Depau Lorenzo, Brunetti Jlenia, Falciani Chiara, Mandarini Elisabetta, Zanchi Marta, Paolocci Maria Francesca, Garfì Marta, Pini Alessandro, Bracci Luisa
Department of Medical Biotechnologies, University of Siena, Siena, Italy.
Front Cell Dev Biol. 2025 Jan 8;12:1505680. doi: 10.3389/fcell.2024.1505680. eCollection 2024.
By virtue of their ability to bind different growth factors, morphogens and extracellular matrix proteins, heparan sulfate proteoglycans (HSPGs) play a determinant role in cancer cell differentiation and migration. Despite a strong conceptual basis and promising preclinical results, clinical trials have failed to demonstrate any significant advantage of administering heparin to oncology patients. We exploited our anti-heparan sulfate branched peptide NT4 to test the opposite approach, namely, targeting HSPGs to interfere with their functions, instead of using heparin as a soluble competitor in human cell lines from pancreas adenocarcinoma, colon adenocarcinoma, rhabdomyosarcoma and two different breast cancers. We found that the anti-heparan sulfate peptide NT4 is more effective than heparin for inhibiting cancer cell adhesion, directional migration, colony formation and even cell growth, suggesting that targeting cell membrane HSPGs may be a more effective anti-metastatic strategy than using soluble heparin. Analysis of NT4 effects on cancer cell directional migration, associated to cellular distribution of HSPGs and cadherins in different migrating cancer cell lines, provided further indications on the molecular basis of HSPG functions, which may explain the efficiency of the HSPG targeting peptide.
硫酸乙酰肝素蛋白聚糖(HSPGs)凭借其结合不同生长因子、形态发生素和细胞外基质蛋白的能力,在癌细胞分化和迁移中起决定性作用。尽管有坚实的理论基础和有前景的临床前研究结果,但临床试验未能证明给肿瘤患者使用肝素具有任何显著优势。我们利用抗硫酸乙酰肝素分支肽NT4来测试相反的方法,即靶向HSPGs以干扰其功能,而不是在胰腺腺癌、结肠腺癌、横纹肌肉瘤和两种不同乳腺癌的人类细胞系中使用肝素作为可溶性竞争者。我们发现,抗硫酸乙酰肝素肽NT4在抑制癌细胞黏附、定向迁移、集落形成甚至细胞生长方面比肝素更有效,这表明靶向细胞膜HSPGs可能是一种比使用可溶性肝素更有效的抗转移策略。对NT4对癌细胞定向迁移的影响进行分析,该影响与不同迁移癌细胞系中HSPGs和钙黏蛋白的细胞分布相关,这为HSPG功能的分子基础提供了进一步线索,这可能解释了HSPG靶向肽的有效性。