Cancer Metastasis: Trying to Catch the Culprits Earlier

Scaffold

Caption: Scaffold of a cancer cell-attracting implant as seen by scanning electron microscopy.
Credit: Laboratory of Lonnie Shea

For many people diagnosed with cancer localized to the breast, prostate, or another organ, the outlook after treatment is really quite good. Still, most require follow-up testing because there remains a risk of the cancer recurring, particularly in the first five years after a tumor is removed. Catching recurrence at an early, treatable stage can be difficult because even a small number of new or “leftover” tumor cells have the ability to enter the bloodstream or lymphatics and silently spread from the original tumor site and into the lung, brain, liver, and other vital organs—the dangerous process of metastasis. What if there was a way to sound the alarm much earlier—to detect tumor cells just as they are starting to spread?

Reporting in Nature Communications [1], an NIH-funded research team from the University of Michigan, Ann Arbor, and Northwestern University, Evanston, IL, has developed an experimental device that appears to fit the bill. When these tiny, biodegradable scaffolds were implanted in mice with a highly metastatic form of breast cancer, the devices attracted and captured migrating cancer cells, making rapid detection possible via a special imaging system. If the results are reproduced in additional tests in animals and humans, such devices might enable earlier identification—and thereby treatment—of one of the biggest challenges in oncology today: metastatic cancer.

Much work has already been done to explore the potential of microfluidic [2] and nanotechnology [3] methods for screening blood for rare circulating tumor cells (CTCs) capable of metastasis. However, CTCs sometimes remain in the blood for many years without ever taking hold in vital organs or tissues. To get around this issue, the team, led by the husband-wife duo of bioengineer Lonnie Shea and surgical oncologist Jacqueline Jeruss at Michigan, decided to focus on detecting cancer cells that have already found their way out of blood or lymphatic vessels and begun colonizing new tissues.

Their solution is a tiny scaffold—about the width of a pencil eraser—made of a microporous, FDA-approved polymer called PLG, short for poly(lactide-co-glycolide). PLG dissolves over time, which explains its widespread use in surgical sutures and other medical application. To further encourage cancer cells to find their way to the scaffolds, the researchers added an inflammatory signal to recruit even more  cancer cells upon implantation.

In experiments involving a mouse model of aggressive human breast cancer, the researchers implanted PLG scaffolds into the animals’ abdominal fat or under the skin just below their necks. Drawing upon the expertise of Vadim Backman at Northwestern, the researchers then used a noninvasive imaging system called Inverse Spectroscopic Optical Coherence Tomography (ISOCT) to detect as few as 15 cancerous cells collected in a scaffold. ISOCT distinguishes between normal and cancerous cells based on differences in their molecular-level structures, which influence the way the cells and extracellular matrix scatter light. Importantly, it makes this distinction without having to tag the tumor cells in advance with chemicals or fluorescent proteins.

Within weeks of implantation, researchers found that breast cancer cells had made their way from distant breast tumors, through the animals’ vasculature, to the scaffolds. In contrast to similar mice that didn’t receive implants, mice with the scaffolds had fewer cancer cells in their livers and lungs, which are sites where breast cancer cells often form secondary tumors. Further study showed that the implants, in fact, act as a decoy—attracting cancer cells before they can colonize other nearby organs.

In the near-term, basic research using tumor cells isolated by these scaffolds will help to advance understanding of the complex factors involved in cancer metastasis. A bit further down the road, such cells may also reveal new strategies for detecting cancer, tracking the effectiveness of therapies, developing new molecularly targeted treatments, and identifying more precise, individualized ways of using drugs and combinations of therapies. Shea even envisions the day when a smartphone app might give patients the ability to scan their own scaffolds!

Smartphone or not, this new device—stemming quite literally from the creative marriage of engineering and medicine—is another promising step in the quest to fight metastatic cancer.

References:

[1] In vivo capture and label-free detection of early metastatic cells. Azarin SM, Yi J, Gower RM, Aguado BA, Sullivan ME, Goodman AG, Jiang EJ, Rao SS, Ren Y, Tucker SL, Backman V, Jeruss JS, Shea LD. Nat Commun. 2015 Sep 8; 6:8094.

[2] Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzikansky A, Ryan P, Balis UJ, Tompkins RG, Haber DA, Toner M. Nature. 2007 Dec 20;450(7173):1235-9.

[3] Sensitive capture of circulating tumour cells by functionalized graphene oxide nanosheets. Yoon HJ, Kim TH, Zhang Z, Azizi E, Pham TM, Paoletti C, Lin J, Ramnath N, Wicha MS, Hayes DF, Simeone DM, Nagrath S. Nat Nanotechnol. 2013 Oct;8(10):735-41.

Links:

Metastatic Cancer (National Cancer Institute/NIH)

Shea Lab (University of Michigan, Ann Arbor)

Jacqueline Jeruss (University of Michigan, Ann Arbor)

Backman’s Biophotonics Laboratory (Northwestern University, Evanston, IL)

Precision Medicine Initiative (NIH)

NIH Support: National Cancer Institute

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