Which is the cart and which the horse?

Dear Editor,

In HL-60 cells lovastatin reduces the intracellular pH in dose- dependent manner and the fall in pH correlates with the extent of DNA degradation (1). More importantly alkalinization suppresses lovostatin-induced apoptosis. A fall in pH is an indication of reductive stress, a stimulus for the expression of HIF, VEGF and NOS. A normal or elevated pH may also be necessary for protein synthesis and cell renewal(2,3). A normal or elevated pH together with the expression of HIF (4) might, therefore, be a sine qua non for neoplastic development, growth and spread. If so how might a normal and particularly an elevated pH be induced and apoptosis inhibited in a tissue at risk of becoming neoplastic?

The ability of adjacent tissues to support the delivery of substrate to newly vascularized tissues is clearly important in maintaining a normal pH but what if it is insufficient to maintain the adequacy of ATP resynthesis by anaerobic glycolysis, the dominant means of ATP resynthesis in tumours? One possibility is that the pH is maintained at normal or elevated levels by the release of ammonia by cellular autophagy, apoptosis and/or necrosis. If so the elevation in pH can be expected to be restricted to a region, possibly the growing edge, interposed between that where there is adequate substrate delivery and that in which there is protein degradation occurring in association with autophagy, apoptosis and/or necrosis. In which case the ability of contiguous tissues to sustain substrate delivery to a growth center might be the critical variable.

Hence the question about the predictive value of VEGF-A and i-NOS expression in adjacent tissues. Might VEGF-A and i-NOS expression in unresected tissue be a better predictor of outcome than that within the tumour, the assumption being that it is the environment, rather than the tumour per se, that determines carcinogenesis and dictates long-term survival? This possibility would have to be examined in a prospective study conducted with surgical cooperation. Which is the cart and which the horse?

Richard G Fiddian-Green

References

1. Perez-Sala D, Collado-Escobar D, Mollinedo F. Intracellular alkalinization suppresses lovastatin-induced apoptosis in HL -60 cells through the inactivation of a pH-dependent endonuclease. J. Biol. Chem., 270:6235-6242, 1995.

2. P E Ballmer, M A McNurlan, H N Hulter, S E Anderson, P J Garlick, and R Krapf. Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Invest. 1995 January; 95(1): 39?45.

3. E Movilli, R Zani, O Carli, L Sangalli, A Pola, C Camerini, G Cancarini, F Scolari, P Feller and R Maiorca. Correction of metabolic acidosis increases serum albumin concentrations and decreases kinetically evaluated protein intake in haemodialysis patients: a prospective study. Nephrology Dialysis Transplantation, Vol 13, Issue 7 1719-1722, 1998.

4. P. H. Maxwell, G. U. Dachs, J. M. Gleadle, L. G. Nicholls, A. L. Harris, I. J. Stratford, O. Hankinson, C. W. Pugh, and P. J. Ratcliffe. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. PNAS July 22, 1997 vol. 94 no. 15 8104-8109.