Study Explains High Platelets in Ovarian Cancer Patients; Survival Reduced

Tracking down cause and effect
The team found elevated platelet counts in three separate mouse models of epithelial ovarian cancer and in pancreatic and uterine cancer models, but not breast cancer.

They also found a connection between high platelet counts and higher levels of large cells called megakaryocytes, which occur in the bone marrow and fragment into platelets under the direction of thrombopoietin.

Next, in a cohort of 150 ovarian cancer patients, they analyzed plasma levels of 10 factors in the blood known to regulate creation of megakaryocytes. Again, 31 percent had thrombocytosis.

Levels of interleukin-6 and thrombopoietin in blood serum were substantially elevated in patients with thrombocytosis. A separate analysis of 310 ovarian cancer patients showed that elevated IL-6 is also associated with reduced progression-free survival.

When oncologists see patients with high platelet levels do they currently treat them in any way?

Dr Sood: Not really any differently.  It is something that we have simply known for a long time.  In this context, given especially that these patients tend to have aggressive behavior (of the tumour), there is a lot of potential clinical implications, but again this is relatively new, so I think we need to do additional work to really figure out what are the best approaches to treat these patients.

Is it better to combine an IL-6 antibody, specially in those patients who have high platelets, along with chemotherapy?  Can drugs like even aspirin or things like that that interfere with platelet function, could those have implications?  There are data that would suggest that patients who are on a daily aspirin tend to live longer in the context of cancer patients. These type of things need to be developed further.

Blocking thrombopoietin and interleukin-6 reduces platelets, shrinks tumors
To understand the functional role TPO and IL-6 play in raising platelet levels, the researchers used short interfering RNA to shut them down separately and together in mice. In each case, platelet levels fell steeply, with thrombocytosis completely eliminated when both IL-6 and TPO were silenced.

To test IL-6 as a target, they treated two strains of mice with ovarian cancer with the IL-6 antibody siltuximab, paclitaxel chemotherapy, or both. All three treatments reduced platelet count and tumor burden. The combination was most effective, reducing tumor growth by 90 percent.

Treatment of mice with an anti-platelet antibody cut both the circulating platelet count and average tumor size in half, reduced cell proliferation by 44 percent and tumor blood vessel density by 51 percent.

More to study: precise mechanisms, potential treatments
While the researchers note that platelets are likely to promote cancer growth by strengthening tumor blood vessels, the precise mechanisms involved remain to be discovered via prospective collection and in-depth analysis of platelets from cancer patients.

The authors note their findings might explain why some blood-thinning agents improve survival in some cancer patients independent of their prevention of vascular blood clotting, and why daily use of aspirin after diagnosis of colorectal cancer also improved survival in a prospective clinical trial.

Platelet levels may also serve as biomarkers for ovarian and other cancers, Rebecca Stone, M.D., clinical fellow in gynecologic oncology and the first author of the study, noted. “If you see high platelets, absent inflammation or iron deficiency, it would be important to look for cancer.”

MD Anderson co-authors with Sood and first author Stone are Alpa Nick, M.D., Hee Dong Han, Ph.D., Justin Bottsford-Miller, M.D., Wei Hu, M.D., Ph.D., Hannah Gershenson, Koji Matsuo, M.D., Mian M.K. Shahzad, M.D., Erin R. King, M.D., of the Department of Gynecologic Oncology; Rajesha Rupaimoole of the Department of Cancer Biology; Guillermo N. Armaiz-Pena, Ph.D., Ibrahim Tekedereli, M.D., Bulent Ozpolat, M.D., Ph.D., and Gabriel Lopez-Berestein, M.D., of the Department of Experimental Therapeutics; Chad Pecot, M.D., Division of Cancer Medicine; Michael Deavers, M.D., of the Department of Pathology; Hernan Vasquez, Ph.D., and Vahid Afshar-Kharghan, M.D., of the Section of Benign Hematology; Diana Urbauer of the Department of Biostatistics and Francisca Gushiken, M.D., of the Department of Leukemia. Sood, Han and Lopez-Berestein also are with the Center for RNA Interference and Non-Coding RNA. Lopez-Berestein also is affiliated with the Department of Nanomedicine and Bioengineering at The University of Texas Health Science Center at Houston.

Collaborating co-authors are Iain McNeish, Ph.D., Frances Balkwill, Ph.D., and Jermaine Coward, Ph.D. of the Barts Cancer Institute, Queen Mary, University of London; Charles Landen, M.D., Department of Obstetrics and Gynecology, University of Alabama, Birmingham; Edward H. Ahn, M.D., and Virginia K. Bond, M.D., of the Department of Obstetrics and Gynecology, University of Maryland, Baltimore; Rui Wang and Wah Chiu, Ph.D., of the Department of Biochemistry and Molecular Biology, Baylor College of Medicine; Angela F. Drew, Ph.D., of the Department of Cancer and Cell Biology, University of Cincinnati; and from the University of Iowa Katherine Collins, Department of Psychology, Koen DeGeest, M.D., of the Department of Obstetrics and Gynecology; and Susan Lutgendorf, Ph.D., of the Departments of Psychology, Urology, Obstetrics and Gynecology and the Holden Comprehensive Cancer Center.

Funding Sources
Funding for this research was provided by Gail MacNeil KOH Research Award from the Gynecologic Cancer Foundation; grants from the National Cancer Institute, a Program Project Development Grant from the Ovarian Cancer Research Fund; the U.S. Department of Defense; the Baylor College of Medicine and M.D. Anderson Cancer Center Multidisciplinary Research Program; the Anne and Henry Zarrow Foundation; the Marcus Foundation, Inc.; the estate of C.G. Johnson, Jr.; the United Kingdom Medical Research Council; the Blanton-Davis Ovarian Cancer Research Program; the Laura and John Arnold Foundation; the RGK Foundation; the Bettyann Asche Murray Distinguished Professorship in Ovarian Cancer Research; and NCI training grants.

About MD Anderson
The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For eight of the past 10 years, including 2011, MD Anderson has ranked No. 1 in cancer care in “Best Hospitals,” a survey published annually in U.S. News & World Report.

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Source: University of Texas M. D. Anderson Cancer Center

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