The vascular and perfusion insufficiencies in tumors may be incriminated, at least in part, for the development of acidic and hypoxic environment in the tumors. Conversely, such an adverse environment may greatly affect the vascularization, i.e., angiogenesis, and also affect the functional integrity of the tumor vasculature. In the early stage of tumor growth, the tumor cells evoke various pathological changes in the nearby host cells and tissues. These affected normal cells, as well as the tumor cells themselves, secrete stimuli, which in turn induces focal fragmentation in the basement membranes of nearby venules. Subsequently, the endothelium of the affected vessels migrate and form sprouts through the fragmented basement membrane. As the endothelial cells are stimulated to proliferate by various growth factors secreted from the tumor cells, the sprouts elongate and interlink, forming a vascular network (2-6). It is not difficult to envision that microenvironmental factors, such as pH and pO2, greatly affect the extremely complex biochemical and molecular process involved in the proliferation and differentiation of endothelial cells. Likewise, the local microenvironment may significantly influence the interaction among endothelial cells and the interaction of endothelial cells with tumor cells.
It has been reported that hypoxia increases expression of vascular endothelial growth factor (VEGF), thereby amplifying angiogenesis (77). Kim et al. (78) recently reported that insulin-like growth factor II (IGF-II) enhances the expression of VEGF in human hepatocellular carcinoma cells, and that this process is enhanced by hypoxia. The binding of insulin to endothelial cells is pH-dependent, with a sharp optimum at pH 7.8, so that the binding of insulin to endothelial cells at pH 7.8 was about 5 times greater than that at pH 6.8 (79). These results strongly suggest that the involvement of IGF-II and VEGF in angiogenesis may be greatly influenced by the intratumor pO2 and pH. Griffiths et al. (80) recently reported that the expression of angiogenic enzyme platelet-derived endothelial cell growth factor (PDECGF) in a breast cancer cell line markedly increased when the medium pH was lowered to 6.3-6.7, and also when the oxygen concentration was lowered to 0.3%. It would be of interest to know how the expression of endothelium growth factors changes when the environment is both acidic and hypoxic, as inside the tumors. The acidic and basic fibroblast growth factors (aFGF and bFGF) also play major roles in proliferation and migration of endothelial cells (81). The pI of aFGF is 5.0, and that of bFGF is 9.6, indicating that their activity may vary, depending on the environmental acidity.
It is known that the mitogenic response of a variety of cells to growth-stimulating agents are accompanied by an transient increase in Na+/H+ exchange, with a resultant increase in pHj, which suggests that alkalization of the intracellular environment may be an initial signal for cell proliferation, as well as possible cell differentiation. In this connection, Grass et al. (82) reported that cellular differentiation was stimulated by agents that increase pH; and was inhibited by agents that block the ATP-dependent H+ pump (Na+/H+ ATPase). The pH; in mammalian cells has been demonstrated to vary, depending on the stages of the cell cycle. In tumor cells, the pH; of S-phase and G2/M cells was slightly higher than that of G0/G1 cells (83). Taylor and Hodson (84) observed that the growth rate of PMC-22 human melanoma cells in culture was normal at pHe 7.2-6.8; the growth rate was reduced as the medium pH was lowered to below 6.8. When the medium pH was lowered to 6.7-6.4, the cells accumulated in G1 phase, and the cell-cycle progression was completely halted as the medium pH was lowered to below 6.3. Note that the above-mentioned studies on the effect of pH on cell proliferation and cell-cycle progression pertain to tumor cells, and there have been no comparative studies for endothelial cells. Nevertheless, assuming the effect of pHe on proliferation of endothelial cells is similar to that on tumor cells, one may surmise that moderately hypoxic and acidic intratumor environments may enhance the activity of various endothelial cell growth factors and promote proliferation of endothelial cells and angiogenesis. On the other hand, extremely hypoxic and acidic environments inhibit the proliferation of endothelial cells.
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