A team of scientists at The University of Texas MD Anderson Cancer Center has published their latest research results in Cancer Cell, showing that circulating tumor cells spread ovarian cancer through the bloodstream, homing in on a sheath of abdominal fatty tissue, the omentum, where it can grow and metastasize to other organs.
The researchers used a parabiosis mouse model, where two mice are joined at the skin from hip to shoulder, sharing blood supply but not lymphatic vessels. Ovarian cancer cells were then injected in the host mouse with metastasis found in the omenta of all host mice, whereas in the guest mice, metastatic cells and tumors were first found in the omentum before spreading to other organs.
“This was the most convincing way to prove that circulating tumor cells (CTCs) play a role in metastasis,” said first author Sunila Pradeep, Ph.D., instructor of Gynecologic Oncology and Reproductive Medicine.
So far, ovarian cancer has been thought mainly to spread through direct surface contact with neighboring organs in the abdominal cavity. “However, it also metastasizes to more distant organs such as the liver and spleen, which seems to indicate arrival through the bloodstream,” said senior author Anil Sood, M.D., professor of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, who has an appointment in Cancer Biology and holds the Betty Ann Asche Murray Distinguished Professorship in Ovarian Cancer Research.
Gene expression between the original ovarian cancer cell line and its metastatic version found in the omentum was compared and expression of HER3, a receptor tyrosine-protein kinase, was highly elevated and activated. Its ligand, NRG1, was abundantly expressed on the metastatic cells, revealing ErbB3- NRG1 axis as the dominant pathway responsible for hematogenous omental metastasis. Blocking NRG1 with siRNA in mice with ovarian cancer significantly reduced metastasis since “the NRG1 ligand expressed in the omentum attracts HER3-positive CTCs,” Sood said.
Furthermore, the majority (>95%) of CTCs recovered from mice with metastatic ovarian cancer were HER3-positive, correlating with a higher tumor burden and shorter survival, with HER3 depletion resulting in impaired omenal metastasis.
The high levels of expression of HER3 in these cells make it a potential biomarker with possible therapeutic options in designing alternative strategies for prevention and treatment of ovarian cancer metastasis.
“The CTCs are not just a correlation, they seem to have a functionally important role in metastasis,” Sood said. Though ovarian tumor cells are found abundantly in the blood vessels of the omentum and CTCs are present in ovarian cancer patients, the role and importance of CTCs was not well understood.
The researchers also analyzed samples from 11 ovarian cancer patients, with the majority of the cells proving to be HER3 positive. In a group of 217 advanced-stage patients, lower HER3 expression correlated with improved overall survival of 4.9 years compared to 3.15 years for high-HER3 tumors.
HER3 expression was significantly correlated with advanced-stage disease at diagnosis and its expression was shown to be higher in human stage 3 and 4 tumors compared to stage 1 and 2 tumors.
Future studies from the team will aim to understand how to intervene in this cancer-spreading process and to further explore routes into drug development.
With HER3 possible becoming a biomarker for occurrence in women at high-risk of developing ovarian cancer, maintaining an anti-HER3 therapy after treatment could prevent metastasis to the omentum. With this prospective in mind, clinical trials are already under way for pertuzumab, an antibody that blocks HER3 family member HER2, to understand if it could actually hinder both proteins in ovarian and breast cancer.