Julio Aguirre-Ghiso, PhD
New research from the Icahn School of Medicine at Mount Sinai has found that cancer cells can spread without the benefit of a primary tumor and remain dormant for months or even years before triggering aggressive, deadly breast cancer metastases. This surprising new model of early cell dissemination and metastasis appeared in the December 14, 2016, issue of Nature. It upsets the long-held scientific belief that tumors only spread from a pathologically defined and highly mutated invasive tumor. In fact, the findings revealed that a primary tumor may never develop.
“As a biologist who has been measuring tumors since I was 20 years old, this was, indeed, a very surprising finding,” says lead author Julio Aguirre-Ghiso, PhD, Professor of Medicine (Hematology and Medical Oncology) at the Icahn School of Medicine at Mount Sinai. “It provides an alternative scenario for how metastases develop, and that could have a profound effect on our work going forward.”
Dr. Aguirre-Ghiso’s preclinical research, which focused on very early-stage breast cancer in animal models, was published with a companion paper authored by a team led by Christoph A. Klein, MD, at the University of Regensburg in Germany. The companion paper supported Mount Sinai’s findings with evidence of the same occurrence in human cancer cells and tumors.
This image captures early disseminating cancer cells in mouse models (cyan) moving toward blood vessels (red).
The studies’ new findings offer insights into several questions that have long puzzled scientists. First, why do as many as 10 percent of cancer patients worldwide have cancer metastases but no original tumor? Equally important, why is it so difficult to treat cancer that has spread? To that point, a key finding was that most early-spread cells remain dormant while most chemotherapeutic and targeted treatments are aimed at cells that are proliferative.
“Those cells that leave early can spend a long time without growing, or they can grow so slowly that any antiproliferative therapy will ignore them,” Dr. Aguirre-Ghiso says.
In women, the spread of early breast cancer cells is an extension of the normal process of creating a branching tree of breast milk ducts. Two major pathways are altered in the process: p38, a tumor suppressor, and HER2, an oncogene. As a mammary tree develops, p38 and HER2 are alternatively turned off and on, allowing cells to move through the mammary gland. In their experiments with mouse models, the researchers found that if HER2 is over-activated or switched on, and p38 is permanently turned off, cells are able to enter the bloodstream and travel to organs such as the lungs and bone marrow, where a growth switch can later activate the metastases.
With the help of a team of researchers from Albert Einstein College of Medicine, the Mount Sinai scientists were able to monitor the movement of oncogene cells that had been tagged with a fluorescent protein as they moved from the mammary tree to surrounding tissue and into the bloodstream. “It was quite amazing,” says Dr. Aguirre-Ghiso.
Developing full-scale biomarkers and mechanisms that can identify early-spread cells is a logical next step for Dr. Aguirre-Ghiso and his team. “If we had tests or imaging tools that could tell us in a minimally invasive way exactly where these cells are and if they’re evolving or growing, then we could take steps to eradicate them or keep them dormant,” he explains. “That kind of approach could truly be transformative.”