Mesenchymal cells delay the progression of breast cancer in mice

Treatment with human stem cells increased the survival rate by 50%, according to a paper published by Stem Cells International.

By Karina Toledo

Agência FAPESP – Treatment with human mesenchymal stem cells (MSCs) increased the survival rate of mice with breast cancer by 50% in experiments performed at the University of São Paulo’s Bioscience Institute (IB-USP) and the Federal University of São Paulo (UNIFESP) in Brazil.

The research was conducted under the aegis of the Human Genome and Stem-Cell Research Center (HUG-CELL), one of the Research, Innovation and Dissemination Centers (RIDCs) supported by FAPESP. The results were published in the journal Stem Cells International.

“Therapy with MSCs didn’t cure the disease but did delay its progression. We administered only two injections of stem cells. It’s possible that continuing treatment, combined with surgery for the removal of tumors, might have had an even more significant result,” said Tatiana Jazedje, coordinator of the research project supported by FAPESP.

Found in practically all organs of both humans and rodents, MSCs assist tissue survival by producing various factors that guarantee support for cell growth and differentiation. Although they are not capable of differentiating into cells in all tissues of the body, as are embryonic stem cells, MSCs are considered interesting from the therapeutic standpoint by virtue of their anti-inflammatory, anti-apoptotic (they avoid cell death) and immunomodulatory properties. These properties are being tested against several diseases.

MSCs can easily be obtained from bone marrow or adipose tissue and grown in laboratory culture. In the case of the research done at IB-USP, they were taken from human fallopian tube tissue discarded after tubal ligation surgery.

“We used a lineage of MSCs first described by our group in 2009 in the Journal of Translational Medicine. Given their original environment, we assumed they played an important immunomodulatory role in fertilization,” Jazedje said. “Because breast cancer is a disease that mostly affects women, we decided to evaluate the effect of these cells in the treatment of breast tumors.”

According to Jazedje, previous studies by other groups with this same objective presented contradictory results and used very different methodologies, preventing comparison.

“There are differences in mouse lineages and ages, as well as in cell management methods,” she said. “The stage of the disease at which treatment began also varied. Moreover, some studies used immunosuppressed rodents, which, in my view, is not advisable. When the immune system doesn’t work, everything goes wrong, but not necessarily because of the MSCs.”

Jazedje’s group opted to administer human tube MSCs to BALB/c female mice by the intraperitoneal route: MSCs were injected into the region of the peritoneum, the membrane that forms the lining of the abdominal cavity.

Cancer was induced by injecting murine mammary adenocarcinoma cells of the 4T1 cell line (the most widely used in this type of study) into the mammary fat pad. Treatment began seven days after the procedure, when the animals already had small palpable tumors.

One group of mice received only placebo, a second group was given a dose of MSCs (1 million cells) seven days after tumor induction, and a third received two doses of the treatment, one after seven days, and one after 14 days.

The control group died between 30 and 35 days after tumor induction. The group given a single dose of the treatment displayed no significant differences compared to the control group. However, the animals treated with two doses of MSCs survived until 45 days after tumor induction; this corresponds to a 50% increase in the survival rate compared with that of the control group.

In another experiment, the researchers mixed MSCs and tumor cells. They then injected this mixture into healthy mice of the same strain (BALB/c).

“These animals died only 15 days after tumor induction,” Jazedje said. “So, their clinical evolution was far worse than that of the untreated control group in the previous experiment. We concluded that when MSCs and tumor cells are co-injected, the factors released by the MSCs favor proliferation of the primary tumor and metastatic dissemination so that the animal dies prematurely.”

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The group also tested treatment with MSCs obtained from human bone marrow and adipose tissue. The animal model was the same as in the first experiment, but in this case, the results were not as good as when fallopian tube MSCs were used.

When the researchers tested a treatment with murine MSCs (taken from mice), they did not observe any increase in the survival rate, but there was an improvement in other aspects. In particular, lung inflammation and metastasis were reduced. Part of this study was performed by master’s student Aline Ribeiro, who was supported by a Scientific Initiation scholarship from FAPESP.

In vitro experiments conducted during Mayra Vitor Pelatti’s research for her master’s degree, supervised by Jazedje, investigated the mechanism by which treatment with human cells had delayed tumor progression in the first experiment.

When the researchers put MSCs and tumor cells in the same culture, they observed a fall in the production of vascular endothelial growth factor (VEGF), a protein with a key role in the formation of new blood vessels that feed growing tumors.

“VEGF is a critical cytokine in tumor angiogenesis, so a reduction in VEGF production can decelerate tumor growth, benefiting individuals with the disease,” Jazedje said.

In her assessment, the findings show that MSCs can have both beneficial and harmful effects, depending on how they are administered.

“Moreover, we know that not all MSCs obtained from fallopian tubes behave identically,” she said. “Each set has a different profile according to the donor. They show potential for use as coadjuvants in the treatment of breast cancer, but more research is needed before we can be sure of their effectiveness.”