{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSpondin‑2 (also known as mindin) is a secreted extracellular matrix protein with a multifaceted role in immune regulation. Its amino‐terminal F‑spondin (FS) domain mediates integrin binding, thereby facilitating efficient T‑cell priming by dendritic cells, whereas its carboxy‑terminal thrombospondin type‑1 repeat (TSR) domain recognizes pathogen components such as lipopolysaccharide to trigger innate immune responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin the tumor microenvironment, Spondin‑2 displays context‑dependent functions. In hepatocellular carcinoma (HCC), for instance, it promotes the recruitment of M1‑like macrophages via distinct integrin signaling pathways that activate RhoA/Rac1 and influence F‑actin reorganization and Hippo pathway components—processes shown to suppress metastasis and be upregulated by thyroid hormone."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "4"}]}, {"type": "t", "text": " In contrast, in colorectal and gastric cancers, elevated Spondin‑2—sometimes induced by oncogenic transcription factors like MACC1—enhances cell viability, migration, invasiveness, and metastatic spread via activation of signaling cascades including NF‑κB, Rho‑GTPases, and the PI3K/AKT/mTOR pathway; its high expression is associated with advanced disease stages and poorer patient outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "12"}]}, {"type": "t", "text": " Moreover, in lung adenocarcinoma and clear cell renal cell carcinoma, Spondin‑2 similarly contributes to tumor aggressiveness and metastatic potential."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOutside the realm of oncology, Spondin‑2 is implicated in diverse pathological processes involving tissue remodeling and inflammatory responses. It exerts protective effects in vascular biology by suppressing abnormal vascular smooth muscle cell proliferation and migration, thus mitigating neointima formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Elevated levels have also been observed in metabolic and renal pathologies—being upregulated in high‑calorie diet models and correlating with podocyte injury in diabetic nephropathy"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "—while decreased serum concentrations have been linked to early‐stage bronchial asthma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " In prostate cancer, Spondin‑2 promotes osteomimicry and bone metastasis through ERK1/2 and PI3K/AKT/mTOR signaling pathways"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ", and pan‑cancer evaluations indicate its emerging value as a prognostic biomarker."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " Furthermore, studies in cardiac hypertrophy have implicated mindin in the inhibition of angiogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yili Li, Chunzhang Cao, Wei Jia, et al. 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