Contribution of platelets to cancer progression
Project type
Honours
| Supervisor(s) | Division | |
| (Primary) | Cancer and Haematology | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Cancer and Haematology | .(JavaScript must be enabled to view this email address) |
Details of project
Platelets are tiny anucleate cells with important roles in haemostasis. In addition to their protective functions, evidence in animal models suggests that the activation of platelets and the coagulation system have a crucial role in the metastatic progression of cancer. Antibody-induced or genetic depletion of platelets inhibits metastasis formation in experimental lung metastasis mouse models, however the overall mechanism is unclear.
It has been proposed that local thrombin generation supports tumour growth, and PAR-4 deficient mice, whose platelets fail to respond to thrombin, showed a marked reduction in experimental pulmonary metastasis. The procoagulant function of platelets refers to their ability to flip phosphatidylserine (PS) to their outer membrane following activation, localising coagulation complexes near the developing blood clot. This critical platelet function promotes thrombin generation from pro-thrombin and the development of a fibrin matrix, both of which are essential to the growth of a stable blood clot.
We have identified two separate pathways in platelets that regulate platelet PS exposure and procoagulant function. An apoptotic pathway where Bak/Bax double deficient platelets have a defect in PS exposure and in vitro thrombin generation in response to apoptotic stimuli; and a necrotic pathway where cyclophilin D deficient mice have a block in strong agonist induced PS exposure. We have now generated mice conditionally lacking Bak/Bax and CyclophilinD in platelets with the PF4-Cre system.
This project will establish the relative contribution of apoptotic and necrotic cell death pathways to platelet procoagulant function in metastasis. Interaction of platelets from these mice (single, double, or triple mutants) with tumour cells known to aggregate platelets will be determined. Results will guide in vivo studies using experimental lung metastasis models such as B1610 melanoma.
Project references
- Erpenbeck L, Schon MP. Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood. 2010 Apr 29;115(17):3427-36. Review.
- Gay LJ, Felding-Haberman B. Contribution of platelets to tumour metastasis. Nat Rev Cancer. 2011 Feb;11(2):123-34. Review.
- Bambace NM, Holmes CE. The platelet contribution to cancer progression. J Thromb Haemost. 2011 Feb;9(2):237-49. Review.
Research interests
- The role of apoptosis in platelet production and function in health and disease.
- Platelet function in immunity and cancer.
- The molecular regulation of platelet production and function.
- Ets transcription factors in hematopoiesis.
Selected publications
- Josefsson EC, James C, Henley KJ, Debrincat MA, Rogers KL, Dowling MR, White MJ, Kruse EA, Lane RM, Ellis S, Nurden P, Mason KD, O’Reilly LA, Roberts AW, Metcalf D, Huang DCS, Kile BT. Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained in order to survive and produce platelets. J Exp Med. 2011, In press.
- Dowling MR, Josefsson EC, Henley KJ, Hodgkin PD, Kile BT. Platelet senescence is regulated by an internal timer, not damage inflicated by hits. Blood. 2010 Sep 9;116(10):1776-8.
- Schoenwaelder SM, Yuan Y, Josefsson EC, White MJ, Yao Y, Mason KD, O'Reilly LA, Henley KJ, Ono A, Hsiao S, Willcox A, Roberts AW, Huang DC, Salem HH, Kile BT, Jackson SP. Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function. Blood. 2009 Jul 16;114(3):663-6.
- Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, Kelly PN, Ekert PG, Metcalf D, Roberts AW, Huang DC, Kile BT. Programmed anuclear cell death delimits platelet life span. Cell. 2007 Mar 23;128(6):1173-86.
Research theme
Cancer
Scientific discipline
- Cell Biology
- Haematology
Keywords
Platelets, metastasis, procoagulant platelets, apoptosis