Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Adv Exp Med Biol. 2020;1245:133-146. doi: 10.1007/978-3-030-40146-7_6.
The tumor microenvironment (TME) is rich in matrix components, growth factors, cytokines, and enzymatic modifiers that respond to changing conditions, to alter the fundamental properties of the tumor bed. Perlecan/HSPG2, a large, multi-domain heparan sulfate proteoglycan, is concentrated in the reactive stroma that surrounds tumors. Depending on its state in the TME, perlecan can either prevent or promote the progression of cancers to metastatic disease. Breast, prostate, lung, and renal cancers all preferentially metastasize to bone, a dense, perlecan-rich environment that is initially a "hostile" niche for cancer cells. Driven by inflammation, production of perlecan and its enzyme modifiers, which include matrix metalloproteinases (MMPs), sulfatases (SULFs), and heparanase (HPSE), increases in the reactive stroma surrounding growing and invading tumors. MMPs act upon the perlecan core protein, releasing bioactive fragments of the protein, primarily from C-terminal domains IV and V. These fragments influence cell adhesion, invasion, and angiogenesis. Sulfatases and heparanases act directly upon the heparan sulfate chains, releasing growth factors from reservoirs to reach receptors on the cancer cell surface. We propose that perlecan modifiers, by promoting the degradation of the perlecan-rich stroma, "flip the molecular switch" and convert the "hostile" stroma into a welcoming one that supports cancer dissemination and metastasis. Targeted therapies that prevent this molecular conversion of the TME should be considered as potential new therapeutics to limit metastasis.
肿瘤微环境（TME）富含基质成分、生长因子、细胞因子和酶修饰物，这些物质可以响应不断变化的条件，改变肿瘤床的基本特性。硫酸乙酰肝素蛋白聚糖 2（HSPG2）是一种大型、多结构域的硫酸乙酰肝素蛋白聚糖，集中在围绕肿瘤的反应性基质中。根据其在 TME 中的状态，硫酸乙酰肝素蛋白聚糖 2 可以阻止或促进癌症向转移性疾病的进展。乳腺癌、前列腺癌、肺癌和肾癌都优先转移到富含硫酸乙酰肝素蛋白聚糖 2 的骨骼中，骨骼是一种密集的、最初对癌细胞来说是“敌对”的环境。在炎症的驱动下，反应性基质中硫酸乙酰肝素蛋白聚糖 2 的产生及其酶修饰物（包括基质金属蛋白酶（MMPs）、硫酸酯酶（SULFs）和乙酰肝素酶（HPSE））增加。MMPs 作用于硫酸乙酰肝素蛋白聚糖 2 的核心蛋白，释放该蛋白的生物活性片段，主要来自 C 端结构域 IV 和 V。这些片段影响细胞黏附、侵袭和血管生成。硫酸酯酶和乙酰肝素酶直接作用于硫酸乙酰肝素链，将生长因子从储库中释放出来，到达癌细胞表面的受体。我们提出，硫酸乙酰肝素蛋白聚糖 2 修饰物通过促进富含硫酸乙酰肝素蛋白聚糖 2 的基质的降解，“翻转分子开关”，将“敌对”基质转化为支持癌症扩散和转移的有利基质。应该考虑将预防这种 TME 分子转化的靶向疗法作为限制转移的潜在新疗法。
