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.
TITLE: Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer
AUTHOR CONTACT:
Olivier Peyruchaud
INSERM Research Unit 403, Université Claude Bernard Lyon 1, Lyon, France.
Phone: 33-478-78-57-38; Fax: 33-478-77-86-63; E-mail: peyruchaud@lyon.inserm.fr.
A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1714.
ACCOMPANYING COMMENTARY:
TITLE: Platelets and metastasis revisited: a novel fatty link
AUTHOR CONTACT:
Joan Massagué
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: 212-639-8975; Fax: 212-717-3298; E-mail: j-massague@ski.mskcc.org.
A PDF of this article is available at: http://www.jci.org/cgi/content/full/114/12/1691.
Journal
Journal of Clinical Investigation