Despite recent improvements, cancer treatment remains associated with several challenges. Cancer development is a multifactorial and multistep process and involves several genetic and epigenetic regulations. In addition, cancer cells possess several unique characteristics, also known as the cancer hallmark, that confer the cells with resistance against the human immune system and cancer treatment. The cancer hallmark includes tumor-promoting inflammation, enabling replicative immortality, avoiding immune destruction, evading growth suppressors, sustaining proliferative signaling, deregulating cellular energetics, resisting cell death, genome instability and mutation, inducing angiogenesis, and activating invasion and metastasis.^1,2 Metastasis, which is the major cause of death among cancer patients, involves multiple processes including extracellular matrix (ECM) remodeling and degradation. Degradation of the ECM is required for tumor cell metastasis; this is achieved by several proteinases such as the plasmin system and particularly, the matrix metalloproteinases (MMPs).^3–6 MMPs are known to play an important role in the tissue invasion and metastasis of cancer cells. The tissue inhibitors of MMPs (TIMPs) are endogenous inhibitors of MMPs, and regulation of MMPs by TIMPs is particularly important for the maintenance of the ECM. Disruption of the balance between the activities of MMPs and TIMPs during carcinogenesis may affect invasion and metastasis^7–9 and may worsen patient outcomes.¹⁰ TIMP-3, a member of the TIMP family, is a 24-kDa secreted glycoprotein, and its gene is located on chromosome 22q12.1–q13.2. Knockout of the TIMP-3 gene in mice resulted in increased MMP, a disintegrin and MMPs with thrombospondin motifs (ADAMTS) activity, and cartilage degradation, suggesting that reduced TIMP-3 levels may cause osteoarthritis.¹¹ In addition, the absence of TIMP-3 leads to poor cardiac remodeling and has been associated with myocardial infarction or hypertension.^12,13 In cancer studies, TIMP-3 plays an important role in the cancer hallmark by controlling cell death, angiogenesis, tumor inflammation, and tumor cell invasion and dissemination.¹⁴ For instance, TIMP-3 restoration in cancer cells inhibits cell growth and promotes cell apoptosis.^15,16 In addition, TIMP-3 overexpression improves the sensitivity of osteosarcoma to clinical drug treatment through interleukin (IL)-6 inhibition.¹⁷ TIMP-3 also acts as a potential antiangiogenesis agent by inhibiting endothelial cell tube formation.¹⁸ Moreover, TIMP-3 can inhibit cancer cell migration, invasion, and metastasis in vitro and in vivo.^19,20 Clinical studies have reported reduced TIMP-3 expression in cases of several cancer types compared with normal controls;^19–22 the loss of TIMP-3 may lead to poor outcomes, including large tumor size, high tumor stage, and metastasis.^23–25 Herein, we review the structure and function of TIMP-3 and discuss its contribution to carcinogenesis and its potential in cancer therapy.

中文翻译：

---

TIMP-3作为癌症的治疗靶标

尽管最近有所改善，但是癌症治疗仍然面临着一些挑战。癌症的发展是一个多因素，多步骤的过程，涉及多个遗传和表观遗传学规定。另外，癌细胞具有几个独特的特征，也称为癌症标志，赋予细胞对人类免疫系统和癌症治疗的抵抗力。癌症的标志包括促进肿瘤的炎症，使复制永生，避免免疫破坏，逃避生长抑制剂，维持增殖信号传导，放松细胞能量，抵抗细胞死亡，基因组不稳定和突变，诱导血管生成以及激活侵袭和转移。^1,2转移是癌症患者死亡的主要原因，转移涉及多个过程，包括细胞外基质（ECM）重塑和降解。肿瘤细胞转移需要ECM降解；这可以通过多种蛋白酶（例如纤溶酶系统，尤其是基质金属蛋白酶（MMP））来实现。已知^3–6 MMP在癌细胞的组织侵袭和转移中起重要作用。MMPs（TIMPs）的组织抑制剂是MMPs的内源性抑制剂，而TIMPs对MMPs的调节对于维持ECM尤为重要。致癌过程中MMP和TIMP活性之间平衡的破坏可能会影响浸润和转移^7-9并可能使患者预后恶化。¹⁰TIMP-3是TIMP家族的成员，是一种24 kDa分泌的糖蛋白，其基因位于22q12.1–q13.2染色体上。所述的敲除TIMP-3在小鼠基因导致增加的MMP，解联蛋白和基质金属蛋白酶与血小板反应蛋白基序（ADAMTS）活性，和软骨退化，这表明减少TIMP-3的水平可能会导致骨关节炎。¹¹此外，缺乏TIMP-3会导致心脏重塑不良，并与心肌梗塞或高血压有关。^12,13在癌症研究中，TIMP-3通过控制细胞死亡，血管生成，肿瘤炎症以及肿瘤细胞的侵袭和扩散而在癌症标志中发挥重要作用。¹⁴例如，癌细胞中TIMP-3的恢复抑制细胞生长并促进细胞凋亡。^15,16此外，TIMP-3的过表达通过白介素（IL）-6的抑制作用提高了骨肉瘤对临床药物治疗的敏感性。¹⁷ TIMP-3还通过抑制内皮细胞管形成而充当潜在的抗血管生成剂。¹⁸此外，TIMP-3能抑制癌细胞的迁移，侵袭和转移的体外和体内。^19,20临床研究报告，与正常对照相比，几种癌症类型的TIMP-3表达降低；^19-22TIMP-3的丢失可能导致不良结果，包括大肿瘤，高肿瘤分期和转移。^23–25本文中，我们回顾了TIMP-3的结构和功能，并讨论了其对致癌作用的贡献及其在癌症治疗中的潜力。