Abstract
Tumor-associated thrombosis is the second leading risk factor for cancer patient death, and platelets activity is abnormal in cancer patients. Discovering the mechanism of platelet activation and providing effective targets for therapy are urgently needed. Cancer cell- derived IgG has been reported to regulate development of tumors. However, studies on the functions of cancer cell-derived IgG are quite limited. Here we investigated the potential role of cancer cell-derived IgG in platelet activation. We detected the expression of CD62P on platelets by flow cytometry and analyzed platelet function by platelets aggregation and ATP release. The content of IgG in cancer cell supernatants was detected by enzyme-linked immune sorbent assay. The distribution of cancer-derived IgG in cancer cells was analyzed by immunofluorescence assay. Western blot was performed to quantify the relative expression of FcγRIIa, syk, PLCγ2. The interaction between cancer cell-derived IgG and platelet FcγRIIa was analyzed by co-immunoprecipitation. The results showed that higher levels of CD62P were observed in cancer patients’ platelets compared with that of healthy volunteers. Cancer cell culture supernatants increased platelet CD62P and PAC-1 expression, sensitive platelet aggregation and ATP release in response to agonists, while blocking FcγRIIa or knocking down IgG reduced the activation of platelets. Coimmunoprecipitation results showed that cancer cell-derived IgG interacted directly with platelet FcγRIIa. In addition, platelet FcγRIIa was highly expressed in liver cancer patients. In summary, cancer cell-derived IgG interacted directly with FcγRIIa and activated platelets; targeting this interaction may be an approach to prevent and treat tumor-associated thrombosis.
Highlights
The association between platelet and cancer has been recognized for centuries, starting with the identification of Trousseau syndrome in 18651
Collagen (0.5 μg/mL) or thrombin (0.04 U/mL), the percentage of aggregated platelets in the group incubated with cancer cell supernatant was significantly higher than that in the group with culture medium incubation (Fig. 3a–d), and ATP release followed the same pattern (Fig. 3e, h). These data indicated that platelet activation could be induced by the cancer cell supernatant, cancer cell supernatant could not induce the aggregation of platelets directly (Supplementary Figure 1)
It has been reported that αIIbβ[3] was essentital for FcγRIIa signaling[36], here we found inhibiting FcγRIIa or αIIbβ[3] both reduced the expression of CD62P, we hypothesize that there may be some factors in the cancer cell culture supernatant that can affect platelet activity by acting on FcγRIIa
Summary
The association between platelet and cancer has been recognized for centuries, starting with the identification of Trousseau syndrome in 18651. The interaction between tumor cells and platelets was shown to play a key role in malignant progression, and platelet activation and platelets have been identified as potential new drug targets for cancer therapy[2]. It is known that platelets can regulate. Miao et al Cell Death and Disease (2019)10:87 monocytes, macrophages, and human platelets. Roles for FcγRIIa have been identified in processes mediating interactions between platelets and immune complexes, specific strains of bacteria[17], and the innate phase proteins serum amyloid P component and C-reactive protein[18]. The cancer cell ligand that stimulates platelet activation by FcγRIIa remains to be elucidated
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