A biophysical basis of enhanced interstitial fluid pressure in tumors

Abstract

It is widely accepted that enhanced interstitial fluid pressure (IFP) in tumors is a major obstacle against delivery of therapeutic agents. On the other hand, the origin of enhanced IFP remains controversial. Here, theVan't Hoff equation is applied to examine how glucose breakdown to CO2and lactate in tumor cells may affect intracellular osmotic pressure. According to the equation, it is found that production of CO2from glucose lowers osmotic pressure inside cells, while glycolytic production of lactate generates significant increases. Crucial to a net enhancement of pressure in cells is the Warburg ratio, the ratio of the fraction of glucose transformed to lactate divided by the fraction of glucose metabolized to CO2: if (and only if) the ratio is higher than 1.0, there is a resulting increase in intracellular osmotic pressure. Under fully anaerobic glycolysis, the enhancement of intracellular pressure is maximal, namely 19.3 mmHg per mM of glucose metabolized to lactate (Van't Hoff equation). Cells are then biological pressure pumps driven by glycolytic production of lactate, causing IFP to raise. It is proposed that a regulatory feedback loop prevents IFP to raise above microvascular 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 the malignant cells and immunological surveillance, and that it indirectly drives outward currents of interstitial fluid, thereby propelling both the process of tumor infiltration of surrounding structures and metastatic spread, depending on deformability and proteolytic capacity of the malignant cells.