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

Min Soon Cho, Kyunghee Noh, Monika Haemmerle, Dan Li, Hyun Park, Qianghua Hu, Takeshi Hisamatsu, Takashi Mitamura, Sze Ling Celia Mak, Satya Kunapuli, Qing Ma, Anil K. Sood and Vahid Afshar-Kharghan

Key points

  • P2Y12 is important in the interaction between platelets and cancer cells.

  • P2Y12 inhibitor or P2Y12 deficiency reduces tumor growth in murine models of ovarian cancer.

Abstract

We investigated the effect of platelets on ovarian cancer, and role of ADP receptors (P2Y12 and P2Y1) on platelets in the growth of primary ovarian cancer tumors. We showed that in murine models of ovarian cancer, P2Y12 inhibitor (Ticagrelor) reduced tumor growth by 60% compared to aspirin and 75% compared to placebo. In P2Y12-/- mice, the growth of syngeneic ovarian cancer tumors was reduced by >85% compared to WT mice. On the other hand, there was no difference in the 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. While in the absence of platelets, ADP, P2Y12 inhibitor, recombinant apyrase, or knockdown of CD39 did not affect cancer cell proliferation; in the presence of platelets, P2Y12 inhibitor and recombinant apyrase reduced, and knockdown of CD39 increased platelet-enhanced cancer cell proliferation. These results suggested that P2Y12 on platelets and ADP concentration at the interface between cancer cells and platelets affected 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.

  • Submitted February 24, 2017.
  • Accepted June 15, 2017.