January 18, 2012

Tumor Cells Prevent Cancer Spread?

(Ivanhoe Newswire) — A new study found that a group of little-explored cells in the tumor microenvironment can likely serve as gatekeepers against cancer progression and metastasis.

One known way of treating cancer is by targeting angiogenesis, or blood vessel growth. Raghu Kalluri, MD, PhD, Chief of the Division of Matrix Biology at Beth Israel Deaconess Medical Center (BIDMC) and Professor of Medicine at Harvard Medical School (HMS) and colleagues, hypothesized whether targeting a specific cell type, the pericytes, (pericytes serves as an important part of the vasculature tissue, it covers blood vessels and supports growth) could inhibit tumor growth in the same way that other antiangiogenic drugs do.

Kalluri and his team began their experiment by creating genetically engineered mice to support drug-induced depletion of pericytes in growing tumors. Next, they deleted pericytes in implanted mouse breast cancer tumors, decreasing pericyte numbers by 60 percent. Compared with wild-type controls, they saw a 30 percent decrease in tumor volumes over 25 days. "If you just look at tumor growth, the results were good," says Kalluri. "But when we looked at the whole picture, we discovered that inhibiting tumor vessels were not controlling the cancer progression. The cancer was, in fact, spreading." The investigators found that the number of secondary lung tumors in the engineered mice had increased threefold compared to the control mice, indicating that the tumors had metastasized.

To understand the mechanism behind this increased in metastasis, Kalluri and his colleagues dug deeper. They examined the tumor´s microenvironment to find out what changes were taking place at the molecular level. What they discovered was a fivefold percentage increase in hypoxic areas in tumors lacking pericytes. "Cancer cells respond to hypoxia by launching genetic survival programs," says Kalluri. "This suggested to us that without supportive pericytes, the vasculature inside the tumor was becoming weak and leaky even more so than it already is inside most tumors and this was reducing the flow of oxygen to the tumor."

Kalluri and his team found evidence of epithelial-to-mesenchymal transition (EMT), a change that makes the cells more mobile, so they can travel through those leaky vessels to new locations, and makes them behave more like stem cells, to better survive. They also found a fivefold increase in activation of Met, a receptor molecule that promotes cell migration and growth. These molecular changes occurred inside the smaller, pericyte-depleted tumors that had increased incidences of secondary tumors within the mouse models´ lungs. "This suggested that smaller tumors are shedding more cancer cells into the blood and causing more metastasis," says Kalluri. "We showed that a big tumor with good pericyte coverage is less metastatic than a smaller tumor of the same type with less pericyte coverage."

To determine if their findings were relevant to human patients, Kalluri and his team examined 130 breast cancer tumor samples, varying in size and within different stages of the disease. Then they compared the pericyte levels with prognosis. They discovered that samples with low numbers of pericytes in tumor vasculature and high levels of Met expression correlated with the most deeply invasive cancers, distant metastasis and 5-and 10-year survival rates lower than 20 percent.

"These results are quite provocative and will influence clinical programs designed to target tumor angiogenesis, says Ronald A. Depinho, president of the University of Texas MD Anderson Cancer Center. "These impressive studies will inform and refine potential therapeutic approaches for many cancers."

SOURCE: Cancer Cell, January 2012