Study Uncovers the Mechanisms of Breast Cancer Metastasis in Absence of Tumor

Metastasis affects as many as 5% of cancer patients around the world.

It has been established that breast cancer can spread to other areas in the body without the presence of a primary tumor. Investigators may have determined how this happens in a pair of studies published in Nature.

Investigators used animal models and human samples to identify the first mechanisms that allow cancer to spread in the early stages of the disease, and contribute to metastasis.

In the study, 2 changes occurred in the mammary cancer cells: a switched-on oncogene and a turned-off tumor suppressor. This change provoked the cancer cells to travel from the breast tissue to the lungs, as well as other areas in the body. There the cells remained dormant until a growth switch was activated, and metastases developed in the lungs.

“The research provides insight into the mechanisms of early cancer spread and may shed light into unexplained phenomena —–among them, why as many as 5% of cancer patients worldwide have cancer that has spread,” said senior investigators, Julio A. Aquirre-Ghiso, PhD, and Kathryn Harper. “Biologically, this new model of early metastasis challenges everything we though we knew about how cancer spreads and forms metastasis. If feels like we are going to have to adjust our ideas about the subject of metastasis. Our hope is that these findings will reshape the way we think about how metastasis should be treated.”

One particularly important finding from the study was that most early-spread cancer cells remain dormant, while most chemotherapy and targeted therapies are aimed at proliferative cells. This means early-spread cancer cells can escape conventional therapies, even if treatment kills a primary tumor, according to the study.

A companion paper by Dr Christoph Klein and Dr Aquirre-Ghiso provided additional key mechanistic clues on how early spread is controlled, as well as proof in human cancer cells and tumors. Each investigator arrived at their findings independently before collaborating.

Both teams studied the very early stages of breast cancer, including ductal carcinoma in situ (DCIS), which 2% to 3% of women treated for DCIS die of metastasis without ever having developed a primary tumor. The authors believe that early metastasis might occur before or as DCIS develops.

An important finding from the second paper is that 80% of metastasis in the mouse models originated from the early spread cells, rather than from the large tumors.

In each study, investigators found that the early spread of cancer cells is an extension of the normal process of creating a branching tree of breast milk ducts. Through an ancient process, 2 major pathways are activated, p38 and HER2. When p38 is switched off and HER2 is turned on, it activates a model of epithelial to mesenchymal transition (EMT) signaling pathway.

Additionally, progesterone receptor signaling is important for the early spread by regulating cues involved in EMT and growth programs, according to the study. As the mammary tree develops, p38, HER2, and EMT are alternatively turned on and off. This process, in combination with progesterone signaling, allows the mammary cells to move through the mammary gland.

“Tweaking these pathways are a normal way of forming hollow branching tubes,” Dr Aguirre-Ghiso said.

However, during the experiment, investigators found that when HER2 is over-activated or mutated, and p38 is permanently turned off, EMT was continually activated. This allowed cells to move out of the mammary gland and travel into the animal’s body through the blood.

“We were able to use organoids in 3-dimensional cultures, and high-resolution imaging directly in the live animal models to actually see these cells enter the blood stream from the mammary tree and travel to the lung, the bone marrow, and other places,” Dr Aguirre-Ghiso said. “We hadn’t though out oncogenes and tumor suppressors in this way before. This is a new function for these pathways.”

John S. Condeelis, PhD, co-director of the Gruss Lipper Biophotonics added, “We were surprised to learn that cancer cells from DCIS-like lesions could show such robust dissemination using similar machinery found in tumor cells from invasive carcinoma. This is a new insight with implications beyond our expectations.”

In addition to several different areas the authors are investigating, they are looking for a growth switch that pushes early spread of dormant cancer cells to form metastases.

“While our findings add a whole new level of complexity to the understanding of cancer, they also add energy to our efforts to finally solve the big issue in cancer —–stop the metastasis that kills patients,” Dr Aguirre-Ghiso said.