Abstract
Cancer prognosis is poor for patients with blood-borne metastasis. Platelets are known to assist cancer cells in transmigrating through the endothelium, but ligands for the platelet-mediated cancer metastasis remain poorly defined. von Willebrand factor (vWF) is a major platelet ligand that has been widely used as a biomarker in cancer and associated inflammation. However, its functional role in cancer growth and metastasis is largely unknown. Here we report that gastric cancer cells from patients and cells from two well-established gastric cancer lines express vWF and secrete it into the circulation, upon which it rapidly becomes cell-bound to mediate cancer-cell aggregation and interaction with platelets and endothelial cells. The vWF-mediated homotypic and heterotypic cell–cell interactions promote the pulmonary graft of vWF-overexpressing gastric cancer BGC823 cells in a mouse model. The metastasis-promoting activity of vWF was blocked by antibodies against vWF and its platelet receptor GP Ibα. It was also reduced by an inhibitory siRNA that suppresses vWF expression. These findings demonstrate a causal role of cancer-cell-derived vWF in mediating gastric cancer metastasis and identify vWF as a new therapeutic target.
Highlights
Metastasis is a major cause of cancer-related death, and its prevention is a significant challenge for efficient cancer treatments[1]
While no difference was found between patients with lymph node metastasis and without, the plasma levels of von Willebrand factor (vWF) were higher in patients with muscle-invasive cancer than in those with serosa-invasive cancer or peritoneal disseminated cancer (Fig. 1c). vWF was higher in patients with late stages III or IV of cancer based on the TNM classification[29], than in those with early stages I or II (Fig. 1d)
We have studied blood and tissue samples from gastric cancer patients and conducted experiments in vitro and in mouse models to investigate the role of vWF in regulating cancer metastasis
Summary
Metastasis is a major cause of cancer-related death, and its prevention is a significant challenge for efficient cancer treatments[1]. Platelets play a key role in cancer development and metastasis[2] and are often regarded as a “death ally” of cancer[1]. Cancer cells from multiple origins stimulate platelets to produce platelet-derived growth factor and matrix metalloprotease 2 to propagate inflammation[3]. They have been widely reported to secrete platelet agonists such as adenosine diphosphate[4] and (vWF) is one of the major platelet adhesion ligands that could potentially regulate cancer development and metastasis. It tethers circulating platelets to the subendothelial matrix exposed at the site of vascular injury, but it promotes platelet adhesion to endothelial cells in disease states[12]
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