Cancer treatment’s biggest failings occur in the metastatic setting, when metastatic cells escaping from the primary tumor colonize and attack critical organs. Much about how cells colonize distant tissues as opposed to remaining in the primary tumor or in circulation without settling in one place remains unknown. But a new bioengineered device could offer insights.
The device is a small implantable scaffold about the size of a pencil eraser that draws metastatic cells out of the blood. It was codeveloped by scientists from the University of Michigan in Ann Arbor and Northwestern University in Evanston, Illinois. When implanted into a mouse model of human breast cancer, the scaffold functioned as a micrometastatic niche. Migrating cancer cells colonized the scaffold, and in a further unexpected finding, mice with the implant had nearly 90% fewer lung metastases than control mice given a sham operation but not the implant itself. The discrepancy between metastatic burdens in treated and control mice suggests that the scaffold served as a therapeutic decoy that protected other organs from breast cancer’s spread, according to study coauthor Jacqueline Jeruss, MD, director of the University of Michigan Breast Care Center. The study appeared last September in Nature Communications.
“We haven’t had a tool that allows us to discriminate between circulating tumor cells [CTCs] that may not affect outcomes and metastatic cells that impact on pathology elsewhere in the body,” she said. “Now we can identify signals that are specific to the metastatic cells and learn more about what makes them unique.”
The research builds on evidence that cancer’s dissemination to particular sites in the body isn’t random, but occurs instead when migrating cells originating from the primary tumor flock to a premetastatic niche populated by other cell types—namely, macrophages, myeloid-derived suppressor cells, neutrophils, and inflammatory monocytes—that suppress antitumor responses.
Jeruss’s husband and collaborator Lonnie Shea, PhD, chair of biomedical engineering at the University of Michigan, constructed the scaffold from polylactide-co-glycolide, a microporous polymer also used to make surgical sutures, grafts, and medical implants. According to Shea, the scaffold was engineered to mimic a premetastatic microenvironment.
“You can think of it as a sponge,” he said. “Blood vessels grow through and around the device, which in turn attracts immune cells that promote metastatic growth.”
Jeruss, Shea, and their colleagues implanted the scaffold into the fat pads of mice inoculated with 231BR cells derived from a human patient with triple-negative breast cancer. Then at 14 and 28 days, they, looked for metastases in the scaffold by using a noninvasive technology called ISOCT (inverse spectroscopic optical coherence tomography). According to Northwestern professor Vadim Backman, PhD, an author on the study, ISOCT is label free, making it possible to hunt for metastases without prior knowledge of the cells or pathways involved. Rather than look for molecular tags on cell receptors, Backman looked for the telltale structural changes that metastatic cells were making to promote their own growth. For instance, metastatic cells remodel collagen and other matrix proteins that adjacent cells deposit. That activity produces nanoscale alterations that Backman could detect and measure to infer how many metastatic cells were present in the scaffold while it was still in the mouse’s body.
Cancer cells invaded the scaffold but not the fat pads of control mice, indicating that it had performed as predicted.
“The research needs to replicated, but the results so far point to an intriguing tool for isolating metastatic subclones for further analysis,” said Lisa Carey, MD, a professor in breast cancer research at the University of North Carolina at Chapel Hill, who was not involved in the study. “At the moment, we still rely on biopsies, which is challenging.”
Carey was also intrigued by the scaffold’s ability to reduce tumor burdens in the lung. She suggested that it might have clinical uses in slowing or delaying metastatic progression. Jeruss had already shown in research dating back to 2008 that if women present with high-stage disease, their long-term prognosis is poor regardless of how well they do in primary treatment.
“Our hope,” Jeruss said, “is that early intervention when the metastatic disease burden is still low would translate to longer progression-free survival time.”
According to Shea, women would be implanted with the scaffold upon completing therapy for breast cancer, and the implant would be checked noninvasively every 3–6 months.
But according to Daniel Hayes, MD, clinical director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center and incoming president of the American Society of Clinical Oncology, no evidence yet indicates that screening asymptomatic women who complete primary breast cancer treatment for occult metastases improves overall survival.
“We already treat micrometastases with adjuvant therapy for years before they are ever detectable,” he said. Other tests for detecting occult metastases are already available; Hayes said—for instance, the CellSearch test for CTCs (in whose development Hayes participated). But although they have prognostic value, CellSearch results rarely change treatment practice beyond what’s indicated by standard measures, such as lymph node status. Moreover, switching from one chemotherapy to another in women with high CellSearch counts is generally ineffective, suggesting that such women are resistant to chemotherapy.
Results from the scaffold might lengthen lead times to detection beyond what’s afforded by detecting CTCs, but “longer lead times might just push us back to the adjuvant setting when we give treatments that we already know work,” Hayes said.
Yet Hayes said that he’s optimistic that the scaffold could isolate an important cell: those that transition from the rigid epithelial CTCs picked by CellSearch to the more flexible mesenchymal cells that colonize tissues.
“We know that patients with CTC counts higher than 5 have a poor prognosis,” Hayes said. “But we don’t know if that’s because of CTC cells per se or because CTCs reflect an additional sublayer of EMT [epithelial–mesenchymal transition] cells that we can’t easily detect.”
EMTs have stem cell–like properties, and studying them might reveal new drug targets applicable to the metastatic setting.
Along with Massimo Cristofanilli, MD, associate director for precision medicine and translational research at Northwestern’s Robert H. Lurie Comprehensive Cancer Center, Jeruss is exploring clinical studies that use the scaffold to delay metastatic progression. Cristofanilli said that two studies are under discussion: the first in the metastatic setting and then another in a more curative setting.
“We know that spreading of metastatic disease occurs early at the time of clinical diagnosis,” Cristofanilli said. “Stage III patients already have CTCs in peripheral blood and they’re associated with a worse outcome. If we can combine standard neoadjuvant therapy with this approach, we might eliminate the migration and recirculation of CTC stem cells. The next frontier is to focus on metastases, and this clever new device gives us an additional tool.”
A version of this blog post first appeared in Journal of the National Cancer Institute.
Featured image credit: Atypical carcinoid tumor of lung metastatic to the adrenal gland Case 255 by Yale Rosen. CC BY-SA 2.0 via Flickr.
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