Assistant Professor of Medicine and Molecular Therapeutics Research Program Medical Director Dr. Deborah Ornstein focused on new findings in coagulation and cancer as part of Grand Rounds at DHMC last Thursday. She emphasized that platelets, tiny, anuclear cells essential for blood clot formation, are powerfully associated with cancer parthenogenesis.
Platelets, or thrombocytes, congregate at the site of a wound, where they release clotting factors and recruit other cells. However, these oblong cells are much more than “little bags of clotting factors” according to Ornstein. Her discussion aimed to explain the relationship between clotting, or thrombosis, with cancer cell proliferation and metastasis. The first half of her lecture focused on the risk of vascular thromboembolism in chemotherapy patients. Targeting these patients for prevention is important, because certain individuals undergoing chemotherapy have elevated risk of developing thromboembolism, when a clot migrates through the body and obstructs vital blood vessels.
Citing a clinical study from Vienna that sought to identify biomarkers that predict chemotherapy-associated thrombosis, Ornstein explained that patients with elevated levels of p-selectin, an adhesion molecule on the surface of activated platelets, are at considerably higher risk for thrombosis. The primary predictive biomarker, Ornstein emphasized, is thrombin, which catalyzes the formation of fibrin, a vital clotting protein.
The second half of Ornstein’s lecture focused on the complementary relationship – how coagulation relates to cancer growth and metastasis. She spoke of a 1930 study in which tumor cells were soaked in heparin, an anticoagulant, and introduced into mice. After three months, there was no observable tumor growth in the heparin mice, while control mice injected with saline-soaked tumor cells universally developed tumors.
Further studies confirmed the efficacy of adding anticoagulation treatments to chemotherapy, particularly in small cell lung cancers. The survival curve, a measure of how many patients remain alive after a certain time, was pushed out noticeably in small-cell lung cancer patients treated with warfirin and heparin. Despite the results, many professionals dismissed the results as a fluke, and the benefits of anticoagulation treatments continued to be hotly debated.
Undeniable, however, are the molecular mechanisms at the basis of the coagulation-cancer connection. Some tumor types express tissue factor on their cell surfaces, which initiates a pathway resulting in the formation of thrombin and fibrin. Not only does fibrin produce an excellent scaffolding for tumor cells, it also aids the development of collateral vessels that feed the cancer. Further, the thrombin receptors that have also been discovered on cancer cells indicate a role in cancer’s growth and metastasis program. Thrombin also stimulates platelets to release their cargo granules, which include metastasis-inducing factors.
Ornstein concluded with an explanation of her own research advancing the relationship between platelets and ovarian cancer. When ovarian cancer cells in her lab were exposed to platelets at varying concentrations, they invaded their environment through membranes at an advanced rate proportional to the platelet concentration. When platelet function is inhibited, fewer tumor cells invade. As Ornstein commented in her final remarks, “it has become clear that the relationship between coagulation and cancer is a two-way street, but much work remains to clarify exactly the extent of their association.”