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Cell Rep. 2018 Apr 17;23(3):808-822. doi: 10.1016/j.celrep.2018.03.092.

Platelets Promote Metastasis via Binding Tumor CD97 Leading to Bidirectional Signaling that Coordinates Transendothelial Migration.

Author information

1
Laboratory of Genitourinary Cancer Pathogenesis, NCI, Bethesda, MD 20892, USA.
2
Laboratory of Cancer Biology and Genetics, NCI, Bethesda, MD 20892, USA.
3
Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
4
Center for Advanced Preclinical Research, NCI, Frederick, MD 21702, USA.
5
Molecular Biology and Genetics Section, NIDDK, Bethesda, MD 20892, USA.
6
Depatment of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA.
7
Laboratory of Genitourinary Cancer Pathogenesis, NCI, Bethesda, MD 20892, USA. Electronic address: kellyka@mail.nih.gov.

Abstract

Tumor cells initiate platelet activation leading to the secretion of bioactive molecules, which promote metastasis. Platelet receptors on tumors have not been well-characterized, resulting in a critical gap in knowledge concerning platelet-promoted metastasis. We identify a direct interaction between platelets and tumor CD97 that stimulates rapid bidirectional signaling. CD97, an adhesion G protein-coupled receptor (GPCR), is an overexpressed tumor antigen in several cancer types. Purified CD97 extracellular domain or tumor cell-associated CD97 stimulated platelet activation. CD97-initiated platelet activation led to granule secretion, including the release of ATP, a mediator of endothelial junction disruption. Lysophosphatidic acid (LPA) derived from platelets induced tumor invasiveness via proximal CD97-LPAR heterodimer signaling, coupling coincident tumor cell migration and vascular permeability to promote transendothelial migration. Consistent with this, CD97 was necessary for tumor cell-induced vascular permeability in vivo and metastasis formation in preclinical models. These findings support targeted blockade of tumor CD97 as an approach to ameliorate metastatic spread.

KEYWORDS:

CD97; LPA; adhesion GPCR; circulating tumor cells; metastasis; platelets; transendothelial migration

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