Slowly proliferating cancer cells were found to be highly resistant to chemotherapy in breast cancer patients.
"All cancers contain some cells that are rapidly proliferating and many that proliferate only very slowly," explains Dr. Sridhar Ramaswamy, an associate professor of medicine at Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston
"Most cancer treatments target rapidly dividing cancer cells but leave the slowly dividing ones unharmed and still capable of causing disease recurrence after the initial treatment," Dr. Ramaswamy adds. "Our goal has been to understand how these slow proliferators are produced in order to devise ways to eliminate them."
Cancer cells usually continue to have the same rate of proliferation when they divide into "daughter cells," but sometimes one of the daughter cells proliferates much more slowly than the other.
In a previous study, Dr. Ramaswamy and colleagues found that when cancer cells asymmetrically suppress expression of the AKT protein before dividing, that cell's daughter cells will proliferate asymmetrically.
One of these cells will have normal AKT levels and proliferate rapidly like the parent cell, but the other will have low levels of AKT and proliferate more slowly. The team's research also found that these slowly proliferating cells were highly resistant to chemotherapy in breast cancer patients.
Asymmetric AKT suppression not 'random fluctuations'
In the new study, which is published in Molecular Cancer Research, Dr. Ramaswamy's team experimented with different molecular biology techniques to produce asymmetric levels of AKT in daughter cells.
They discovered that decreased signaling through a molecule found on the surface of cancer cells - beta1-integrin - decreased activity in the signaling molecule FAK. The consequence of this decreased activity is an increase in activity among the mTORC2 group of signaling molecules, which results in a suppression of AKT1 protein levels by the TTC3 molecule.
"Prior to these studies, we thought that asymmetric suppression of AKT might just relate to random fluctuations in protein levels during cell division," says Dr. Ramaswamy. He adds:
"We discovered that this is not the case; it is actually regulated by a potentially targetable signaling pathway, which may offer new avenues for reducing the proliferative heterogeneity within tumors for therapeutic effect."
Dr. Ramaswamy says that as these molecules are already under intensive study as drug targets for various cancer types, the team is now designing strategies to target the signaling pathway in animal models.
In 2014, the journal Chemistry & Biology published the findings of a study that suggested chemotherapy efficacy could be boosted by blocking the DNA repair mechanisms of cancer cells.
The researchers - from the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France - reported that the hypertension drug spironolactone could be a useful adjuvant to chemotherapy, as it is effective at blocking the division of malignant cells, thus preventing tumor growth.
As chemotherapy works by inducing lesions in the DNA of cancer cells, tumors would become less resistant to the treatment if their cells are unable to repair this DNA damage.