Turning Tumor Cells Against Cancer – The Scientist

Schematic of the process of tumor cell self-targetingUNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER, ELEONORA DONDOSSOLA5 years ago, scientists at the Memorial Sloan Kettering Cancer Focus in Brand-new York City showed that circulating tumor cells (CTCs) could the two colonize Brand-new metastases and travel spine to their tumors of origin. Taking advantage of this bidirectional CTC movement, researchers at the University of Brand-new Mexico and their colleagues injected mice along with CTCs that were genetically modified (GM) to express an anticancer cytokine. In a mouse study, the researchers discovered that these GM CTCs were able to estate to tumors and release the cytokine, leading to decreased tumor growth. The results, published today (February 8) in PNAS, suggest cancer cells might be valuable 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 that was not involved along with the work. “To leverage the cancer cell’s powerful ability to travel all of over the physique versus tumors is fascinating.”

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

The University of Brand-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 revealed to damage tumor vasculature, among others anticancer activities. “It’s really potent as an anticancer agent yet additionally really toxic, which makes it a excellent payload to usage as a targeted agent,” Pasqualini told The Scientist. “As soon as offered just locally, the efficacy is increased and the toxicity decreases.”

When any type of of the three types of TNF-α–expressing CTCs were injected in to immunocompetent mice along with implanted mammary adenocarcinoma, the tumors’ growth rates were reduced. Challenging the mice that had the TNF-α–expressing tumor cells in flow along with additional, cancer-initiating tumor cells appeared to steer clear of the formation of tumors, suggesting that the GM CTCs helped protect mice from Brand-new tumors. The researchers additionally observed that the TNF-α–expressing CTCs did not propagate in vivo. “The cells that are creating TNF eventually die, so we are not injecting cells most likely to backfire,” which could fuel cancer growth, said Pasqualini. “They are surrounded by TNF-α—booby-trapped, so to speak.”

When injected in to mice along with the corresponding primary tumors, each of the three TNF-α–expressing CTC lines resulted in inhibition of tumor growth by 50 percent to 65 percent, the researchers reported.  Injecting the GM CTCs in to the bloodstream appeared a lot more efficient compared to subcutaneous administration, they noted.

To test whether the GM CTCs could impact metastasis, the researchers very first injected standard tumor cells in to mice along with growing primary tumors. Regular CTCs formed lung metastases, yet As soon as the mice along with metastatic tumors were injected along with the GM CTCs, the researchers observed fewer metastatic colonies formed compared to in manage animals.

“While so numerous scientists are attempting to design nanoparticles delivery agents to delivering drugs selectively to tumors, [the authors] have actually capitalized in the inherent ability of certain tumor cells to “’elf seed,’” Bruce Zetter, that studies the mechanisms of tumor progress at Harvard and was not involved in the work, told The Scientist in an email. “It’s appealing that the tumor cells ought to have the ability to discover their counterparts the two in primary and in secondary tumor sites.”

Using TNF-α as a “warhead” was an excellent very first choice, wrote Zetter. “TNF-α is probably functioning below principally as an antivascular agent. . . . One Can easily imagine that others will certainly employ numerous various types of agents over time.”

Comen noted that the challenge, now, will certainly be to guarantee the GM CTCs don’t contribute to metastasis. To Arap’s mind, irradiatiating the engineered cells—so they cannot divide—is one potential solution. (In the present study, the researchers showed that irradiated GM CTCs inhibited tumor growth, yet not to the very same extent as nonirradiated GM CTCs did.)

Going forward, Massagué said he would certainly love to see an attempt to target an endogenous tumor in mice along with modified CTCs derived from the very same tumor. “If that experiment worked, the [cancer] field would certainly grab excited,” he told The Scientist.

E. Dondossola et al., “Self-targeting of TNF-releasing cancer cells in preclinical models of primary and metastatic tumors,” PNAS, doi:10.1073/pnas.1525697113, 2016.