First model of aggressive ovarian cancer demonstrates immune system's active role in tumor progression
Aggressive ovarian tumors begin as malignant cells kept in check by the immune system until, suddenly and unpredictably, they explode into metastatic cancer. New findings from scientists at The Wistar Institute demonstrate that ovarian tumors don't necessarily break "free" of the immune system, rather dendritic cells of the immune system seem to actively support the tumor's escape. The researchers show that it might be possible to restore the immune system by targeting a patient's own dendritic cells.
"Our model shows where the cancer is kept in check for relatively long periods, but once they become noticeable, tumors grow exponentially," said Jos- R. Conejo-Garcia, M.D., Ph.D., an associate professor at Wistar and leader of the Tumor Microenvironment and Metastasis Program of Wistar's Cancer Center. "More importantly, we show that by depleting these dendritic cells of the immune system, we can reverse the effect, once again allowing our immune system to recognize the ovarian tumors."
Their findings, presented in the March issue of the Journal of Experimental Medicine, available online now, represent the first successful attempt to model the tumor microenvironment of human ovarian cancer in a mouse model of the disease. In essence, the model replicates the inflammatory surroundings that ovarian tumors experience in humans. The more accurate model provides a better tool for researchers to understand, prevent, and treat tumors.
"Our system uses oncogene-driven tumors that are spontaneously antigenic, thus avoiding the use of artificial foreign antigens that do not accurately replicate what drives anti-tumor immune responses in humans," Conejo-Garcia said.
Ovarian cancer remains one of the most deadly forms of cancer in women. According to the National Cancer Institute, 21,990 women will be diagnosed with ovarian cancer, and 15,460 women will die of the disease this year Because early-stage ovarian cancer does not often exhibit noticeable symptoms, many women are not diagnosed until the cancer is at a later stage, when it is most difficult to treat.
"While we have seen an increase in survival rates for most cancers over the last 40 years, ovarian cancer survival has only improved slightly since the 1970's," Conejo-Garcia said. "We created our ovarian cancer model to get a better understanding of how these tumors acquire such aggressive characteristics and evade the immune system."
According to Conejo-Garcia, their model demonstrates how a localized ovarian tumor flares into an aggressive metastatic disease.
"You can see where, if one ovary is cancerous, it is almost unrecognizable until an instantaneous moment, when it explodes into exponential growth," Conejo-Garcia said. "The key to this moment, our evidence suggests, is in the phenotypic changes taking place in the dendritic cells that are part of the tumor microenvironment."
In healthy tissue, dendritic cells function as sort of alarm system to alert the adaptive part of the immune system to potential threats. They work as antigen-presenting cells, offering foreign or disease-causing molecules (called antigen) to the white blood cells that can then respond to an infection or, in this case, tumorous growths. Amid the ovarian cancer microenvironment, dendritic cells also induce the immune system to attack tumor cells and inhibit their growth.
Until, that is, dendritic cells seem to switch sides.