<p>Dihydrodiosgenin inhibits endothelial cell-derived factor VIII and platelet-mediated hepatocellular carcinoma metastasis</p>

Abstract

Background: Our previous studies have demonstrated that diosgenin and diosgenin derivatives exhibit excellent antithrombotic activity via regulating platelet function and coagulation factor level. Platelets and blood coagulation system are highly associated with tumor hematogenous metastasis. Therefore, the purpose of this study was to evaluate whether dihydrodiosgenin (dydio) mediated-platelet inhibition or coagulation factor level modulation is involved in hepatocellular carcinoma cell (HCC) metastasis. Methods: Cell viability was examined by MTT and colony formation assays. Platelet aggregation text and morphology were used to assess dydio’s role on tumor cell-induced platelet activation (TCIPA). Scratch assay, adhesion assay and Western blot were used to evaluate dydio’s role on platelet-mediated metastasis. Western blot and fluorescence detection were performed to clarify dydio's role on endothelial cell (EC) function. The mice lung metastasis model was constructed to investigated dydio’s function on coagulation factor and platelet-mediated metastasis. Results: This study found that pretreatment with dydio caused a significant inhibition of TCIPA. Platelets exposed to dydio significantly inhibited their adhesion to tumor cells, meanwhile, releasates of platelets that pretreated with dydio led to diminished cancer cell proliferation and migration along with the increase of epithelial markers E-cadherin and loss of mesenchymal phenotype. Additionally, ECs pretreated with dydio suppressed factor VIII (FVIII) level which in turn restrained the activation of platelets and the adhesion of cancer cells or platelets to ECs. Interestingly, our study demonstrated that FVIII could promote HCC proliferation. In vivo study revealed that mice intragastrical (i.g.) administration with dydio significantly inhibited the lung metastasis of hepal-6 cells which is highly correlated with the altered platelet function and coagulation level. Conclusion: Taken together, these results demonstrated that dydio altered platelet function and coagulation FVIII level, resulting in decreased metastatic potential of HCC. Thus, our study reveals that dydio exerts novel mechanisms of antitumor action beside its direct antitumor activity.

Platelets as Key Factors in Hepatocellular Carcinoma

“…In vivo and in vitro studies on melanoma and breast cancer metastasis have shown that platelets activate the coagulation cascade by secreting thrombin and tissue factor, which results in a meshwork of platelets and fibrin shielding tumor cells and allows them to escape immune-surveillance and successfully invade distant sites [29,33]. A recent paper by Zhuang et al, shows evidence that this process also occurs in a metastatic HCC-mouse model [34]. They found that activated platelets adhere to tumor cells and that pharmacological inhibition of platelet activation, with diosgenin and diosgenin derivates, inhibits platelet adherence to tumor cells and decreases metastasis.…”

“…They found that activated platelets adhere to tumor cells and that pharmacological inhibition of platelet activation, with diosgenin and diosgenin derivates, inhibits platelet adherence to tumor cells and decreases metastasis. In vitro studies have also shown a direct effect of platelet lysates on tumor cell migration and invasion, suggesting the pro-metastatic effect is not merely a result of avoiding immune-surveillance, but also due to the direct effect of their stored growth factors [16,34]. Platelets have also been reported to alter the response to chemotherapeutic agents.…”

Till Death Do Us Part—The Multifaceted Role of Platelets in Liver Diseases

“…Furthermore, high platelet counts correlate with an increased risk of developing extrahepatic metastasis [ 116 ]—likely due to platelet-mediated cell growth, tumor aggressiveness and migration [ 117 ]. Moreover, platelet-mediated metastasis is prevented by the inhibition of coagulation factor FVIII, which plays a role in platelet-cancer cell interaction [ 118 ]. However, beside their proliferating effects, platelets also promote HCC cell apoptosis [ 105 ].…”

Underlying mechanisms and drug intervention strategies for the tumour microenvironment

“…Yang et al demonstrated that salvianolic acid A can block the secretion of glucose-regulated protein 78 (GRP78) to inhibit cancer-related angiogenesis [ 156 ]. Zhuang et al demonstrated that dihydrodiosgenin (DYDIO) can inhibit platelet activation and reduce endothelial cell-derived factor VIII (FVIII) to inhibit HCC metastasis [ 157 ].…”