Platelets and Cancer: Friend or Foe?
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationships relevant to this field of study.
Synopsis: Paraneoplastic thrombocytosis is supported by a paracrine circuit initiated by tumor-derived cytokines and is responsible for poor survival in ovarian cancer patients. Amelioration of these factors through targeted agents may provide a new avenue of systemic therapy for these patients.
Source: Stone RL, et al. Paraneoplastic thrombocytosis in ovarian cancer. New Engl J Med 2012;366:610-618.
It has been long recognized that thrombocytosis (defined as a platelet count > 450,000/mm3) frequently accompanies the diagnosis of advanced cancer and has been associated with poor outcomes. How platelets illicit this effect is not well understood and was systematically explored in this study. Clinical data from 619 patients with epithelial ovarian cancer were interrogated to explore the relationship between platelet counts and disease outcome. In addition, human samples and mouse models of epithelial ovarian cancer were investigated to clarify the underlying mechanisms of paraneoplastic thrombocytosis, including the effects of platelets on tumor growth and angiogenesis. The authors found that thrombocytosis was a common phenomena of patients presenting with ovarian cancer, occurring in nearly one-third. Thrombocytosis was significantly associated with advanced disease and shortened survival. In addition, plasma levels of thrombopoietin and interleukin-6 were significantly elevated in these patients and strongly correlated with thrombocytosis.
To determine the origin and temporal relationship of these factors on the tumor phenotype, mouse models of ovarian cancer were studied. In these models, increased hepatic thrombopoietin synthesis occurred in response to interleukin-6, which was specifically derived from ovarian tumors. Blocking these factors, either exogenously or via genetic manipulation of the murine model, reversed thrombocytosis. This was associated with reduced tumor growth. In addition, neutralizing interleukin-6 in mouse models of epithelial ovarian cancer significantly enhanced the therapeutic efficacy of paclitaxel. Of interest, these platelets were found to preferentially localize in tumors (as compared to peritoneum or areas of inflammation). Treatment with an antiplatelet antibody (dosed to reduce platelet counts by 50%) was associated with significantly reduced tumor growth and angiogenesis. Similarly, patients treated with the anti-interleukin-6 antibody, siltuximab, in an ongoing Phase 1/2 clinical trial, demonstrated significantly reduced platelet counts. These novel findings strongly support the existence of a feed-forward paracrine circuit driven by tumor-derived interleuin-6, which subsequently drives hepatic production of thrombopoietin promoting thrombocytosis and tumor infiltration of secretory platelets. Understanding this mechanism may now lead to rationally targeted therapy approaches for women with ovarian cancer.
It is estimated that as many as 40% of patients who present with asymptomatic thrombocytosis in the absence of iron deficiency anemia or benign inflammatory conditions will be diagnosed with cancer. Similarly, as many as 25% of patients presenting with a vascular thrombotic event (VTE), without an antecedent history, will be diagnosed with a malignancy.1 The relationship is not new; the prognostic impact has been well known for more than a century (Trousseau, 1867). However, the mechanism underlying these observations is not well understood. Previously, platelets have been suspected as promoting cancer progression through, among others, tumor cell immune escape, stimulation of angiogenesis, and prevention of tumor cell apoptosis. The current report provides new evidence as to "why" the condition exists and, perhaps more importantly, "how" the paraneoplastic cycle may be disrupted. The latter appears to lead to tumor regression in animal models, and, as such, a new modality of cancer therapy. Indirect clinical observations already support the merit of this contention. For instance, the use of low molecular-weight heparin improves survival among patients with cancer, independently of morbidity/mortality associated with VTE.2 In addition, daily aspirin use among patients with colorectal cancer is associated with decreased all-cause and cancer-specific mortality.3 Nevertheless, much more work is necessary to clearly understand how abrogation of these effectors will impact outcome and toxicity for women with ovarian cancer.
- Hettiarachchi RJ, et al. Undiagnosed malignancy in patients with deep vein thrombosis: Incidence, risk indicators, and diagnosis. Cancer 1998;83:180-185.
- Akl EA, et al. Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation. Cochrane Database System Review CD006652; 2007.
- Chan AT, et al. Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009;302:649-658.