Paraneoplastic Thrombocytosis in Ovarian Cancer

Abstract

BACKGROUND The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear. METHODS We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained. RESULTS Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumor-derived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti–interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis. CONCLUSIONS These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. (Funded by the National Cancer Institute and others.)

Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation

“…(31) In contrast, solid tumors enhance hepatic thrombopoietin synthesis by releasing thrombopoietic cytokines, whereas more aggressive tumors induce a greater degree of thrombocytosis. (7,32) Accordingly, parenchymal liver disease status and tumor biology were significantly different between the 2 groups in this study. Because some determinants of PLT are also contributors to posttransplant outcomes, the success of the study mainly depends on determining whether or not the PLT is an epiphenomenon.…”

Antitumor effect of antiplatelet agents in gastric cancer cells: an in vivo and in vitro study

“…Although aspirin did not inhibit tumor cell growth in the absence of platelets, it did inhibit the proliferative effect of platelets. Thrombocytosis is common in patients with advanced tumors [7,17], and it is thought that the paraneoplastic increase in platelet count can promote tumor growth. Indeed, among 260 patients with T2-4 gastric cancer who underwent gastrectomy in our hospital, patients with platelet counts over 250,000/ll showed significantly poorer survival compared to those with platelet counts under 250,000/ll (data not shown).…”

“…Paraneoplastic thrombocytosis is observed in 10-57 % of patients with cancer, and elevated platelet counts can lead to cancer progression and metastasis [6,7]. Suppressing platelet activity may improve outcomes in patients with cancer.…”

“…This antitumor effect is considered to be driven by the inhibition of cyclooxygenase-2 (COX-2), which is overexpressed in cancer cells [10,11], or by platelet adhesion to tumor cells, the latter of which is essential for preventing immune surveillance by natural killer cells [12]. Stone et al proposed that the paracrine signal pathway mediates paraneoplastic thrombocytosis in ovarian cancer [7]; interleukin-6 secreted from cancer cells stimulates hepatic thrombopoietin production, which could promote thrombocytosis. However, it is not known whether reducing platelet counts is effective in tumor suppression or which functions of aspirin have antitumor activity in gastric cancer cells.…”

Colorectalis daganatokban a 2-es típusú cukorbetegség és a thrombocytosis előfordulása, a túlélésre gyakorolt hatásuk, a primer tumor műtéti eltávolítása előtt és után

“…A CRC-betegek jelentős többségénél emelkedik a thrombocyták száma, thrombocytosis alakul ki [12,[41][42][43], melynek hátterében több feltételezett mechanizmus állhat [15,44]. A T2DM-ről is ismert, hogy a betegség progressziója során a thrombocyták diszfunkciója alakul ki [45][46][47][48].…”