Role of platelets in tumor growth and metastasis in ovarian cancer
Final Report Abstract
Ovarian cancer is a highly aggressive disease with a poor prognosis. Most women are diagnosed in late stages of disease. In more than 40% of ovarian cancer patients, thrombocytosis (increased number of platelets in the blood as defined by > 450.000 / µl according to the National Heart Lung and Blood Institut [NHLBI]) is present and associated with significant worse overall and disease-free survival. Therefore, this project focused on the role of platelets and their interaction with tumor cells in tumor growth and metastasis of ovarian cancer. With different orthotopic mouse models of ovarian cancer I could clearly show that platelet numbers are crucial for proliferation and apoptosis in vitro and tumor growth as well as metastasis in vivo. Metastatic processes induced by thrombocytosis were dependent on tumoral expression of YAP, as siRNA-mediated knockdown of YAP in vivo completely abrogated this effect. Additionally, I could show that platelets are decisive for tumor rebound growth after withdrawal of anti-angiogenic therapy. Interestingly, this was dependent on platelet infiltration into the tumor microenvironment, direct tumor cellplatelet interaction and on expression of focal adhesion kinase (FAK) within platelets. Using a mouse model where FAK was specifically knocked out in the platelets or treatment with a FAK inhibitor completely abrogated increased tumor growth after cessation of anti-angiogenic therapy. Therefore inhibition of FAK provides a new strategy for ovarian cancer patients with developed resistance to anti-angiogenic therapy. Our results were published in the Journal of Clinical Investigation and additionally highlighted in Nature Reviews Clinical Oncology in May 2016. Overall, my results strengthen the concept that thrombocytosis is not only a bystander effect of tumorigenesis but that platelets play a crucial and active role inside and outside the tumor microenvironment. Interestingly, long-term treatment with aspirin significantly reduced risk for cancer, including ovarian cancer indicating that either lowering platelet counts or inhibiting their function would represent an important additional strategy in cancer patients. However, lowering platelet numbers in cancer patients needs careful titration as thrombocytopenia can easily lead to life-threatening bleeding complications. Interestingly, a clinical study combining anti-programmed Cell Death-1 ligand (aPDL-1) antibody atezolizumab with aspirin was launched and is about to start recruiting ovarian cancer patients (https://clinicaltrials.gov/: NCT02659384). This is based on results which showed that aspirin increased T-cells infiltration into the tumor tissue in ovarian cancer. However, to what extent platelets are involved in this process is not known so far, but will be of great interest for future studies. In 2016, my research was honored by “The Diane Denson Tobola Fellowship in Ovarian Cancer Research” and a Young Investigator Award of the Nonprofit Organization ‘Ovarcome’ Nonprofit Inc. Additionally, I got selected as one of 50 participants for the AACR workshop “Molecular Biology in Clinical Oncology” for physician scientists in July 2016 which provided a substantive overview of key areas in molecular biology and translational cancer research for aspiring physician-scientists.
Publications
- Platelet FAK is a critical regulator of tumor growth after withdrawal of anti-angiogenic therapy. J Clin Invest. 2016 May 2; 126(5):1885-96. (Highlighted in Nature Reviews Clinical Oncology (2016): FAK – new target for antiangiogenic therapy)
Haemmerle M, Bottsford-Miller J, Pradeep S, Taylor ML, Choi H, Hansen JM, Dalton HJ, Stone RL, Cho MS, Nick AM, Nagaraja AS, Gutschner T, Gharpure KM, Mangala LS, Rupaimoole R, Han HD, Zand B, Armaiz-Pena GN, Wu SY, Pecot CV, Burns AR, Lopez-Berestein G, Afshar-Kharghan V, Sood AK
- Differential platelet levels affect response to taxane-based therapy in ovarian cancer. Clin Cancer Res. 2015; 21(3):602-10
Bottsford-Miller J, Choi HJ, Dalton HJ, Stone RL, Cho MS, Haemmerle M, Nick AM, Pradeep S, Zand B, Previs RA, Pecot CV, Crane EK, Hu W, Lutgendorf SK, Afshar-Kharghan V, Sood AK
(See online at https://doi.org/10.1158/1078-0432.CCR-14-0870)
