Abstract Number: VPB0759
Meeting: ISTH 2022 Congress
Background: Platelets play pathophysiological roles in cancer-associated thrombosis (CAT). One of the underlying mechanisms is the membrane protein podoplanin. Some types of tumor cells expressing podoplanin can induce platelet aggregation via the platelet activation receptor C-type lectin-like receptor 2 (CLEC-2).
In addition to tumor cells, cancer-associated fibroblasts (CAFs) also express podoplanin. CAFs are the most abundant cancer-stromal cells; they promote cancer progression through cell-cell interactions and release extracellular vesicles (EVs). However, the relationship between CAFs and platelets in CAT remains unstudied.
Aims: We investigate whether CAFs and their EVs potentially promote CAT in 3LL mouse lung cancer model.
Methods: Podoplanin expression in EVs purified from NIH/3T3 cell-conditioned medium and 3LL tumor was analyzed by immunoblotting. Mouse platelet aggregation was induced by NIH/3T3 cells and their EVs. Plasma podoplanin level was compared between healthy mice and 3LL-bearing mice. At the femoral vein, the time to occlusion after ferric chloride injury was measured in healthy mice and 3LL-bearing mice. Tumor-bearing mice were treated with rat anti-mouse CLEC-2 monoclonal antibody 2A2B10 or control rat IgG four days before ferric chloride injury.
Results: EVs purified from NIH/3T3 cell-conditioned medium and 3LL tumor presented podoplanin. NIH/3T3 cells and their EVs induced platelet aggregation in a CLEC-2 dependent manner. The 3LL-bearing mice showed increased podoplanin levels in plasma and a shortened time to occlusion compared to healthy mice. In the tumor-bearing state, antibody-induced CLEC-2 depletion extended the time to occlusion compared to control IgG-treated mice.
Conclusion(s): Podoplanin-expressing EVs released from CAFs impact circulating podoplanin levels, which promote venous thrombosis. Antiplatelet therapy targeting CLEC-2 may be effective in treating CAT mediated by podoplanin derived from CAFs as well as tumor cells.
To cite this abstract in AMA style:Shirai T, Sasaki T, Tsukiji N, Ohishi S, Yokomori R, Takano K, Suzuki-Inoue K. Cancer-associated fibroblasts promote venous thrombosis through C-type lectin-like receptor 2/podoplanin in 3LL lung cancer mouse model [abstract]. https://abstracts.isth.org/abstract/cancer-associated-fibroblasts-promote-venous-thrombosis-through-c-type-lectin-like-receptor-2-podoplanin-in-3ll-lung-cancer-mouse-model/. Accessed November 29, 2023.
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