Table 3.

Roles of platelet/megakaryocyte-derived proteins in carcinogenesis and metastasis

Protein	Function in carcinogenesis/metastasis
TGFβ	Suppresses growth of early tumours but later promotes tumour invasion and migration[138]. Inhibits NK cell-mediated tumour cell destruction[94] Activates TGFβ/Smad and NF-κB pathways in cancer cells inducing their transition to an invasive mesenchymal-like phenotype[100]
SDF1	Recruits CXCR4+ tumour cells, bone marrow-derived HPCs and endothelial progenitors to sites of vasculogenesis[88].
PF4	Inhibits growth and metastasis of murine models of melanoma and colon carcinoma[139–141]. Regulates vasculature by inhibiting endothelial cell proliferation and migration[142, 143].
TSP1	Both pro- and anti-metastatic effects have been reported. Inhibits endothelial cell migration, proliferation[144] and tumour angiogenesis[64, 145] TSP1 mRNA and protein expression is higher in metastatic breast carcinoma than in patients with locally invasive, non-metastatic disease[146, 147]. Stimulates tumour cell adhesion to vessel walls[148] TSP1 knock-down was associated with reduced metastasis to blood and to lung in spontaneous mouse models of breast cancer metastasis, thought to be due to TSP1-induced activation of TGFβ. [149]. Mediate haplotaxis and chemotaxis of human melanoma and carcinoma cells in vitro[150]
P-selectin, vWF, GPIIb/IIIa and Ib-IX	Mediate initial rolling/tethering of circulating tumour cells to endothelium in vessels of metastatic organs[97–99].
MMP9, MMP2	Digestion of local tissue matrix enabling invasion of local tissues and activation via cleavage of surface-bound factors[151]
Angiogenic growth factors	See Table 2.
Coagulation factors: Thrombin, tissue factor	In tumour cells lines B16-F10 and UMCL, thrombin promotes GRO-a and Twist gene expression leading to a more malignant phenotype, enhancing cell motility and angiogenesis. Inhibition of thrombin decreased tumour growth and metastasis in 4TI mice that develop spontaneous breast carcinoma[152–154] Tissue factor expression mediates haematogenous metastasis of melanoma and generation of thrombin[155, 156].
Bioactive lipids: S1P and LPA	S1P promotes vascular maturation by mediating N-cadherin function[157]. LPA receptors are found in human breast cancer and platelet LPA stimulates osteolytic bone metastases in studies using the breast cancer cell line MDA-BO2 [158]. LPA mediates proliferation, migration, and invasion of MDA-BO2 cells through activation of a Ga/ERK1/2-dependent signalling pathway[159]. LPA and S1P act directly on endothelial cells to stimulate angiogenesis and also induce breast cancer cells to VEGF[159].