Timothy Yadegar

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 pathway^4-7. 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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