Role of ADP receptors on platelets in the growth of ovarian cancer.

Abstract:

:We investigated the effect of platelets on ovarian cancer and the role of adenosine diphosphate (ADP) receptors (P2Y12 and P2Y1) on platelets in the growth of primary ovarian cancer tumors. We showed that in murine models of ovarian cancer, a P2Y12 inhibitor (ticagrelor) reduced tumor growth by 60% compared with aspirin and by 75% compared with placebo. In P2Y12-/- mice, the growth of syngeneic ovarian cancer tumors was reduced by >85% compared with wild-type (WT) mice. In contrast, there was no difference in tumor growth between P2Y1-/- and WT mice. Reconstitution of hematopoiesis in irradiated P2Y12-/- mice by hematopoietic progenitor cells from WT mice (WT→P2Y12-/-) restored tumor growth in P2Y12-/- mice. Finally, knockdown of ecto-apyrase (CD39) on ovarian cancer cells increased tumor growth in tumor-bearing mice. Although in the absence of platelets, ADP, the P2Y12 inhibitor, recombinant apyrase, or knockdown of CD39 did not affect cancer cell proliferation, in the presence of platelets, the P2Y12 inhibitor and recombinant apyrase reduced and knockdown of CD39 increased platelet-enhanced cancer cell proliferation. These results suggest that P2Y12 on platelets and ADP concentration at the interface between cancer cells and platelets affect the growth of primary ovarian cancer tumors in mice. If additional studies in mice and in pilot human trials confirm our results, inhibition of P2Y12 might be a new therapeutic option that can be used in adjuvant to the traditional surgery and chemotherapy in patients with ovarian cancer.

journal_name

Blood

journal_title

Blood

authors

Cho MS,Noh K,Haemmerle M,Li D,Park H,Hu Q,Hisamatsu T,Mitamura T,Mak SLC,Kunapuli S,Ma Q,Sood AK,Afshar-Kharghan V

doi

10.1182/blood-2017-02-769893

subject

Has Abstract

pub_date

2017-09-07 00:00:00

pages

1235-1242

issue

10

eissn

0006-4971

issn

1528-0020

pii

blood-2017-02-769893

journal_volume

130

pub_type

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