When cancer is associated with aberrant signaling and receptor activation, scientists are inclined to round up the usual suspects—membrane-bound receptors or external receptor ligands. Scientists interrogate the genes that code for these proteins, looking for genetic mutations that could trigger out-of-control cell proliferation or heightened cell mobility. Yet it turns out that by paying too much attention to genetic screens, investigators may allow nongenetic cancer culprits to slip away unnoticed.

Unexpectedly, cancer can be caused solely by protein imbalances with cells. This finding, which emerged from a study of ovarian cancer, was reported by researchers from the University of Leeds and the University of Texas MD Anderson Cancer Center. They published their results July 27 in the journal Oncogene, in an article entitled, “Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer.”

As this title indicates, the scientists focused on the Akt pathway, a signaling pathway within cells that drives cancer formation and the spread of cancers through the body. After the scientists studied aberrant activation of the oncoprotein Akt in isolated cancer cells, they expanded their investigation, taking in mouse models. Eventually, they tracked down protein levels in patient tissues.

Under normal conditions, the cell receives external signals through a cell wall-bound receptor (FGFR2 in this study). As a result of this stimulus, the receptor is “switched on” inside the cell. This results in the recruitment of signaling proteins and the initiation of the Akt pathway, which is responsible for committing the cell to proliferate. In some cancerous cells, this pathway is permanently switched on.

The new study looked at isolated cancer cells without external stimulation and found that the Akt pathway could be activated without genetic modifications. Two proteins; Plcγ1 (pronounced “plc-gamma-1”) and Grb2 (pronounced “grab-2”), compete for binding to FGFR2. The relative concentration of these proteins will dictate which one binds. When Plcγ1 prevails, it triggers the Akt pathway. In this way, an imbalance in the amount of the two proteins can lead to cell proliferation and cancer formation.

The scientists confirmed that this mechanism occurred in a mouse model. Here, Grb2 depletion was found to result in the development of multiple tumors in the vicinity of a primary tumor, indicating that protein imbalance can have a role in metastasis, the spread of a cancer through the body. This makes sense because Plcγ1 can play a role in increasing cell movement.

Finally, the researchers looked at whether imbalance between Grb2 and Plcγ1 was predictive of the progress of ovarian cancers in patients. Measuring the levels of the proteins in patient tissues followed by database analysis of clinical information from The Cancer Genome Atlas and other sources revealed that a high level of Grb2 relative to Plcγ1 and FGFR2 was associated with a significantly more favorable prognosis than patients with elevated levels of Plcγ1.

“Reducing cellular Grb2 results in upregulation of Plcγ1 and depletion of the phospholipid PI(4,5)P2,” wrote the authors of the Oncogen article. “We show that the decrease in PI(4,5)P2 level under non-stimulated conditions inhibits PTEN activity leading to the aberrant activation of the oncoprotein Akt. This results in excessive cell proliferation and tumor progression.”

Statistical data reveal that just under 40% of patients with a favorable balance were still alive seven years after samples were taken. Less than 10% of patients with high levels of Plcγ1 and FGFR2 binding sites survived the same length of time.

“From the patient's point of view, the key findings are that these proteins are biomarkers,” said lead author Professor John Ladbury, dean of the University of Leeds' faculty of biological sciences and professor of mechanistic biology. “They could offer information to clinicians on who is going to benefit from therapy and, just as importantly, who is not. On the treatment side, the proteins' interaction could be a valid therapeutic target: you could, for instance, target Plcγ1 to ensure it does not overwhelm the cell.”

“There has been huge investment in sequencing the human genome with the idea that if we get all the relevant genetic information we can predict whether you have a predisposition to cancer and, ultimately, use a precision medicine-based approach to develop a therapeutic approach,” Professor Ladbury continued. “Our study demonstrates that genetic screening alone is not enough.”

Previous research findings have emphasized the roots of cancer in genetic mutation. Some studies have pointed to cancers that occur without genetic causes, such as through epigenetic modifications of proteins, however the present study reveals that signaling though cell wall-based receptors can occur without receptor activation and therefore that non-genetic causes may be critical to understanding cancer in large numbers of patients.

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