Cancer cells tend to turn their extracellular environment acidic, thus helping these rogue cells thrive while creating a hostile environment for normal ones. Acidosis promotes tumor growth, metastasis and drug resistance, while helping tumor cells evade the immune system. But it’s not clear exactly how this occurs.
Using a fluorescently-labeled peptide called pHLIP that only inserts itself into the membranes of cells under acidic conditions, they mapped the acidic regions of mammary tumors produced by human breast cancer cell lines in mice. The pH probe provided striking images, for the first time at cell-level resolution, that confirmed what previous methods had suggested: acidosis is not confined to the hypoxic tumor core, but rather extends to the boundary between tumors and healthy tissue. Called the tumor-stroma interface, this boundary is the advancing edge of a malignant tumor, where cells spread aggressively and break into blood vessels and nearby healthy tissues. Again using fluorescent markers, the researchers found that the acidic regions displayed signatures of tumor invasiveness: increased expression of matrix metalloproteases in the cells at the acidic tumor-stroma interface as well as degradation of the basement membrane surrounding healthy tissues.
It revealed that the majority of cells at the interface were carrying out glycolysis, a type of metabolism that perpetuates an acidic environment. Hypoxia, or low oxygen, can force cells to resort to anaerobic glycolysis; however, glycolysis was occurring at the tumor-stroma interface even in the presence of oxygen. Together, the results suggest that aerobic glycolysis may be a primary driver of acidosis at the interface, spurring cells to invade. “The next logical steps would be looking into the causes of tumor acidity that are independent of glycolysis and hypoxia because it’s still relatively unknown,” says Ian Robey, a tumor biologist at the University of Arizona Cancer Center who was not involved with the research.
Using a fluorescently-labeled peptide called pHLIP that only inserts itself into the membranes of cells under acidic conditions, they mapped the acidic regions of mammary tumors produced by human breast cancer cell lines in mice. The pH probe provided striking images, for the first time at cell-level resolution, that confirmed what previous methods had suggested: acidosis is not confined to the hypoxic tumor core, but rather extends to the boundary between tumors and healthy tissue. Called the tumor-stroma interface, this boundary is the advancing edge of a malignant tumor, where cells spread aggressively and break into blood vessels and nearby healthy tissues. Again using fluorescent markers, the researchers found that the acidic regions displayed signatures of tumor invasiveness: increased expression of matrix metalloproteases in the cells at the acidic tumor-stroma interface as well as degradation of the basement membrane surrounding healthy tissues.
It revealed that the majority of cells at the interface were carrying out glycolysis, a type of metabolism that perpetuates an acidic environment. Hypoxia, or low oxygen, can force cells to resort to anaerobic glycolysis; however, glycolysis was occurring at the tumor-stroma interface even in the presence of oxygen. Together, the results suggest that aerobic glycolysis may be a primary driver of acidosis at the interface, spurring cells to invade. “The next logical steps would be looking into the causes of tumor acidity that are independent of glycolysis and hypoxia because it’s still relatively unknown,” says Ian Robey, a tumor biologist at the University of Arizona Cancer Center who was not involved with the research.
n the study, when researchers fed sodium bicarbonate (baking soda) to mice with mammary or lung tumors, the tumor boundaries became less acidic and the proliferative and metastatic signatures of the tumor cells decreased. “It adds to the sense that this pH dynamic is not permanent. It’s reversible,” Robey says. “I think that’s an important addition to an ongoing discussion about the role of pH in tumor behavior.”
While baking soda may not be a realistic treatment for humans, clinical trials are currently testing nanoparticles and other agents that zero in on the low pH environment surrounding solid tumors and raise extracellular pH in an attempt to shut down metastasis. “It’s an exciting possibility to essentially have pH-sensitive therapeutics that that might become active upon encountering the acidity of the microenvironment,” adds Gertler.
Gertler and study coauthor Nazanin Rohani, now a cell biologist at the National Research Council Canada in Montreal, say that future work will focus on investigating whether the pH-induced transcriptional changes their team observed can explain the mechanisms underlying metastasis and possibly identify new therapeutic targets.
Reference:
Acidification of tumor at stromal boundaries drives transcriptome alterations associated with aggressive phenotypes
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