Post-Resection Exhaustion of Intra-Platelet Serotonin: Also an Indicator of Early Hepatocellular Carcinoma Recurrence?

Abstract

Purpose: Serotonin (5-hydroxytryptamine, 5-HT) is well known for its growth stimulatory effect on several types of carcinoma and tumor cells. Since a large portion of 5-HT is stored and transported by platelets, the aim of this study was to assess the influence of platelet-sequestered 5-HT on post-resection hepatocellular carcinoma (HCC) recurrence.Methods: This pilot study was conducted in a cohort of forty patients diagnosed with HCC undergoing partial hepatectomy. 5-HT levels in serum, plasma and intra-platelet (IP) were monitored preoperatively and four weeks after liver resection. The patients were followed every three months after the surgery.Results: Follow-up was standardized to a fixed length of time. Fifteen patients (37.5%) developed HCC recurrence during 18 months follow-up. Patients with recurrence had significantly reduced serum and IP 5-HT levels at four weeks of liver resection (P = 0.003 and P = 0.014 respectively). Accordingly, in the Cox regression hazard model, serum and IP 5-HT were able to independently predict the recurrence (hazard ratio = 0.1, 95% confidence interval = 0.01 - 0.75 and hazard ratio = 0.1, 95% confidence interval = 0.01 - 0.89 respectively). The optimal cut-off value of 42.77 ng/ml for serum [area under the curve (AUC): 0.78, P = 0.003] and 0.3117 ng per 106 platelets (AUC: 0.733, P = 0.015), on receiver operating characteristic (ROC) curve corresponded to maximum sensitivity and specificity of prediction. The disease free interval was significantly worse in patients with low serum and IP 5-HT (P = 0.001 and P = 0.029 respectively).Conclusion: IP 5-HT monitored during early follow-up, after liver resection may represent a useful marker of early HCC recurrence.

Deciphering Platelet Kinetics in Diagnostic and Prognostic Evaluation of Hepatocellular Carcinoma

“…In patients who underwent hepatic resection, the presence of a lower level caused a 0.67-fold increase in the risk of overall mortality and a 0.44-fold increase in the risk of disease-free death in comparison with a higher level [ 28 ]. In our previous study, we also observed the postresection depletion of platelet count in patients who developed early HCC recurrence [ 29 ].…”

“…Deb et al observed depleted IP serotonin in patients with cervical cancer and found that platelets from cancer patients released more serotonin on thrombin stimulation than the control group [ 46 ]. In a homogenous prospective cohort of patients with HCC, we found a postresection exhaustion of IP serotonin was able to predict early HCC recurrence [ 29 ]. The study conducted by Padickakudy et al, with a highly standardized preparation of platelet, and our study, however, referred to different postresection time points; the former study monitored IP serotonin during early postoperative period whereas we measured it after 4 weeks of liver resection.…”

Predictive Value of Diminished Serum PDGF-BB after Curative Resection of Hepatocellular Cancer

“…Platelet-stored PDGF-BB is easily available for the tumor and surrounding stroma[14]; thus sPDGF-BB reflects the magnitude of proangiogenic influence related to the growth factor. Platelet dysfunction is already a known phenomenon in cancer progression; platelets hyperactivity and platelet exhaustion are frequently seen in cancer patients[17–20]. We previously observed exhaustion of IP serotonin in patients with early cancer recurrence[17]; likewise, we speculated that the depleted sPDGF-BB might attribute to the platelet exhaustion; however, we observed a weak trend with total platelet (IP) PDGF-BB.…”

The “Janus Face” of Platelets in Cancer

“…Concerning the pro-angiogenic effect, the mutual influence of platelets and tumor cells also is not fully determined. A recent study performed on twenty-four women with active breast cancer and ten healthy controls showed that breast cancer and its chemotherapeutic treatment influence platelet phenotype, by increasing VEGF release and modulating the response to antiplatelet therapy [119]. Noticeably, an autocrine-paracrine loop, occurring in the bone marrow microenvironment and involving VEGFR-1-dependent megakaryocyte maturation has been documented [120].…”