Thrombin cleavage of osteopontin initiates osteopontin’s tumor‐promoting activity Academic Article uri icon

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abstract

  • Background

    Osteopontin (OPN) is a multifunctional proinflammatory matricellular protein overexpressed in multiple human cancers and associated with tumor progression and metastases. Thrombin cleavage of OPN reveals a cryptic binding site for α4 β1 and α9 β1 integrins.

    Methods

    Thrombin cleavage-resistant OPNR153A knock-in (OPN-KI) mice were generated and compared to OPN deficient mice (OPN-KO) and wild type (WT) mice in their ability to support growth of melanoma cells. Flow cytometry was used to analyze tumor infiltrating leukocytes.

    Results

    OPN-KI mice engineered with a thrombin cleavage-resistant OPN had reduced B16 melanoma growth and fewer pulmonary metastases than WT mice. The tumor suppression phenotype of the OPN-KI mouse was identical to that observed in OPN-KO mice and was replicated in WT mice by pharmacologic inhibition of thrombin with dabigatran. Tumors isolated from OPN-KI mice had increased tumor-associated macrophages with an altered activation phenotype. Immunodeficient OPN-KI mice (NOG-OPN-KI) or macrophage-depleted OPN-KI mice did not exhibit the tumor suppression phenotype. As B16 cells do not express OPN, thrombin-cleaved fragments of host OPN suppress host antitumor immune response by functionally modulating the tumor-associated macrophages. YUMM3.1 cells, which express OPN, showed less tumor suppression in the OPN-KI and OPN-KO mice than B16 cells, but its growth was suppressed by dabigatran similar to B16 cells.

    Conclusions

    Thrombin cleavage of OPN, derived from the host and the tumor, initiates OPN's tumor-promoting activity in vivo.

authors

  • Peraramelli, Sameera
  • Zhou, Qi
  • Zhou, Qin
  • Wanko, Bettina
  • Zhao, Lei
  • Nishimura, Toshihiko
  • Leung, Thomas H
  • Mizuno, Seiya
  • Ito, Mamoru
  • Myles, Timothy
  • Stulnig, Thomas M
  • Morser, John
  • Leung, Laurence

publication date

  • May 2022