In a previous post, Staffan and Dean noted that there is strong
experimental as well as epidemiological evidence to incriminate dietary
salt (actually sodium) in the etiology of stomach cancer.   Less well
appreciated is the evidence to suggest that dietary sodium may act as a
universal promoter of  multiple cancers separate from the
gastrointestinal tract.
        Although the notion that dietary sodium may influence the
development of a wide variety of cancers may at first seem to be
unfounded, there is sufficient data from a number of lines of evidence
to point to this connection.
        There is a well established link between dietary sodium and
hypertension.  Therefore, if sodium is somehow related to the promotion
of cancer, there should be an epidemiological relationship between
hypertension and cancer mortality.  And indeed there is, although the
information is relatively obscure and unrecognized.  I have included 4
references (1,2,3,4) which show this link.  Certainly, epidemiological
studies cannot establish cause and effect, and the relationship could
simply be a spurious one existing because of confounding variables.  In
the four studies which show the correlation between oncogenesis and
hypertension, no attempt was made to mechanistically explain the
relationship.
        In human hypertension, there is a well documented increase in
the intracellular Na+ concentration.  In basically what amounted to a
meta analysis, Hilton (5) reviewed 20 studies (involving 965
hypertensives and 1,857 controls) and found the pooled data revealed an
increased (p<0.001) intracellular erythrocyte sodium concentration in
the hypertensives.  A more recent study (6) utilizing sophisticated NMR
analyses has shown that dietary salt loading caused intracellular sodium
to increase in all subjects, whereas in salt sensitive subjects there
were additional elevations cytosolic free calcium and suppression of
intracellular pH and free magnesium levels.
        More than 20 years ago, Cone (7,8) pointed out that sustained
lowering of the transmembrane potential initiates the mitogenic process
and that processes which reduce activity of the sodium pump in the cell
surface membrane will initiate and sustain mitosis.  A prediction of
Cone's model is that the intracellular concentration of sodium will be
elevated in rapidly dividing normal and tumor cells.  Burns and
Rozengurt (9) have shown that sodium influx is a necessary event in the
mechanism whereby peptide growth factors stimulate initiation of DNA
synthesis and that changes in Na fluxes influence the movement of other
ions, namely K+ and H+.  Thus, sodium fluxes universally represent an
early mitotic event whereby quiescent cells are stimulated to
proliferate.
        There is a wealth of information in the hypertension literature
to show that the expanded extracellular fluid volume brought about by
ingestion of sodium chloride likely causes an increase in endogenous
natriuretic substances which inhibit the sodium pump (10) which
ultimately leads to the increased intracellular sodium concentrations
demonstrated in hypertensive subjects.  It is likely that this same
mechanism alters the ionic flux in cancer patients.
        Should dietary sodium inhibit the sodium pump, then it would be
reasonable to expect to find elevated sodium concentrations in a wide
variety of tumor cells.  Indeed, this is the case (11,12,13,14,15).
        An additional, but not so convincing line of evidence is the
observation made by many  early 20th century frontier doctors treating
unacculturated peoples (who generally had limited access to dietary
sodium) was the general absence of all types of cancer (16).
        In summary, a lifetime of high (relative to our evolutionary
levels) dietary sodium tends to inhibit the Na/K ATPase pump via
endogenous natriuretic factors; the inhibition of the pump changes ionic
flux across the membrane such that intracellular Na and Ca levels are
increased; and K+, Mg+, H+ levels are reduced.  Changes in intracellular
ionic concentrations are necessary early events in both mitosis and
oncogenesis causing quiescent cells to proliferate.
        Interested readers can find more on this topic by my friend
Birger Jansson who is the originator of this fascinating concept (17).

                        Cordially,


                        Loren Cordain, Ph.D.
                        ESS Dept
                        Colorado State University	
                        Ft. Collins, CO 80523
                        (970) 491-7436
                        FAX (970) 491-0445


                        References


1.      Goldbourt, U., Holtzman E., Yaari, S., Cohen, L. Katz, L. &
Neufeld, H.N. (1986). Elevated blood pressure as a predictor of
long-term cancer mortality: analysis by site and histologic subtype in
10,000 middle-aged and elderly men. Journal of the National Cancer
Institute, 77: 63-70.
2.      Khaw, K., Barrett-Connor, E.B. (1984). Systolic blood pressure
and cancer mortality in an elderly population. American Journal of
Epidemiology, 120: 550-558.
3.      Dyer, A.R., Stamler, J., Berkkson, D.M. et al. (1975). High
blood pressure: a risk factor for cancer mortality? Lancet, 1:
1051-1064.
4.      Svardsudd, K., Tibblin G. (1979).  Mortality and morbidity
during 13.5 years' follow-up in relation to blood pressure. Acta Medica
Scandinavica, 205: 483-92.
5.      Hilton, P.J. (1986). Cellular sodium transport in essential
hypertension. New England Journal of Medicine, 314: 222-29.
6.      Resnick LM, Gupta RK, Difabio B, Barbagallo M, Mann S, Marion R,
Laragh JH. (1994).  Intracellular ionic consequences of dietary salt
loading in essential hypertension. Journal of Clinical Investigation,
94: 1269-1276.
7.      Cone, C.D. (1971). Unified theory on the basic mechanism of
normal mitotic control and oncogenesis. Journal of Theoretical Biology,
30: 151-81.
8.      Cone, C.D. (1974).  The role of the surface transmembrane
potential in normal and malignant mitogenesis. Annals of the New York
Academy of Sciences, 238: 420-35.
9.      Burns CP, Rozengurt E. (1984). Extracellular Na and initiation
of DNA synthesis: role of intracellular ph and K. The Journal of Cell
Biology 98: 1082-89.
10.     Kramer, H.J., Meyer-Lehnert, H., Michel, H., Predel H. G.
(1991). Endogenous natriuretic and ouabain-like factors. Their roles in
body fluid volume and blood pressure regulation. American Journal of
Hypertension, 4: 81-89.
11.     Pieri, C., Giuli, C., and Bertoni-Freddari, C. (1983). X-ray
microanalysis of monovalent electrolyte contents of quiescent,
proliferating as well as tumor rat hepatocytes. Carcinogenesis, 4:
1577-81.
12.     Zs. Nagy et al. (1983). Correlation of malignancy with the
intracellular Na+:K+ ratio in human thyroid tumors. Cancer Research 43:
5395-5402.
13.     Davies, R.J. et al. (1987). Sodium transport in a mouse model of
colonic carcinogenesis. Cancer Research, 47: 4646-50.
14.     Davies, R.J. et al. (1990). Uncoupling of sodium chloride
transport in premalignant mouse colon. Gastroenterology, 98: 1502-08.
15.     Zs. Nagy et al. (1981).  Intracellular Na:K ratios in human
cancer cells as revealed by energy dispersive x-ray microanalysis. The
Journal of Cell Biology 90: 769-777.
16.     Stefansson V. (1960).  Cancer: Disease of Civilization?  New
York: Hill & Wang.
17.     Jansson B.  Geographic cancer risk and intracellular
potassium/sodium ratios.  Cancer Detection and Prevention 1986;9:171-94.