Thrombin Cleavage of Osteopontin and the Host Anti-Tumor Immune Response

Abstract

Osteopontin (OPN) is a multi-functional protein that is involved in various cellular processes such as cell adhesion, migration, and signaling. There is a single conserved thrombin cleavage site in OPN that, when cleaved, yields two fragments with different properties from full-length OPN. In cancer, OPN has tumor-promoting activity and plays a role in tumor growth and metastasis. High levels of OPN expression in cancer cells and tumor tissue are found in various types of cancer, including breast, lung, prostate, ovarian, colorectal, and pancreatic cancer, and are associated with poor prognosis and decreased survival rates. OPN promotes tumor progression and invasion by stimulating cell proliferation and angiogenesis and also facilitates the metastasis of cancer cells to other parts of the body by promoting cell adhesion and migration. Furthermore, OPN contributes to immune evasion by inhibiting the activity of immune cells. Thrombin cleavage of OPN initiates OPN’s tumor-promoting activity, and thrombin cleavage fragments of OPN down-regulate the host immune anti-tumor response.

Obesity modulates the cellular and molecular microenvironment in the peritoneal cavity: implication for ovarian cancer risk

“…SPP1 activates signaling cascades via binding to integrins or CD44; these pathways upregulate the expression of pro-survival genes, enhance proliferation, migration, progression, metastasis, angiogenesis ( 76 ) and adhesion via increasing CD44 and Integrin B1 expression ( 77 ). Receptor activation by SPP1 in immune cells affects cytokine production, immune cell differentiation and function, communication between the adaptive and innate immune system, and acts as an immune checkpoint to suppress the anti-cancer immune cell activity ( 78 ). Spp1 was elevated by both the HFD and the cancer cells in the OFB; the HFD also elevated the cancer-mediated increase in Spp1 expression in the OFB and, to a lesser extent, in the pmWAT and rpWAT.…”

Dynamics of Matricellular Protein Levels in Blood Predict Recovery in Patients with Human Immunodeficiency Virus-Tuberculosis Coinfection

“…The C-terminal domain of OPN binds to CD44 and induces macrophage chemotaxis, and a non-overlapping N-terminal OPN domain binds to beta(3)-integrin receptors and induces cell spreading and subsequent activation [44]. Very recently, it was proposed that the thrombin cleavage of OPN facilitates tumor progression and suppresses host anti-tumor immune responses [45]. Both cleaved and FL-OPN levels are elevated in the blood of various infectious diseases [14].…”

Preliminary Study of the Relationship between Osteopontin and Relapsed Hodgkin’s Lymphoma

“…Notably, thrombin has been shown to cleave SPP1 and secrete a specific SPP1 isoform (known as osteopontin-R), which contains domains for interacting with various integrin and CD44 receptors present on immune cells such as dendritic cells, mast cells, T cells, and neutrophils, thereby triggering an immune response in these cells [19]. Furthermore, through the use of alternative translation start sequences and splice mutations, SPP1 exists in an intracellular form (iOPN) that is involved in several cellular functions such as migration, fusion, and proliferation [20][21][22][23]. In particular, the OPN-c variant has been implicated in breast tumor metastasis, where it appears to be unable to anchor to the extracellular matrix [24].…”