Tumor Induced Platelet Aggregation Promote Tumor Growth Through the Podoplanin/CLEC-2 Pathway
Introductions. Cancer is a major public health problem worldwide and is the second leading cause of death in the United States1. Different types of cancers have different symptoms, either specific to the cancer or general to a variety of illnesses2. This make it more difficult to catch a cancer before metastasis where current treatments, such as surgery, radiation, chemotherapy, and immunotherapy, are more beneficial1. This is why we looked at a mechanism of metastasis called tumor-induced platelet aggregation. This phenomenon is present in several types of cancer including squamous cell carcinoma, lung and skin cancer, mesotheliomas, and cancer-associated fibroblast3. It promotes both tumor growth, via the release of PDEGF and tumor metatstasis through promoting angiogenesis, protection from shear rates and immune cells, and tumor cell extravasation3. The effectiveness of this mechanism was confirmed when a mice with lung squamous cell carcinoma had no tumor growth when podoplanin, the cell receptor for platelet adhesion, is knocked out4. Methods. PCR, immunofluorescence analysis, immunohistochemistry, western blot, platelet aggregation assay, and other assays were done on several different types of cancer cell lines including lung squamous cell carcinoma, and ovarian squamous cell carcinoma, all of which express the podoplanin-CLEC-2 pathway4-7. Results. The first step is the lymphocytes and macrophage in the tumor body secreting IFN-γ and TGF-β5. This leads to the increase production of podoplanin on the tumor invasive front via the activation of the SMAD-STAT signaling pathway5. The podoplanin then binds to the CLEC-2 receptor on the platelet. This receptor is uniquely specific for podoplanin as opposed to platelet’s other functions of adhering to collagen or thrombin6. Once CLEC-2 is activated, Syk and PLCγ2 is phosphorylated and the dense granules are secreted7. One of those factors, PDEGF, play a role in the promotion of tumor growth4. Conclusions. This pathway is vital for the early metastasis of certain types of cancers. A therapeutic can target this pathway either by modified immunoglobulins or modified platelets8. Modified platelets would have a distinct advantage of also binding to GpIIb-IIIa disrupting platelet-to-platelet adhesion. This target can uniquely target metastasis, as opposed to traditional therapies.
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