Two-Way Traffic

In mice, malignant cells genetically modified to express an anticancer cytokine home in on tumors and reduce their growth.

By | April 1, 2016

CANCER CELLS IN ACTION: Fusion of cell nuclei (red) in emerging cancer cells in a mouse model of human breast cancer. Actin filaments in the cell cytoplasm are stained green.THOMAS RIED/NCI CENTER FOR CANCER RESEARCHFive years ago, scientists at the Memorial Sloan Kettering Cancer Center in New York City showed that circulating tumor cells (CTCs) could both colonize metastatic sites and travel back to their tumors of origin. Taking advantage of this bidirectional CTC movement, researchers at the University of New Mexico and their colleagues injected mice with CTCs that were genetically modified (GM) to express an anticancer cytokine. The team found that these GM CTCs were able to home to tumors and release the cytokine, leading to decreased tumor growth. The results, published February 8 in PNAS, suggest that cancer cells may be useful tools for anticancer therapies.

“This paper is an elegant example of thinking outside the box,” said Elizabeth Comen, a medical oncologist and researcher at Memorial Sloan Kettering who was not involved with the work. “To leverage the cancer cell’s powerful ability to travel all over the body against tumors is fascinating.”

“The idea is interesting and audacious,” Joan Massagué of Memorial Sloan Kettering, who was a coauthor on the 2009 paper showing bidirectional CTC movement but was not involved in the present study, wrote in an email to The Scientist.

The University of New Mexico’s Wadih Arap, Renata Pasqualini, and their colleagues engineered murine tumor cells derived from three tumor types—melanoma, lung, and mammary adenocarcinoma—to express and release tumor necrosis factor alpha (TNF-α). TNF-α is a cytokine shown to damage tumor vasculature, among other anticancer activities. “It’s extremely potent as an anticancer agent but also extremely toxic, which makes it a perfect payload to use as a targeted agent,” Pasqualini told The Scientist. “When given only locally, the efficacy is increased and the toxicity decreases.”

An elegant example of thinking outside the box. To leverage the cancer cell’s powerful ability to travel all over the body against tumors is fascinating.—Elizabeth Comen,
Memorial Sloan Kettering Cancer Center

Injection of any of the three types of TNF-α–expressing CTCs into immunocompetent mice with implanted mammary adenocarcinoma reduced the tumors’ growth rates. Challenging mice that had the TNF-α–expressing tumor cells in circulation with additional cancer-initiating tumor cells did not lead to the formation of tumors, suggesting that the GM CTCs helped protect mice from cancerous growth. The researchers also observed that the TNF-α–expressing CTCs did not propagate in vivo. “The cells that are producing TNF eventually die, so we are not injecting cells likely to backfire,” and fuel cancer growth, said Pasqualini. “[The GM CTCs] are surrounded by TNF-α. Booby-trapped, so to speak.”

When injected into mice with the corresponding primary tumors, each of the three TNF-α–expressing CTC lines inhibited tumor growth by 50 percent to 65 percent, the researchers reported. Injecting the GM CTCs into the bloodstream appeared to be more effective than subcutaneous administration, they noted.

To test whether the GM CTCs might affect metastasis, the researchers first injected standard tumor cells into mice where the cells formed primary tumors. Normal CTCs formed lung metastases, but when the mice with metastatic tumors were injected with the GM CTCs, the researchers observed fewer metastatic colonies formed than in control animals.

“While so many scientists are trying to design nanoparticles delivery agents to bring drugs selectively to tumors, [the authors] have capitalized on the inherent ability of certain tumor cells to ‘self seed,’” Bruce Zetter, who studies the mechanisms of tumor progression at Harvard and was not involved in the work, told The Scientist in an email. “It’s appealing that the tumor cells should be able to find their counterparts both in primary and in secondary tumor sites.”

Using TNF-α as a “warhead” was a good first choice, wrote Zetter. “TNF-α is probably working here principally as an antivascular agent. . . . One can imagine that others will employ many different types of agents over time.”

Comen noted that the challenge, now, will be to make sure the GM CTCs don’t contribute to metastasis. Arap suggests irradiating the engineered cells so they cannot divide as a potential solution. In the present study, however, the researchers showed that irradiated GM CTCs inhibited tumor growth, but not to the same extent as nonirradiated GM CTCs did.

Going forward, Massagué said he would like to see an attempt to target an endogenous tumor in mice with modified CTCs derived from the same tumor. “If that experiment worked, the [cancer] field would get excited.” 

A version of this article, entitled “Turning Tumor Cells Against Cancer,” appeared on the-scientist.com on February 8, 2016.

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