Acidic Extracellular pH Promotes Experimental Metastasis of Human Melanoma Cells in Athymic Nude Mice

Abstract

Extracellular pH (pH e ) is lower in many tumors than in the corresponding normal tissue. The significance of acidic pH e in the development of metastatic disease was investigated in the present work. Human melanoma cells (A-07, D-12, and T-22) were cultured in vitro at pH e 6.8 or 7.4 (control) before being inoculated into the tail vein of BALB/c nu/nu mice for formation of experimental pulmonary metastases. Cell invasiveness was studied in vitro by using Matrigel invasion chambers and angiogenesis was studied in vivo by using an intradermal assay. Protein secretion was measured by ELISA and immunocapture assays. Cells cultured at acidic pH e showed increased secretion of proteinases and proangiogenic factors, enhanced invasive and angiogenic potential, and enhanced potential to develop experimental metastases. Acidity-induced metastasis was inhibited by treatment with the general matrix metalloproteinase (MMP) inhibitor GM6001, the general cysteine proteinase inhibitor E-64, or blocking antibody against vascular endothelial growth factor-A (VEGF-A) or interleukin-8 (IL-8). Our study indicates that acidic pH e promotes experimental pulmonary metastasis in A-07, D-12, and T-22 human melanoma cells by a common mechanism involving acidity-induced up-regulation of the proteolytic enzymes MMP-2, MMP-9, cathepsin B, and cathepsin L and acidity-induced up-regulation of the proangiogenic factors VEGF-A and IL-8. One consequence of this observation is that treatment strategies involving deliberate tumor acidification to improve the efficacy of chemotherapy, photodynamic therapy, and hyperthermia should be avoided. Moreover, the possibility that the pH e of the primary tumor may be an important prognostic parameter for melanoma patients merits clinical investigation. (Cancer Res 2006; 66(13): 6699-707)

Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions

“…Extracellular acidosis is an important factor in the malignant progression of tumors (Rofstad et al, 2006), and tumor cells must develop resistance to this stressinduced cytotoxicity. Under tumor microenvironmental stresses, the defect in the p53 tumor suppressor protein is a critical factor for apoptosis resistance and cancer cell survival (Soengas et al, 1999).…”

“…Solid tumors are commonly characterized by a unique pathophysiologic microenvironment (Tannock and Rotin, 1989;Vaupel et al, 1989;Tomida and Tsuruo, 1999). This hostile microenvironment activates several intracellular signaling pathways that promote malignant progression and metastatic dissemination (Harris, 2002;Rofstad et al, 2006;van den Beucken et al, 2006). On the other hand, to survive under such stress conditions, tumor cells must also develop resistance to the microenvironmental stress-induced cytotoxicity (Graeber et al, 1996), although the underlying mechanisms remain unclear.…”

BAX inhibitor-1 enhances cancer metastasis by altering glucose metabolism and activating the sodium-hydrogen exchanger: the alteration of mitochondrial function

“…The evidence for MMPs as active contributors to cancer progression comes from animal studies (Schmalfeldt et al, 2001). Furthermore, acidic media (pH 5.4-6.5) increases MMP activity in cell culture (Rofstad et al, 2006). Overall, the expression of these enzymes correlates with tumor aggressiveness (Westermarck and Kahari, 1999;Jones et al, 2004).…”

“…Increased glycolysis is a phenotypic trait almost invariably observed in human cancers that confers a selective growth advantage on transformed cells by creating an acidic environment toxic to competitors but is relatively harmless to themselves (Schornack and Gillies, 2003;Rofstad et al, 2006). The rates of glucose consumption ( Figure 3a) and lactate formation (Figure 3b) in BI-1 cells were significantly greater than those in Neo and CDBI-1 cells.…”

“…Most tumors/cancers develop a pathophysiological microenvironment characterized by hypoxic conditions, including low oxygen tension and elevated interstitial fluid pressure (Rofstad et al, 2006). Alterations of glucose metabolism regulate cancer metastasis by high glucose uptake, high lactate formation, low extracellular pH (pH e ) and reduction of intratumoral pH (Bhujwalla et al, 2002;Schornack and Gillies, 2003;Gatenby and Gillies, 2004;Gatenby et al, 2006).…”