Methods that target the causes of acidity could become part of precision medicine cancer treatments and therapies

Researchers at Massachusetts Institute of Technology (MIT) have found that acidic environments enable tumor cells to strengthen through protein production. And that when acidic surfaces extend beyond a tumor’s interior, and come into contact with healthy tissue, cancer can spread.

The results of their study will interest anatomic pathologists who review tissue biopsies to diagnose cancer and help identify the most effective therapies for cancer patients. Currently, there are no new clinical laboratory tests under development based on MIT’s research.

The researchers published their findings in the journal Cancer Research. Their paper also shared how tumor acidity can be identified and reversed.

 “Our findings reinforce the view that tumor acidification is an important driver of aggressive tumor phenotypes, and it indicates that methods that target this acidity could be of value therapeutically,” noted Frank Gertler, PhD (above), in a news release. Gertler is an MIT Professor of Biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and a Senior Author of the study. (Photo copyright: MIT News.)

Acidity is a Tumor Cell’s Friend

Acidity results from lack of oxygen in tumors and enables tumor cell growth. “Acidification of the microenvironment plays established roles in tumor progression and provides a hostile milieu that advantages tumor cell survival and growth compared to non-cancerous cells,” the researchers wrote in Cancer Research.

In their study, the MIT scientists sought to learn:

  • What areas of a tumor are actually acidic?
  • How does acidosis propel cells to invade surrounding healthy tissues?

They used a nanotechnology platform called pHLIP (pH Low Insertion Peptide) to sense pH at the surface of cancer cells and then insert a molecular probe into the cell membranes. “This brings nanomaterial to close proximity of cellular membrane,” noted a research study conducted at the University of Rhode Island by scientists who developed the pHLIP technology.

Medical News Today reported that the MIT scientists used pHLIP to map the acidity in human breast cancer tumors implanted in mice. When it detected a cell in an acidic environment, pHLIP sent a small protein molecule into the cell’s membrane. The scientists found that acidosis was not confined to the oxygen-rich tumor core. It extended to the stroma, an important boundary between healthy tissue and malignant tumor cells.

“We characterized the spatial characteristics of acidic tumor microenvironments using pHLIP technology, and demonstrated that tumor-stroma interfaces are acidic, and that cells within the acidic front are invasive and proliferative,” the scientists wrote in Cancer Research.

What Stimulates Acidity and How to Reverse It?

The MIT researchers sought the reasons, beyond hypoxia, for high acidity in tumor tissue.

“There was a great deal of tumor tissue that did not have any hallmarks of hypoxia that was quite clearly exposed to acidosis. We started looking at that, and we realized hypoxia probably wouldn’t explain the majority of regions of the tumor that were acidic,” Gertler pointed out in the MIT news release.

So what did explain it? The researchers pointed to aerobic glycolysis, a “condition in which glucose is converted to lactate in the presence of oxygen,” according to an article published by StatPearls. “Cancer stem cells (CSC) within a tumor are notorious for aerobic glycolysis. Thus, extensive aerobic glycolysis has been indicative of aggressive cancer,” the paper’s authors noted.

During their study, the MIT scientists found:

  • Cells at the tumor surface shifted to aerobic glycolysis, “a type of metabolism that generates lactic acid, making way for high acidity,” and
  • Proteins—Mena and CD44—were linked with metastasis.

“Tumor acidosis gives rise to the expression of molecules involved in cell invasion and migration. This reprogramming, which is an intracellular response to a drop in extracellular pH, gives the cancer cells the ability to survive under low-pH conditions and proliferate,” said Nazanin Rohani, PhD, former postdoctoral researcher in the MIT Koch Institute for Integrative Cancer Research, and Lead Author of the study, in the news release.

Could a Reduction in Acidity Reverse Tumor Growth?

In another experiment, the researchers fed sodium bicarbonate (baking soda) to mice with breast or lung tumors. The tumors became less acidic and metastatic.  

“It adds to the sense that this pH dynamic is not permanent. It’s reversible. I think that’s an important addition to an ongoing discussion about the role of pH in tumor behavior,” said Ian Robey, PhD, in an MIT blog post. Robey is a Research Assistant Professor, Department of Medicine at the University of Arizona, and Full Investigator at the Arizona Cancer Center. He was not involved in the MIT research.

Spreading the Word on How Cancer Spreads

The MIT study is important—not only to anatomic pathologists—but also to oncologists and cancer patients worldwide. Cancer is not simple to diagnose and treat. The MIT study may provide important insights into targeting cancer care and precision medicine treatments.  

—Donna Marie Pocius

Related Information:

Acidic Environment Triggers Genes That Help Cancer Cells Metastasize

Acidification of Tumor at Stromal Boundaries Drives Transcriptome Alterations Associated with Aggressive Phenotypes

Decoration of Nanovesicles with pH (low) Insertion Peptide (pHLIP) for Targeted Delivery

How Does Tumor Acidity Help Cancer Spread?

Tumors Create an Acidic Environment That Helps Them Invade Surrounding Tissues