the mecha-

nisms by which n -3 PUFA may be chemoprotective and have resulted in

signi & #64257;cant advances in

our mechanistic understanding of n -3 PUFA action on tumour

growth.Various interrelated and

integrated mechanisms may be at work by which n -3 PUFA in & #64258;uence

cancer at all stages of ini-

tiation,promotion,progression,and neoplastic transformation.More

recently,experimental

studies have reported enhanced tumour cell death with chemotherapy

when & #64257;sh oil is provided

while toxic side effects to the host are reduced.Furthermore,cancer-

associated wasting has been

shown to be attenuated by & #64257;sh oil supplementation.Clinical evidence

suggests that the n -3

PUFA status of newly diagnosed cancer patients and individuals

undergoing chemotherapy is

low.Therefore,both the disease itself and therapeutic treatments may

be contributing factors in

the decline of n -3 PUFA status.Dietary supplementation to maintain

and replenish n -3 PUFA

status at key points in the cancer disease trajectory may provide

additional health bene & #64257;ts and

an enhanced quality of life.The present review will focus on and

critically examine current

research efforts related to the putative anti-cancer effects of n -3

PUFA and their suggested abil-

ity to palliate cancer-associated and treatment-associated symptoms.

... Dietary polyunsaturated fatty acids:prevention and

risk reduction of cancer

There are several prevailing streams of thought regarding

the contribution of dietary fat to cancer.Animal studies in

particular have allowed the delineation of these points

through the use of diets with de & #64257;ned fat components.The

quantity and energy contribution of fat to energy intake and

the composition of that fat independently in & #64258;uence cancer

risk and the growth of established tumours.Within fat com-

position,the importance of the PUFA:saturated fatty acids

ratio in the diet as well as the levels of different speci & #64257;c

fatty acids on tumour incidence,growth and anti-tumour

immune responses have been recognised (Sasaki et al.

1998; et al.2001).The balance between n -3 and

n -6 PUFA is important,but this may also extend to other

biologically active fatty acids such as conjugated linoleic

acid (Wahle & Heys,2002),oleic acid (Bartsch et al.

1999),and individual fatty acids within the n -3 and n -6

PUFA family.

Epidemiological and experimental evidence

The results from epidemiological studies examining the

effect of & #64257;sh consumption on the development of human

cancer has been reviewed extensively (de Deckere,1999;

Cohen,2000;Weisburger,2000;Zock,2001;Temple,

2002;Dennis et al.2003;Terry et al.2003).Although stud-

ies suggest a bene & #64257;cial and protective effect of & #64257;sh oil con-

sumption,overall,epidemiological evidence cannot be used

to de & #64257;nitively conclude that n -3 PUFA consumption is

chemoprotective.There are two signi & #64257;cant shortcomings

inherent in most epidemiological studies.Reviewed collec-

tively,studies fail to demonstrate that cancer risk or tumour

burden is lowered by n -3 PUFA consumption.Second,such

approaches do not rigorously address mechanisms of

action.The inconsistent & #64257;ndings re & #64258;ect the dif & #64257;culty in

evaluating the relative contribution of minor fatty acids in

the diet which are not easily dissected from a large matrix

of confounders.The list of confounders appears endless and

highlights the many challenges in interpreting these types

of studies.

Given the recognised limitations of various epidemiologi-

cal study formats (i.e.case –control,retrospective and

prospective studies;Temple,2002;Dennis et al.2003),the

fact remains that there is a trend that suggests a role for

dietary n -3 PUFA in cancer prevention.Whereas the epi-

demiological data have primarily provided correlative evi-

dence for cancer prevention and risk reduction,experimental

data from animal models and cell lines demonstrate that

dietary n -3 PUFA can inhibit tumour growth in a variety of

cancer models such as breast,colon and prostate (e et

al.1999;Connolly et al.1999;Chen & Istfan,2000;Chung

et al.2001).A large body of in vitro and animal model data

links n -3 PUFA to physiological and morphological changes

that reduce tumour weight,size and multiplicity.

Various mechanisms may be at work by which n -3

PUFA can prevent cancer at all stages of initiation,promo-

tion,progression,and then neoplastic transformation of

benign tumours to malignant tumours.A survey of the liter-

ature reveals a multitude of mechanisms currently being

investigated,broadly related to apoptosis,cell proliferation,

cell signalling,gene regulation,angiogenesis and metasta-

sis;these are summarised in Fig.1.Well-studied mecha-

nisms have been discussed in detail in several recent

reviews (Jiang et al.1998;Bartsch et al.1999;Bougnoux,

1999;Rose & Connolly,1999 b ,2000;Simopoulos,1999,

2002;Woutersen et al.1999;Stoll,2001;Hardman,2002;

McEntee & Whelan,2002;Chajes & Bougnoux,2003);

therefore,we will highlight,or summarise in brief,areas of

emerging interest.

... most epidemiological studies.Reviewed collec-

tively,studies fail to demonstrate that cancer risk or tumour

burden is lowered by n -3 PUFA consumption.Second,such

approaches do not rigorously address mechanisms of

action.The inconsistent & #64257;ndings re & #64258;ect the dif & #64257;culty in

evaluating the relative contribution of minor fatty acids in

the diet which are not easily dissected from a large matrix

of confounders.The list of confounders appears endless and

highlights the many challenges in interpreting these types

of studies.

Given the recognised limitations of various epidemiologi-

cal study formats (i.e.case –control,retrospective and

prospective studies;Temple,2002;Dennis et al.2003),the

fact remains that there is a trend that suggests a role for

dietary n -3 PUFA in cancer prevention.Whereas the epi-

demiological data have primarily provided correlative evi-

dence for cancer prevention and risk reduction,experimental

data from animal models and cell lines demonstrate that

dietary n -3 PUFA can inhibit tumour growth in a variety of

cancer models such as breast,colon and prostate (e et

al.1999;Connolly et al.1999;Chen & Istfan,2000;Chung

et al.2001).A large body of in vitro and animal model data

links n -3 PUFA to physiological and morphological changes

that reduce tumour weight,size and multiplicity.

Various mechanisms may be at work by which n -3

PUFA can prevent cancer at all stages of initiation,promo-

tion,progression,and then neoplastic transformation of

benign tumours to malignant tumours.A survey of the liter-

ature reveals a multitude of mechanisms currently being

investigated,broadly related to apoptosis,cell proliferation,

cell signalling,gene regulation,angiogenesis and metasta-

sis;these are summarised in Fig.1.Well-studied mecha-

nisms have been discussed in detail in several recent

reviews (Jiang et al.1998;Bartsch et al.1999;Bougnoux,

1999;Rose & Connolly,1999 b ,2000;Simopoulos,1999,

2002;Woutersen et al.1999;Stoll,2001;Hardman,2002;

McEntee & Whelan,2002;Chajes & Bougnoux,2003);

therefore,we will highlight,or summarise in brief,areas of

emerging interest.

... At diagnosis

Population studies illustrate the large variation of n -3 levels

in blood and cell lipids in individuals from different coun-

tries and regions (de Deckere,1999;Amiano et al.2002;

Augustsson et al.2003;Terry et al.2003).Thus it seems

clear that any reports of PUFA status in cancer patients at

any stage must be interpreted in the light of national or

regional context.In a comprehensive review of intakes of

& #64257;sh and marine fatty acids in relation to hormone-related

cancers,Terry et al.(2003)point out that the difference

between the highest and lowest n -3 intakes internationally

are as much as 15-fold (i.e.1500,400 and 100 mg/d in

Japan,Scandinavian countries and North America,respec-

tively).The dietary n -6:n -3 fatty acids ratio shows a similar

degree of variation.

The fatty acid status of patients at the time of a cancer

diagnosis can be assumed to be a function of previous

dietary intakes and the effect,if any,speci & #64257;c to disease and

disease stage.Only one study to date has reported plasma

fatty acid levels in patients with a new diagnosis of pancre-

atic,non-small-cell lung and stomach or oesophageal cancer

(Zuijdgeest-van Leeuwen et al.2002).The disease stage was

not reported;however,up to 23 %of patients had metastatic

cancer at diagnosis.These were compared with normal

healthy controls from a local population (The Netherlands).

This report suggests impairments in essential fatty acid

metabolism as the levels of fatty acids of the n -6 and n -3

series typically were lower than those of healthy subjects;

however,the degree of difference and the speci & #64257;c fatty acids

that are affected appear to vary between cancer types.

... The information on fatty acid status and fatty acid sup-

plementation in patients with advanced cancer,taken

together,provides a rationale for developing dietary recom-

mendations based on formal assessments of fatty acid status

and fatty acid requirements.This is particularly pertinent in

countries where n -3 fatty acid intakes are generally low and

n -6:n -3 ratios are high.Current intakes of total n -3 fatty

acids are about 1 ·6 g/d (0 ·7 %of energy intake)in the USA

(Kris-Etherton et al.2002).Of this,á -linolenic acid

accounts for about 1 ·4 g/d,and only 0 ·1 to 0 ·2 g/d comes

from EPA and DHA.Formal population-based dietary rec-

ommendations for n -3 fatty acids have been made by the

WHO and the North Atlantic Treaty Organization and also

exist in several countries including Canada,Sweden,the

UK,Australia and Japan.Typical recommendations for

EPA+DHA are 0 ·3 to 0 ·5 g/d,and for á -linolenic acid are

0 ·8 to 1 ·1 g/d.Dietary reference intakes for energy and

macronutrients were recently released by the Food and

Nutrition Board,Institute of Medicine,and The National

Academies (USA),in collaboration with Health Canada.

These institutions placed the acceptable macronutrient dis-

tribution range for á -linolenic acid at 0 ·6 to 1 ·2 %of

energy,or 1 ·3 to 2 ·7 g/d on the basis of a 8370 kJ (2000

kcal)diet (Kris-Etherton et al.2002).This is nearly ten

times the current intake of EPA+DHA of typical North

Americans.In view of suggestions that the n -3 PUFA status

in cancer patients may be even poorer than in the general

population,it would appear obvious that dietary supple-

mentation to maintain and replenish n -3 PUFA status at key

points in the cancer disease trajectory is required.Dietary

recommendations for such supplementation have not been

adopted by cancer centres or agencies,and the number and

type of supplements and n -3-containing products suited to

the patient populations are very limited.For those wishing

to advise upon or implement n -3 supplementation,the

American Heart Association position paper on & #64257;sh oil and

n -3 fatty acid consumption (Kris-Etherton et al.2002)is a

useful reference.

Cheers, Alan Pater