A biophysical basis of enhanced interstitial fluid pressure in tumors

It is widely accepted that enhanced interstitial fluid pressure (IFP) in tu mors is a major obstacle against delivery of therapeutic agents. On the oth er hand, the origin of enhanced IFP remains controversial. Here, the Van't Hoff equation is applied to examine how glucose breakdown to CO2 and lactat e in tumor cells may affect intracellular osmotic pressure. According to th e equation, it is found that production of CO2 from glucose lowers osmotic pressure inside cells, while glycolytic production of lactate generates sig nificant increases. Crucial to a net enhancement of pressure in cells is th e Warburg ratio, the ratio of the fraction of glucose transformed to lactat e divided by the fraction of glucose metabolized to CO2: if (and only if) t he ratio is higher than 1.0, there is a resulting increase in intracellular osmotic pressure. Under fully anaerobic glycolysis, the enhancement of int racellular pressure is maximal, namely 19.3 mmHg per mM of glucose metaboli zed to lactate (Van't Hoff equation). Cells are then biological pressure pu mps driven by glycolytic production of lactate, causing IFP to raise. It is proposed that a regulatory feedback loop prevents IFP to raise above micro vascular pressure (MVP). Accordingly, enhanced IFP in tumors is the result of high rates of tumor glycolysis, and enhancement of IFP is limited by MVP . It is thus concluded that a high rate of glycolytic production of lactate in tumor cells ultimately prevents both access of therapeutic agents to th e malignant cells and immunological surveillance, and that it indirectly dr ives outward currents of interstitial fluid, thereby propelling both the pr ocess of tumor infiltration of surrounding structures and metastatic spread , depending on deformability and proteolytic capacity of the malignant cell s. (C) 1999 Harcourt Publishers Ltd.