Platelets are essential for the maintenance of haemostasis, however, increasing evidence suggests a further role in cancer progression. Experimentally, platelet depletion or functional inhibition slows metastatic progression in mouse models of cancer. However, further studies are needed on the impact of platelets in lung cancer models more closely resembling human disease. Lung cancer is the leading cause of cancer death in Australia and worldwide, and the poor prognosis for the majority of patients highlights the importance of developing improved treatment options. In this study we assessed the effect of platelets on disease progression using sophisticated lung cancer models.
Using two different mouse models with reduced platelets, Mpl-/-(10% of WT), and BclxPlt20/Plt20 (25% of WT), and cell lines derived from spontaneously arising tumours in mice with conditional mutations in Kras-G12D/p53 and p53/Rb1, we modelled blood borne metastasis of lung adenocarcinoma (LAC) and small cell lung cancer (SCLC), respectively.
Following i.v. transplant of Kras/p53 cells into Mpl-/-, BclxPlt20/Plt20, and WT mice, we observed significantly longer disease survival in thrombocytopenic mice, demonstrating a role for platelets in furthering disease progression in LAC. As platelets degranulate upon activation, we assessed blood serum levels of platelet granule protein P-selectin, detecting a two-fold increase in WT mice with a high tumour load compared to non-transplanted WT mice.
Transplanting p53/Rb1 cells i.v. into thrombocytopenic mice resulted in significantly reduced tumour load in both models of thrombocytopenia, indicating an important role for platelets in SCLC. Additionally, we found a strong positive correlation between soluble P-selectin serum concentration and tumour load in this model.
Using lung cancer models closely mimicking human LAC and SCLC, we have demonstrated an association between the level of platelet activation and disease burden, and provided further evidence for the significance of platelets in metastatic lung cancer progression. Additionally, to our knowledge, this is the first demonstration that reducing platelet counts in a mouse model of LAC not only affects metastasis, but also extends survival.