Extraerythrocytic hemoglobin--a possible oxygen transporter in human malignant tumors

We hypothesize that extraerythrocytic hemoglobin (Hb) serves as an oxygen transporter for human malignant tumors. According to our hypothesis, oxygen transport via intraerythrocytic hemoglobin (Hb), meaning Hb found within erythrocytes, is complemented by oxygen transport via extraerythrocytic Hb, meaning Hb found outside erythrocytes, which circulates in intercellular channels of the tumor. The channels may be derived from processes, including vasculogenic mimicry or endothelial cell retraction. We propose the following scenario: Firstly, hemolysis is caused by the irregular and disruptive endothelial cell-lined tumor vasculature, thus generating extraerythrocytic Hb-O2. Secondly, this Hb-O2 is transported together with plasma through the intercellular channels of the tumor. Thirdly, extra-erythrocytic Hb-O2 delivers oxygen to the hypoxic tumor cells. Finally, oxygen passes from the intraerythrocytic Hb-O2 in endothelial cell-lined tumor vessels to extraerythrocytic Hb due to the higher affinity of extraerythrocytic Hb for oxygen, thus starting a new cycle of oxygen delivery to the tumor tissue. Based on this hypothesis, we predict that inhibiting oxygen binding to extraerythrocytic Hb inhibits malignant tumor growth.