Podoplanin promotes cancer-associated thrombosis and contributes to the unfavorable overall survival in an ectopic xenograft mouse model of oral cancer

Lee, Hsing-Ying; Yu, Ni-Yen; Lee, Shiang-Hsuan; Tsai, Hui Ju; Wu, Chih‐Ching; Cheng, Ju‐Chien; Chen, Ding‐Ping; Wang, Ying-Ru; Tseng, Ching Ping

doi:10.1016/j.bj.2019.07.001

Cited by 25 publications

(27 citation statements)

References 47 publications

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“…Overexpression of PDPN in vascular endothelial cells could also induce thrombo-inflammation, possibly promoting PDPN-induced cellular interactions between platelets, cancer cells and endothelial cells. Platelet aggregation was enhanced by PDPN-positive oral squamous carcinoma cells, and mice developing PDPN-positive tumors have a reduced survival rate ( 31 ). Podoplanin expression by human brain tumors also induces platelet aggregation and is associated with hypercoagulability and a high risk of VTE ( 32 ).…”

Section: Cancer-associated Thrombosis and Thrombo-inflammationmentioning

confidence: 99%

Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues

et al. 2021

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Although platelets are critically involved in thrombosis and hemostasis, experimental and clinical evidence indicate that platelets promote tumor progression and metastasis through a wide range of physical and functional interactions between platelets and cancer cells. Thrombotic and thromboembolic events are frequent complications in patients with solid tumors. Hence, cancer modulates platelet function by directly inducing platelet-tumor aggregates and triggering platelet granule release and altering platelet turnover. Also, platelets enhance tumor cell dissemination by activating endothelial cell function and recruiting immune cells to primary and metastatic tumor sites. In this review, we summarize current knowledge on the complex interactions between platelets and tumor cells and the host microenvironment. We also critically discuss the potential of anti-platelet agents for cancer prevention and treatment.

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Section: Cancer-associated Thrombosis and Thrombo-inflammationmentioning

confidence: 99%

Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues

et al. 2021

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“…The epithelial-mesenchymal transition (EMT) occurs during cancer progression. A loss or a decrease in EpCAM expression and an increase in mesenchymal markers such as N-cadherin, vimentin, and podoplanin in cancer cells may accompany the EMT [33,40,41]. The number of EpCAM + -CTCs is likely to decrease when the disease status of patients changes from SD to PD.…”

Section: Discussionmentioning

confidence: 99%

Sequential Circulating Tumor Cell Counts in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma: Monitoring the Treatment Response

Rau

Liu

Hsiao

et al. 2020

JCM

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Hepatocellular carcinoma (HCC) is among the most common causes of cancer death in men. Whether or not a longitudinal follow-up of circulating tumor cells (CTCs) before and at different time points during systemic/targeted therapy is useful for monitoring the treatment response of patients with locally advanced or metastatic HCC has been evaluated in this study. Blood samples (n = 104) were obtained from patients with locally advanced or metastatic HCC (n = 30) for the enrichment of CTCs by a negative selection method. Analysis of the blood samples from patients with defined disease status (n = 81) revealed that those with progressive disease (PD, n = 37) had significantly higher CTC counts compared to those with a partial response (PR) or stable disease (SD; n = 44 for PR + SD, p = 0.0002). The median CTC count for patients with PD and for patients with PR and SD was 50 (interquartile range 21–139) and 15 (interquartile range 4–41) cells/mL of blood, respectively. A longitudinal analysis of patients (n = 17) after a series of blood collections demonstrated that a change in the CTC count correlated with the patient treatment response in most of the cases and was particularly useful for monitoring patients without elevated serum alpha-fetoprotein (AFP) levels. Sequential CTC enumeration during treatment can supplement standard medical tests and benefit the management of patients with locally advanced or metastatic HCC, in particular for the AFP-low cases.

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“…Western blotting was performed as described previously [ 20 , 59 ]. Proteins were separated by SDS-PAGE under reducing condition, transferred to a polyvinylidene fluoride membrane and blocked with 5% non-fat milk for 1 h. The membrane was incubated with primary antibody at room temperature (RT) for 1.5 h followed by secondary antibody for 1 h. Protein expression was detected by ECL-Plus reagents.…”

Section: Methodsmentioning

confidence: 99%

Integrin αIIbβ3 outside-in signaling activates human platelets through serine 24 phosphorylation of Disabled-2

et al. 2021

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Background Bidirectional integrin αIIbβ3 signaling is essential for platelet activation. The platelet adaptor protein Disabled-2 (Dab2) is a key regulator of integrin signaling and is phosphorylated at serine 24 in eukaryotic cells. However, the mechanistic insight and function of Dab2-serine 24 phosphorylation (Dab2-pSer24) in platelet biology are barely understood. This study aimed to define whether and how Dab2 is phosphorylated at Ser24 during platelet activation and to investigate the effect of Dab2-pSer24 on platelet function. Results An antibody with confirmed specificity for Dab2-pSer24 was generated. By using this antibody as a tool, we showed that protein kinase C (PKC)-mediated Dab2-pSer24 was a conservative signaling event when human platelets were activated by the platelet agonists such as thrombin, collagen, ADP, 12-O-tetradecanoylphorbol-13-acetate, and the thromboxane A2 activator U46619. The agonists-stimulated Dab2-pSer24 was attenuated by pretreatment of platelets with the RGDS peptide which inhibits integrin outside-in signaling by competitive binding of integrin αIIb with fibrinogen. Direct activation of platelet integrin outside-in signaling by combined treatment of platelets with manganese dichloride and fibrinogen or by spreading of platelets on fibrinogen also resulted in Dab2-pSer24. These findings implicate that Dab2-pSer24 was associated with the outside-in signaling of integrin. Further analysis revealed that Dab2-pSer24 was downstream of Src-PKC-axis and phospholipase D1 underlying the integrin αIIbβ3 outside-in signaling. A membrane penetrating peptide R11-Ser24 which contained 11 repeats of arginine linked to the Dab2-Ser24 phosphorylation site and its flanking sequences (RRRRRRRRRRR19APKAPSKKEKK29) and the R11-S24A peptide with Ser24Ala mutation were designed to elucidate the functions of Dab2-pSer24. R11-Ser24 but not R11-S24A inhibited agonists-stimulated Dab2-pSer24 and consequently suppressed platelet spreading on fibrinogen, with no effect on platelet aggregation and fibrinogen binding. Notably, Ser24 and the previously reported Ser723 phosphorylation (Dab2-pSer723) occurred exclusively in a single Dab2 molecule and resulted in distinctive subcellular distribution and function of Dab2. Dab2-pSer723 was mainly distributed in the cytosol of activated platelets and associated with integrin inside-out signaling, while Dab2-pSer24 was mainly distributed in the membrane fraction of activated platelets and associated with integrin outside-in signaling. Conclusions These findings demonstrate for the first time that Dab2-pSer24 is conservative in integrin αIIbβ3 outside-in signaling during platelet activation and plays a novel role in the control of cytoskeleton reorganization and platelet spreading on fibrinogen.

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Podoplanin promotes cancer-associated thrombosis and contributes to the unfavorable overall survival in an ectopic xenograft mouse model of oral cancer

Cited by 25 publications

References 47 publications

Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues

Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues

Sequential Circulating Tumor Cell Counts in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma: Monitoring the Treatment Response

Integrin αIIbβ3 outside-in signaling activates human platelets through serine 24 phosphorylation of Disabled-2

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