Conventional ideas about the way cancer spreads may need to be revised. According to two new studies, cancer can sow its metastatic seeds widely before it even gets around to forming a primary tumor. Even earlier studies had hinted that cancer has this “early spread” capability, but the new studies, from researchers based at the Mount Sinai School of Medicine and the University of Regensburg, have detailed the underlying molecular mechanisms.
Both studies appeared December 14 in the journal Nature. In the Mount Sinai study (“Mechanism of Early Dissemination and Metastasis in Her2+ Mammary Cancer”), two changes in mammary cancer cells—a switched-on oncogene and a turned-off tumor suppressor—motivated cells to travel from breast tissue to the lungs and other parts of the body. There, the cells stayed quiet until a growth switch was activated and metastases developed in lungs.
The University of Regensburg study (“Early Dissemination Seeds Metastasis in Breast Cancer”) uncovered additional mechanistic clues on how early spread is controlled. For example, it found that the hormone progesterone (PGR) appears to drive dissemination by triggering the secretion of the proteins WNT4 and RNAKL. These signals, from PGR-expressing cells, imbue epithelial cells that do not express PGR with increased migratory potential.
“In early lesions in mice and before any apparent primary tumour masses are detected, there is a sub-population of Her2+…early cancer cells that is invasive and can spread to target organs,” wrote the authors of the Mount Sinai study. “Intra-vital imaging and organoid studies of early lesions showed that Her2+ eDCC [early disseminated cancer cell precursors] invaded locally, intravasated, and lodged in target organs.”
“By studying metastasis in a HER2-driven mouse breast cancer model, we show that progesterone-induced signalling triggers migration of cancer cells from early lesions shortly after HER2 activation, but promotes proliferation in advanced primary tumour cells,” added the authors of the Regensburg study. “The switch from migration to proliferation was regulated by increased HER2 expression and tumour-cell density involving microRNA-mediated progesterone receptor downregulation, and was reversible.”
An important finding from the Mount Sinai team, which was led by Julio A. Aguirre-Ghiso, Ph.D., is that most early spread cells remain dormant and most chemotherapy and targeted therapies are aimed at those cells that are proliferative. So, early spread cancer cells would escape these conventional therapies, even if the therapy kills a primary tumor.
A key finding from the Regensburg team, which was led by Christoph Klein, Ph.D., is that in the mouse models, 80% of metastasis originated from the early spread cells and not from the large tumors. In fact, the Regensburg team identified a mechanism by which spread is more efficient in early lesions than in large tumors: “Cells from early, low-density lesions displayed more stemness features, migrated more and founded more metastases than cells from dense, advanced tumours.”
In both studies, investigators found that early cancer cell spread is an extension of the normal process of creating a branching tree of breast milk ducts in females.
Two major pathways are activated in this ancient process—p38, a tumor suppressor, and HER2, an oncogene. Switching off p38 and turning on HER2 activates a module of the epithelial-to-mesenchymal transition (EMT) signaling pathway. EMT promotes movement of cells during embryogenesis and tissue development. The Klein team also shows that PGR receptor signaling, which controls branching of the mammary tree, is important for this early spread by regulating cues involved in EMT and growth programs.
As a mammary tree develops, p38, HER2, and EMT are alternatively turned on and off. This, in cooperation with PGR signaling, allows mammary cells to move through the mammary gland, hollowing out a tubular, branching network of milk ducts that flow to the nipple.
“Tweaking these pathways is a normal way of forming hollow branching tubes,” elaborated Dr. Aguirre-Ghiso. But in their experiments, they found that if HER2 is overactivated (not switched off) or mutated, and p38 is permanently turned off. EMT was continually activated, allowing cells to move out of the mammary gland and into the animal's body through the blood.
“We were able to use organoids in three-dimensional cultures and high-resolution imaging directly in the live animal models to actually see these cells enter the bloodstream from the mammary tree and travel to the lung, the bone marrow, and other places,” Dr. Aguirre-Ghiso explained. “We hadn't thought about oncogenes and tumor suppressors in this way before. This is a new function for these pathways.”
“This 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 metastases but no original tumor, and, most importantly, why it is so difficult to treat cancer that has spread,” Dr. Aguirre-Ghiso concluded. “Biologically, this new model of early metastasis challenges everything we thought we knew about how cancer spreads and forms metastasis.
“It 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.”