Deadly allies: the fatal interplay between platelets and metastasizing cancer cells

Abstract

The general notion that functional platelets are important for successful hematogenous tumor metastasis has been inaugurated more than 4 decades ago and has since been corroborated in numerous experimental settings. Thorough IntroductionMetastasis is the main cause of cancer-related death and a major challenge in today's cancer management. Although many new therapies against malignant tumors have been developed over the last years, the prognosis of most malignancies remains unfavorable, once metastatic spread has occurred. This challenge underlines the importance of understanding the details of metastasis to develop specific therapies to impede tumor dissemination.The highly complex process of hematogenous tumor cell spreading includes detachment of cancer cells from the primary site, migration into and transport along the bloodstream, and, finally, tumor cell arrest and proliferation within the distant tissue. Thus, survival of the tumor cells within the bloodstream and adhesion in the vasculature at the metastatic sites are crucial for tumor cell dissemination. There is a plethora of studies indicating that the interaction of tumor cells with platelets within the bloodstream is essential during this early phase of metastasis and that agents directed against specific platelet receptors involved in this process may give rise to new therapies for patients with a high risk of metastasis or for minimizing the risk of cancer cell dissemination during antitumor surgery. Platelets in hematogenous metastasisThe involvement of platelets and coagulation factors in hematogenous tumor metastasis has long been recognized. A relationship between venous thromboembolism and cancer has been observed at least since 1865, 1 and more recent studies have shown that the risk of a diagnosis of cancer is clearly elevated after primary deep venous thromboembolism or pulmonary embolism. 2 As a more direct evidence of platelet involvement in the development of malignant tumors, a relationship between elevated platelet count and malignant tumors was reported by Reiss et al in 1872. 3 So far, thrombocytosis or even platelet counts that are within the upper normal range have been shown to be associated with advanced, often metastatic, stages of cancer and to be a negative prognostic marker for many different tumor entities, including endometrial carcinoma, 4,5 cervical cancer, 6 ovarian cancer, 7 gastric cancer, 8 or esophageal cancer. 9 Clearly, it is difficult to differentiate whether elevated platelet levels actually constitute a predisposition toward a more aggressive disease per se. To our knowledge, there are no prospective studies evaluating the possible development of cancer and aggressive metastatic disease in initially healthy people with elevated platelet levels compared with people with low platelet counts. Although animal models certainly show a role for platelets in cancer metastasis, in patients it is harder to distinguish between a mere correlation between thrombocytosis and cancer and an actual causality. It seems most p...

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