Tumor cells and platelets are known to form an unholy alliance increasing cancer progression in numerous ways. After extravasation into circulation a cancer cell is subjected to immune surveillance and natural killer cell-mediated cytolysis. Furthermore, shear force caused by the blood stream reduces the chance of extravasation. Cancer cell-induced platelet activation is a trick of cancer cells to “hijack” the services of host cells. Activated platelets bind to cancer cells and form a protective cloak which helps them to escape the immune system. Platelet adhesion to cancer cells facilitate tethering and arrest of disseminated cancer cells in the vasculature, enhance invasive potentials and thus extravasation of cancer cells. However, the exact mechanisms how platelets influence blood-borne metastasis remain poorly understood.
We discovered a new mechanism of platelet-cancer cell interaction: A dynamin-dependent uptake of platelets by cancer cells followed by the recycling of the platelet-specific proteins and its incorporation into cancer cells’ plasma membrane (shown for CD42a).
We use different techniques to investigate the interaction of human non-small lung cancer cells (A549) with freshly isolated human platelets.
Time laps of differential interference contrast microscopy images of A549 cells and isolated human platelets deposited on collagen I (image interval 30s, total time 90minutes).
Quantitative nanomechanical mapping (AFM) of a living platelet. Data channel visualize submembraneous vesicles in an activated platelet.
3D view of one platelet beside and three platelets on a A549 cell. The AFM image gave the impression that platelets fuse with plasma membrane of A549 cells.
We discovered a new mechanism of platelet-cancer cell interaction: A dynamin-dependent uptake of platelets by cancer cells followed by the recycling of the platelet-specific proteins and its incorporation into cancer cells’ plasma membrane (shown for CD42a).
3D representation of two A549 cells after incubation with PKH67 stained platelets (green). The cancer cell plasma membrane was stained with WGA-Alexa 555 (red) and the nuclei with DAPI (blue). This video shows clearly the distribution of platelet fragments inside the cell. Additionally, the left cell shows a large PKH67 stained structure penetrating the A549 cell`s plasma membrane.
Protective effect of Heparins
Since cancer patients show an increased risk of venous thromboembolism, anticoagulant treatment with vitamin K antagonists or heparins is customary. A meta-analysis of clinical trials of the past 20 years showed an improved survival in cancer patients treated with heparin. This effect of heparin is based on mechanisms that are different from its antithrombotic effect and linked to the ability of influencing directly the tumor biology. Tumor cells in blood stream adhere to platelets and this adhesion is probably mediated by platelet surface molecules like GPIIb/IIIa, GPIb and P-selectin. Heparin blocks P-Selectin and this might be responsible for reduced malignancy by inhibiting the initial step of platelet-tumor cell interaction. However the interacting receptors and adhesion molecules remain to be elucidated.
Binding of platelets to tumor cells is a crucial step for the malignancy of cancer. Therefore, insights into this process may contribute to the optimization of tumor therapies.
We use optical imaging methods and single-cell force spectroscopy (SCFS) to investigate and to quantify the interaction of human non-small lung cancer cells (A549) with platelets. A focus in this project is to quantify the inhibitory effect of different types of heparins and to identify interacting receptors and adhesion molecules.
