Dec. 31, 2004 Malignant tumors have the ability to transfer disease from organ to another. The depletion of blood platelets by many mechanisms has been shown to result in a reduction of metastases to lung and bone in experimental tumor transplant models. This effect has long been attributed to platelet-mediated enhancement of tumor cell survival and tumor cell escape from the blood into the surrounding tissue, as well as the development of new blood vessels to support tumor growth. In the December 15 issue of the Journal of Clinical Investigation, Olivier Peyruchaud and colleagues from Université Claude Bernard Lyon, France, describe two additional roles of platelets in the metastasis of breast and ovarian cancer cells to the bone. They show that platelets act as: (i) a direct source of lysophosphatidic acid (LPA), which promotes tumor cell division; and (ii) indirect activators of bone breakdown.
The authors demonstrate in mice that tumor cells encourage platelet aggregation and activation and the subsequent release from platelets of LPA. LPA causes tumor cells to release the immune cell–growth stimulants IL-6 and IL-8 into the bone marrow, causing bone breakdown to exceed bone formation. Treatment of these mice after initial bone metastasis with Intergrilin, an inhibitor of platelet aggregation, resulted in decreased circulating LPA levels and a significant reduction in bone metastasis formation. However the authors did not interfere specifically with LPA signaling, leaving open the possibility that this anti-metastatic effect could be due to an LPA-independent pathway.
These findings in addition to other data suggest that platelet inhibition may slow the rate of tumor progression and metastasis. However to date, clinical trials of the antiplatelet agents aspirin and heparin have yielded inconclusive, albeit promising, evidence that platelet inhibition may enhance the survival of cancer patients. One major reason for the difficulty in translating these results into effective anticancer therapies is the need to consider the important role that platelets play in arresting bleeding, for example in the event of a nosebleed or following injury or surgery.
In an accompanying commentary, Gaorav Gupta and Joan Massagué from Memorial Sloan-Kettering Cancer Center in New York discuss the implications of this study. These authors remind us that "cancer patients receiving cytotoxic chemotherapy who suffer from bleeding due to platelet toxicity are regularly transfused with large numbers of platelets from healthy donors." Leading us to question "[is] this life-saving therapy…simultaneously facilitating metastasis of their cancerous cells?" Gutpa and Massagué stress that any effective therapies that modulate platelet activity will need to be specific for the pathological tumor cell–platelet interaction, without effecting normal platelet function. Platelet-specific integrin inhibitors like Integrilin fall into this category. The study also suggests that drug-mediated inhibition of platelet-derived LPA and LPA receptors present on tumor cells may be another promising target for reducing or preventing bone metastasis.
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