Death for dormant tumor cells

Fred Hutch researchers have found a way to target disseminated tumor cells, which hide in bone marrow and could lead to metastasis

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SEATTLE—Dormant tumor cells might sound like they don't require as much attention as active tumor cells, but recent research out of the Fred Hutchinson Cancer Research Center has found that targeting these “sleeper” cells could help prevent metastasis in breast cancer.
The cells in question are dormant disseminated tumor cells (DTCs), which are cancer cells that break off before a tumor is formed and go dormant elsewhere in the body. The research was published in Nature Cell Biology in a paper titled “Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy.”
“It’s always been assumed that dormant cells cannot be killed by any kind of chemotherapy because they’re not dividing,” said translational researcher Dr. Cyrus Ghajar, who runs the Laboratory for the Study of Metastatic Microenvironments at Fred Hutch. “But what we’re showing is that’s not true. They’re relying on survival signaling in their microenvironment, in this case specifically from blood vessels within the bone marrow. And if you can take away that signaling, you can sensitize them to chemotherapy.”
These cells' preference for the bone marrow is well known, as dormant tumor cells have been discovered in breast cancer patients' bone marrow as early as ductal carcinoma in situ (DCIS, also known as non- or pre-invasive cancer) or stage 0, according to a press release by Diane Mapes of the Fred Hutch News Service. And their presence is often a predictor of future metastatic recurrence.
“Patients with breast cancer cells in the marrow recur more often than patients who don’t have cells in the bone marrow,” noted Ghajar, who collaborated with Fred Hutch researchers on this work, as well as scientists from the University of Colorado Anschutz Medical Campus and the University of California, San Diego. “And tumor cells in the bone marrow predict metastasis in a variety of different sites. They even predict metastasis in cancers that never get bone mets.”
Metastasis is a primary concern in any cancer, but it can be particularly difficult in breast cancer—this cancer type can reappear and go metastatic five or more years after patients stop treatment and are thought to be disease-free. In fact, the press release by Mapes reported that “the metastatic recurrence rate for all breast cancer patients is thought to be between 20 and 30 percent.”
In hopes of determining exactly how these dormant cells survive chemotherapy, Ghajar and colleagues experimented with mouse models of breast cancer and organotypic cultures (in-vitro human blood vessels and bone marrow tissues). The mice were treated with chemotherapy, and when their bone marrow was examined for DTCs, the tumor cells that survived were located near the microvasculature. Human breast cancer cells were added to the organotypic cultures, after which the cells near blood vessels went dormant while those that weren't nearby blood vessels continued replicating. These models were then treated with chemotherapy like the mice were.
“When we added increasing doses of chemotherapy, we noticed that without blood vessels, the breast tumor cells died,” Ghajar explained. “And with the blood vessels, the breast tumor cells didn’t die. So maybe the blood vessels were protective.”
Using a growth factor, the dormant tumor cells were “woken up” and then hit with chemotherapy. However, despite their active state, “the chemotherapy had no effect because the blood vessels were there,” according to Ghajar.
How exactly blood vessels shielded cancer cells was the next question that needed to be answered. Together with Peter Nelson's laboratory at Fred Hutchinson, the team applied RNA sequencing and protein analysis and found that the presence of blood vessels boosted molecules that bind integrins, proteins that play a role in cell signaling.
According to Molecular Biology of the Cell (4th edition) on the National Center for Biotechnology Information website, part of the U.S. Library of Medicine, “[T]he principal receptors on animal cells for binding most extracellular matrix proteins—including collagens, fibronectin, and laminins—are the integrins. These constitute a large family of homologous transmembrane, cell-matrix adhesion receptors. In blood cells, as we have seen, integrins also serve as cell-cell adhesion molecules, helping the cells bind to other cells, as well as to the extracellular matrix.”
The site also notes that “Integrins and conventional signaling receptors cooperate to stimulate many types of cell response. Many cells in culture, for example, will not grow or proliferate in response to extracellular growth factors unless the cells are attached via integrins to extracellular matrix molecules. For some cell types, including epithelial, endothelial, and muscle cells, even cell survival depends on signaling through integrins.” Endothelial cells are the cells that line the interior of blood vessels, adding another link in the chain connecting integrins and DTCs. Interestingly, the website adds that when cells such as epithelial, endothelial and muscle cells “lose contact with the extracellular matrix, they undergo programmed cell death, or apoptosis,” which could be another reason the presence of integrins keeps dormant tumor cells alive and protected.
When the researchers followed up on this discovery by administering integrin inhibitors together with chemotherapy in their human in-vitro model, they were able to not only kill DTCs, but do so without awakening them and “without inducing DTC proliferation or exacerbating chemotherapy-associated toxicities,” as noted in the Nature Cell Biology paper.
“When we interrupted signaling from those two integrins, we started sensitizing cells to chemotherapy. Chemo on its own would kill one third of all the single cells in our culture. But when we combined integrin inhibition and chemotherapy, we killed over 90 percent of the single cells in our cultures,” Ghajar said.
Their results were similarly impressive in the mouse models—the combination approach led to a reduction of the reservoir of DTCs in the mice's bone marrow by 94 percent and a reduction in the chance of recurrence. Ghajar remarked that “With only chemo, over 70 percent of the mice relapsed with mets. But when we used the combo, only about 22 percent of them relapsed with bone mets. We were able to save a lot of mice from relapsing with breast cancer metastases using this approach.”
“We’re trying to find a way that we can augment therapy up front to kill the roots of metastasis before they arise,” he said. “Would this possibly be a way to eliminate the cells that are going to seed the second met or the third met or the fourth? There’s potential, but it’s not something we trialed experimentally.”
Moving forward, Ghajar reports that the next task is developing human versions of the molecule used to inhibit integrins and testing its safety in humans.

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