Acidic priming enhances metastatic potential of cancer cells

Abstract

Metabolic acidosis is a common feature of tumor microenvironment and may affect the phenotype of tumor cells, including invasive capacity and formation of metastases. We tested whether previous exposure to an acidic environment alters metastatic potential of two rat carcinoma cell lines in the animal model. In addition, we determined the effect of an acidic environment on motility and invasive capacity of AT-1 prostate carcinoma cells in culture. Exposure of tumor cells to an acidic environment (pH 6.6, 5 % CO2, 6 h) prior to tail vein injection in rats enhanced formation of lung metastases significantly. In culture, acidosis increased cellular motility of AT-1 cells. When the tumor cells were transferred back to pH 7.4, enhanced motility persisted for at least 3 h but vanished after longer periods (24 h), therefore presenting a "short-term memory effect." Although acidosis augmented phosphorylation of ERK1/2 and p38, and inhibition of ERK1/2 phosphorylation or of p38 kinase activity reduced basal motility at pH 7.4, acidosis-induced increase in motility was not dependent on ERK1/2 or p38 kinase. Src family kinases were not involved either. By contrast, scavenging reactive oxygen species (ROS), known to be increased in AT-1 cells under acidic conditions, blunted acidosis-induced motility increase. Our data indicate that tumor cells may acquire enhanced motility in an acidic micromilieu, at least in part due to enhanced ROS formation. Because enhanced motility persists for at least 3 h after leaving the acidic environment, this may promote metastasis formation, as observed in our in vivo model.

Cancer metabolism in space and time: Beyond the Warburg effect

“…This re sults from the ab nor mal meta bolic ac tiv ity of can cer cells, in clud ing in creased gly colytic flux and lac tic acid re lease [150]; car bon diox ide pro duc tion by the TCA cy cle and the pen tose phos phate path way (PPP) [151][152][153][154]; over ex pres sion or up reg u lated ac tiv ity of car bonic an hy drases [155,156] and pro ton trans porters [156]; and de creased pro ton clear ance in the tu mor en vi ron ment [157]. Pro ton ex tru sion and ex tra cel lu lar acid i fi ca tion make ad her ent junc tions lose [158], stim u late mi gra tion and cy toskele ton re or ga ni za tion [159][160][161][162][163], and pro mote the ex pres sion [164,165], re lease [166,167] and ac tiv ity [167,168] of pro teases that de grade the ex tra cel lu lar ma trix. Hence, acidic prim ing was shown to be suf fi cient to in crease lung col o niza tion fol low ing sar coma and melanoma tu mor cell in jec tion in the tail vein of mice [163,167,169,170].…”

“…Pro ton ex tru sion and ex tra cel lu lar acid i fi ca tion make ad her ent junc tions lose [158], stim u late mi gra tion and cy toskele ton re or ga ni za tion [159][160][161][162][163], and pro mote the ex pres sion [164,165], re lease [166,167] and ac tiv ity [167,168] of pro teases that de grade the ex tra cel lu lar ma trix. Hence, acidic prim ing was shown to be suf fi cient to in crease lung col o niza tion fol low ing sar coma and melanoma tu mor cell in jec tion in the tail vein of mice [163,167,169,170].…”

Relationship between hypoxia and response to antiangiogenic therapy in metastatic colorectal cancer

“…Several reports in the literature have demonstrated a straight correlation between hypoxia and the increase of metastatic potential, suggesting several hypotheses to explain this [67, 68, 72, 73]. Hypoxia condition activates the transcription factor HIF-1α, that induces activation of p53 and cyclin-dependent kinase inhibitors [74].…”

“…HIF-1α also induces the expression of carbonic anhydrase IX, that promotes cell survival and invasion [75]. Moreover, the production of reactive oxygen species (ROS) can promote cell motility [72] and create a favorable condition for gene mutation and genomic instability [76] (Figure 2). …”

Tumor proliferation and diffusion on percolation clusters

“…Cao and colleagues found that the interaction between the vascular endothelial growth factor and the tumor necrosis factor in the microenvironment could affect tissue angiogenesis and promote tumor diffusion and metastasis in mice [16]. Ruemann et al found that tumor cells secreted angiotensin receptor 1, which could improve the proliferation of tumor vessels and promote tumor movement and then facilitated tumor metastasis and invasion [17]. The process that tumor cells can successfully transfer to an organ and form metastases is divided into two stages [8]; (1) the cancer cells are transferred to and captured by the target organ and (2) the cells adapt to the target tissue microenvironment and gain the ability to form colonies.…”