Highly elevated platelet levels fuel tumor growth and reduce the survival of ovarian cancer patients, an international team of researchers led by scientists at The University of Texas MD Anderson Cancer center reports in the New England Journal of Medicine.
By pinpointing a powerful cause-and-effect relationship at the heart of a clinical observation that dates back more than 100 years, the team’s findings reveal a new factor in cancer progression and new potential approaches for treatment.
“We’ve long known that ovarian cancer patients often have markedly increased platelet counts but we haven’t known why this happens or understood its relevance, if any, to disease progression,” said senior author Anil Sood, M.D., professor in MD Anderson’s Departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology.
“Our collaborative study not only identified a mechanism that explains platelet count elevation, but also connects this state, called thrombocytosis, to the severity of ovarian cancer,” Sood said. “This suggests drugs that interfere with coagulation might be a useful addition to conventional therapies.”
Tumor makes IL-6, liver produces TPO, platelets abound, tumor grows
Drawing on clinical data from ovarian cancer patients and following up with mouse model experiments and a clinical trial, Sood and colleagues discovered:
High platelet counts often occur due to an underlying medical condition. Many people with thrombocytosis also have cancer, especially ovarian gastrointestinal, ovarian and lymphoma. In many cases, high platelet counts are considered to be an initial cancerous sign.
Some people might be at a significantly higher risk of developing high platelet levels within the blood. These people include those who have recently undergone any type of surgical procedure, and those who have iron-deficiency anemia.
* Ovarian cancers produce the inflammatory cytokine interleukin-6 (IL-6);
* Triggering creation of the platelet-production regulating hormone thrombopoietin (TPO) in the liver;
* Causing platelet counts to soar to more than 450,000 per cubic millimeter in the blood, the threshold for thrombocytosis, and
* Stimulating tumor growth and continuation of the cycle.
“Platelets may function as a fuel depot for tumors by providing them with growth factors,” Sood said. They were found not only in the blood but also in the tumor’s microenvironment, in the tumor bed, and in ascites, fluid build-up in the abdominal cavity common in ovarian cancer.
THE ROLE OF PLATELETS IN OVARIAN CARCINOMA
Platelets represent one of the largest storage pools of angiogenic and oncogenic growth factors in the human body. The observation that thrombocytosis (platelet count >450,000/uL) occurs in patients with solid malignancies was made over 100 years ago. However, the clinical and biological implications as well as the underlying mechanism of paraneoplastic thrombocytosis associated with ovarian carcinoma remains unknown and were the focus of the current study.
Following IRB approval, patient data were collected on 619 patients from 4 U.S. centers and used to test associations between platelet count at initial diagnosis, clinicopathologic factors, and outcome. In vitro effects of plasma-purified platelets on ovarian cancer cell proliferation, docetaxel-induced apoptosis, and migration were evaluated using BrdU-PI flow cytometric and two-chamber chemotaxis assays. In vivo effects of platelet depletion on tumor growth, proliferation, apoptosis, and angiogenesis were examined using an anti-platelet antibody (anti-mouse glycoprotein 1ba, Emfret) to reduce platelets by 50%. Complete blood counts and number of mature megakaryocytes in the spleen and bone marrow were compared between control mice and ovarian cancer-bearing mice. Plasma levels of key megakaryo- and thrombopoietic factors including thrombopoietin (TPO), IL-1a, IL-3, IL-4, IL-6, IL-11, G-CSF, GM-CSF, stem cell factor, and FLT-3 ligand were assayed in a subset of 150 patients at the time of initial diagnosis with advanced stage, high grade epithelial ovarian cancer using immunobead-based cytokine profiling coupled with the Luminex® xMAP platform. Plasma cytokines significantly associated with thrombocytosis in ovarian cancer patients were subsequently evaluated in mouse models of ovarian cancer using ELISA immunoassays. The results of human and mouse plasma cytokine profiling were used to inform subsequent in vivo studies evaluating the effect of siRNA-induced silencing of select megakaryo- and thrombopoietic cytokines on paraneoplastic thrombocytosis.
Rebecca L. Stone, University of Texas Graduate School of Biomedical Sciences at Houston
In a clinical trial conducted at the Barts Cancer Institute, Queen Mary, University of London, the team also found that treatment of 18 ovarian cancer patients in a phase I/II clinical trial with siltuximab, an antibody to IL-6, sharply reduced platelet counts over a three-week period.
Clinical observation leads to survival connection
“This research comes from clinical observations,” Sood said. “We have many ovarian cancer patients with thrombocytosis and decided to look into the causes for it.”
The crux of the research was nicely summed in the MD Anderson press release:
“Highly elevated platelet levels fuel tumor growth and reduce the survival of ovarian cancer patients.”
A literature search revealed that the association between what was then called a “hyper-coagulable state” and cancer was noted as far back as 1867, but no relationship between the two had been established.
Of 619 ovarian cancer patients, 192 (31 percent) had thrombocytosis. Importantly, less than 2 percent of those had an iron deficiency or a non-cancerous inflammatory condition, the two most common causes of elevated platelet levels.
Patients with thrombocytosis survived for a median of 2.62 years, compared to 4.65 years for those with normal platelet counts. After accounting for age, disease stage, tumor grade and type and the extent of surgical tumor reduction, thrombocytosis remained an independent predictor of poor survival.