Abstract Number: OC 58.3
Meeting: ISTH 2021 Congress
Background: Osteopontin (OPN), a circulating pleiotropic matricellular protein, is highly expressed in cancer with a thrombin cleavage site (at Arg168 in human and Arg153 in mouse) in OPN that when cleaved exposes a previously cryptic α4β1 and α9β1 integrin-binding site at the new C-terminus. Thrombin-cleaved OPN-Arg (OPN-R) has enhanced α4β1-dependent cell-binding activity, that is abolished when the C-terminal arginine is cleaved by carboxypeptidase N, or thrombin-activatable carboxypeptidase B2, converting it to OPN-Leu (OPN-L). Elevated OPN-R and OPN-L levels are present in inflammatory arthritis joint fluid, and cerebral spinal fluid in glioblastoma, demonstrating that these cleavages occur in vivo.
Aims: Define source of OPN and role of its cleavage products.
Methods: Comparison of the thrombin-resistant OPN-knock in (KI) mouse (substitutiion of Arg153 with alanine (OPNR153A) with wild type and OPN deficient mice (OPN-KO) in a melanoma models.
Results: OPN-KI and OPN-KO mice significantly suppressed tumor growth and pulmonary metastasis. OPN production by B16 cells is undetectable but YUMM3.1 melanoma cells express it but do not show tumor suppression in OPN-KI mice. In WT mice, thrombin inhibition with dabigatran replicated tumor suppression in both B16 (Fig. 1) and YUMM3.1 lines showing that the source of the OPN for generation of the thrombin fragments can be either host or tumor. Tumor suppression depends on macrophages shown by the elimination of the phenotype in immune deficient NOG-OPN-KI mice or by macrophage depletion with clodronate in WT mice. Tumor-associated macrophages (TAMs) were increased in tumors from OPN-KO and OPN-KI mice, with a switch from tumor-promoting M2 macrophages to TAMs with a different activation profile (Fig. 2).
Conclusions: This is a new molecular link in the crosstalk between thrombosis, inflammation and immunity, defining the role of OPN in cancer progression. Thrombin cleavage of OPN initiates OPN’s tumor-promoting activity in vivo (Fig. 2I). Its significance may not be limited to cancer.
To cite this abstract in AMA style:Peraramelli S, Zhou Q, Zhou Q, Wanko B, Leung TH, Mizuno S, Ito M, Myles T, Stulnig TM, Morser J, Leung LL. The Tumor Promoting Activity of Osteopontin Is Solely Dependent on its Cleavage by Thrombin [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/the-tumor-promoting-activity-of-osteopontin-is-solely-dependent-on-its-cleavage-by-thrombin/. Accessed January 21, 2022.
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