therapy, and can cause relapse months or years after therapy with curative intent. New research has identified the signaling pathway through which these malignant "sleeper" cells are spawned.
The finding offers the potential to restore drug sensitivity to the cells and for new targeted therapies to prevent these residual cells from reactivating and multiplying.
The report was published online January 12 in Molecular Cancer Research.
"All cancers contain some cells that are rapidly proliferating and many that proliferate only very slowly," explained senior author Sridhar Ramaswamy, MD, associate professor of medicine at the 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. Our goal has been to understand how these slow proliferators are produced in order to devise ways to eliminate them," he said in a statement.
"There is what appears to be a fundamental pathway that regulates a type of cell division that we call asymmetric cancer cell division," Dr Ramaswamy told Medscape Medical News.
"The result of the triggering of that pathway during cell division is to allow cancer cells to produce a daughter cell, which essentially stops its transit through the cell cycle," he explained. "When it's in that kind of sleeping phase — at least in the experiments we have done so far — it appears to be quite resistant to a variety of different therapies."
This study builds on earlier research by Dr Ramaswamy's team that showed that during cellular division, cancer cells sometimes produce one duplicate daughter cell and a second daughter cell that has a much slower cell division time than its parent or sibling cells.
The aberrant daughter cells are low in AKT, a protein kinase integral to cellular division. The team previously identified these rare low-AKT cells in patients with breast cancer and determined that these cells, because of their indolent reproductive pattern, are highly resistant to combination chemotherapy with doxorubicin, cyclophosphamide, and paclitaxel.
This suggests that "these slow proliferators may constitute an important but unappreciated reservoir of treatment resistance in patients with breast cancer," the researchers write.
"When we first observed that this kind of asymmetric division was happening, a natural question was whether this was something that was largely a random process" related to random fluctuations in protein levels during cell division, Dr Ramaswamy told Medscape Medical News.
"Our most recent work," he continued, "suggests that this actually relates to a pathway that involves a number of different molecules, and a number of these molecules are now actively being explored as targets in a wide variety of different tumor types."
In their study, Dr Ramaswamy and colleagues report that decreased signaling through the cell-surface molecule beta 1-integrin decreases activity of the signaling molecule FAK (also known as protein tyrosine kinase 2 [PTK2]). The reduced FAK signaling leads to increased activity of the mTORC2 protein complex, which in turn leads to suppression of AKT1 levels because of a one-two hit from TTC3, a ubiquitin protein, and the proteasome complex, a cellular housekeeping service.
In preclinical studies, the researchers are actively exploring potential therapeutic strategies in a variety of tumor types. The strategies could include reactivating the slow proliferators to make them more susceptible to therapies targeted against rapidly dividing malignancies, such as combination chemotherapy, or, alternatively, keeping the cells dormant for significantly longer periods of time.
The study was supported by funds from Stand Up To Cancer, the National Cancer Institute, the Howard Hughes Medical Institute, Susan G. Komen, the Prostate Cancer Foundation, CNPq (the National Council for Scientific and Technological Development in Brazil), and Instituto de Salud Carlos III in Spain. Dr Ramaswamy has disclosed no relevant financial relationships.
Mol Cancer Res. Published online January 12, 2015. Abstract
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου