Posted September 11, 2014
Anil Sood, M.D., The University of Texas M.D. Anderson Cancer Center
Ovarian cancer is often diagnosed in the later stages of disease, when patients present with advanced metastases. The metastases, which are generally confined to the abdomen, were previously thought to have occurred by direct surface contact of the tumor, although studies have shown that ovarian cancer patients can present with a large number of circulating tumor cells (CTCs) in the blood. Dr. Anil Sood, an FY12 OCRP Outcomes Consortium Development Award (OCDA) recipient, has made the game-changing discovery that the ErbB3(HER3)-neuregulin 1(NRG1) axis is a dominant pathway responsible for ovarian tumor metastasis to the omentum through the bloodstream. The apron-like layer of tissue that surrounds abdominal organs, called the omentum, is a known "hot spot" for ovarian cancer metastasis.
The focus of the OCDA mechanism is to identify and understand the predictors of disease outcomes for ovarian cancer patients. The study, led by Dr. Sunila Pradeep, Dr. Sood's mentee, established a system to monitor CTCs and metastasis patterns in a "host/guest" paired mouse model with the mice sharing only a blood supply. The "host" mice were injected with ovarian cancer cells, resulting in primary tumor development and subsequent patterns of metastasis. The "guest" mice were observed to form metastasis first in the omentum prior to spreading to other organs. Gene expression of the metastatic tumors found in the omentum of the guest mice showed that the cancer cells had increased expression and activation of HER3. The most likely cause of this activation is through the binding of the HER3 ligand, NRG1, which is found to be highly expressed in the omentum as compared to other tissues. The researchers observed that 95% of the CTCs collected from mice with metastatic ovarian cancer were HER3-positive. In addition, tumor samples from 11 ovarian cancer patients revealed that 90% of cells were HER3-positive and tumor cells found in omental blood vessels of five patients had strong HER3 expression. In further analysis of 217 advanced stage cancer patients, decreased expression of HER3 correlated with improved overall survival compared with high-HER3 tumors. HER3 expression was also significantly higher in late-stage tumors as compared with early-stage tumors. The investigators also showed that blocking HER3 significantly decreased protein expression, tumor growth, and metastasis in mouse models. An antibody that targets the HER3 protein also reduced the size and number of metastases in treated mice. These findings provide strong evidence that direct surface contact may not be the only mode of spread for ovarian cancer in the abdominal cavity, as previously thought, and that spread through the blood supply may also be an important route. Also, CTCs could be a reliable predictor of long-term survivorship for ovarian cancer patients.
Pradeep S, Kim SW, Wu SY, et al. 2014. Hematogenous metastasis of ovarian cancer: Rethinking mode of spread. Cancer Cell 26(1):77-91.