Georgia Tech’s Regents Professor Mostafa El-Sayed (front) is one of the most highly decorated and cited living chemists. With his team for this research from left to right: Yue Wu, Professor Ronghu Wu, and Yan Tang. Credit: Georgia Tech / Christopher Moore
Researchers have found a way to virtually halt cell migration, a key component in metastasis, in vitro, in human cells. In past in vivo studies in mice, treated cancer did not appear to recur. No significant side effects were observed. Cancer cells often cover themselves bristly leg-like protrusions that enable them to creep. The researchers have used minuscule gold rods heated gently by a laser to mangle the protrusions, according to a new study.
The treatment can also easily kill cancer cells, but in this experiment, it was vital to specifically show that it virtually halts cell migration. The experimental treatment also spared healthy cells, in these and in prior experiments, making the method potentially much less taxing on patients than commonly used chemotherapy. In past tests in mice, the researchers have uncovered no toxic side effects from the gold used in the treatment, and have found no observable damage to healthy tissue from the low-energy laser.
And they did not see recurrence of the treated cancer. “The method appears to be very effective as a locally administered treatment that also protects the body from cancer’s spread away from the treated tumors, and it is also very mild, so it can be applied many times over if needed,” El-Sayed said.
Many people think of cells as watery balloons — fluid encased in a membrane sheath with organelles floating around inside. But that picture is incomplete. Cells have support grids called cytoskeletons that give them form and that have functions. The cytoskeletons also form bristly protrusions called filopodia, which extend out from a weave of fibers called lamellipodia that are on the cell’s fringes. The protrusions normally help healthy cells shift their location in the tissue that they are part of. But in malignant cancer, normally healthy cell functions often lunge into destructive overdrive. Lamellipodia and filopodia are wildly overproduced.
“All these lamellipodia and filopodia give the cancer cells legs,” said Yue Wu, a graduate student in bioanalytical chemistry. “The metastasis requires those protrusions, so the cells can travel.” The gold nanorods thwart the protrusions in two ways. The rods are comprised of a small collection of gold atoms – nano refers to something being just billionths of meters (or feet) in size. First, El-Sayed’s nanorods are introduced locally, where they encumber the leggy protrusions on cancerous cells. The rods are coated with molecules (RGD-peptides) that make them stick specifically to a type of cell protein called integrin.
“The targeted nanorods tied up the integrin and blocked its functions, so it could not keep guiding the cytoskeleton to overproduce lamellipodia and filopodia,” said Yan Tang, a postdoctoral assistant in computational biology who worked on the study. The binding of the integrin alone slowed down the migration of malignant cells. But healthy cells were not targeted. “There are certain, specific integrins that are overproduced in cancerous cells,” said Moustafa Ali. “And you don’t find them so much in healthy cells.”
In the second phase, researchers hit the gold nanoparticles with a low-energy laser with near-infrared (NIR) light. It appeared to bring the migration of the cancer cells to a halt. “The light was not absorbed by the cells, but the gold nanorods absorbed it, and as a result, they heated up and partially melted cancer cells they are connected with, mangling lamellipodia and filopodia,” Ali said. “It didn’t kill all the cells, not in this experiment. If we killed them, we would not have been able to observe whether we stopped them from migrating or not.”
Early treatments in animal models in vivo with hotter lasers didn’t work as well. “That caused inflammation, which made it possible to heat one time only,” Ali said. “As a result, that high temperature would wipe out many cancer cells, but not all of them. Some hidden ones might have survived, and also still been able to migrate.” “This gentle laser didn’t burn the skin or damage tissue, so it could be dosed multiple times and more thoroughly stop the cancer cells from being able to travel,” said researcher Ronghu Wu.
The researchers presently envision treating head, neck, breast, and skin cancers with direct, local injections, and the low-power near-infrared laser they use can hit gold nanorods 2-3 centimeters (a bit under or over an inch) deep inside tissue. “But it could go as deep as 4-5 centimeters,” Ali said. Deeper tumors could conceivably be treated with deeper injections of nanorods. “Then you’d need to go in with a fiber optic or endoscopic laser,” El-Sayed said. Injecting the nanorods directly into the bloodstream as a broad treatment would not currently be a viable option.
El-Sayed’s group has previously published in vivo studies in the Proceedings of the National Academy of Sciences together with Emory University School of Medicine on promising treatments on mice. That study showed no observable toxicity from the gold in mice 15 months after treatment. “A lot of it ended up in the liver and spleen,” El-Sayed said. “But the functions of these organs appeared intact upon examination, and treated mice were alive and healthy over a year later.” http://www.news.gatech.edu/2017/06/26/thwarting-metastasis-breaking-cancers-legs-gold-rods
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