摘要
胰腺癌基质在肿瘤进展、侵袭、转移和治疗抵抗中扮演着重要角色,单纯的靶向肿瘤细胞治疗策略已无法满足延长患者生存期的临床治疗需求。越来越多的研究着眼于靶向胰腺癌基质治疗与化疗、放疗和免疫疗法联合用药方案的开发。胰腺癌复杂的基质成分、互相串扰的信号通路和畸形增生的新生血管给靶向药物的研究开发带来了巨大挑战的同时也提供了相应的机遇。本文主要从细胞外基质(extracellular matrix,ECM)、肿瘤相关成纤维细胞(cancer associated fibroblasts,CAFs)和血管3个方面,综述了近期靶向胰腺癌基质治疗策略研究进展并加以分析讨论,以期为胰腺癌的靶向治疗提供新思路。
胰腺癌是高度致死的实体肿瘤,由于早期诊断困难,绝大多数患者确诊时已是晚

Figure 1 Fibrotic pancreatic cancer strom
细胞外基质由黏多糖、糖蛋白和胶原构
透明质酸(hyaluronic acid,HA)在大量实体肿瘤中普遍存在,晚期肿瘤中尤

Figure 2 Enhanced chemotherapy with pancreatic cancer stroma targeting PEGPH2
A: High interstitial fluid pressure of pancreatic cancer hampers the convection and perfusion of molecues. B: PEGPH20 digests HA to attenuate IFP and impair physical barriers. C: Combined therapy of PEGPH20 and gemcitabine to enhance chemotherapy for pancreatic cancer.(Pi: interstitial fluid pressure; Pv: intravascular pressure)
Zinger
胰腺癌基质中的细胞组分由成纤维细胞、胰腺星状细胞(pancreatic stellate cells,PSCs)、血管内皮细胞和淋巴细胞构
在胰腺癌细胞分泌的多种细胞因子刺激下,静息的成纤维细胞和胰腺星状细胞大量活化为具有肌成纤维细胞表型的肿瘤相关成纤维细胞,成为纤连结缔组织增生的首要制造
CAFs: Cancer associated fibroblasts; PSCs: Pancreatic stellate cells
全反式维甲酸(all-trans retinoic acid,ATRA)是最具活性的维生素A代谢物,在健康的胰腺中,PSCs可以存储维生素A的代谢物维甲酸,而在胰腺炎和胰腺癌患者中,由于分泌功能受损,PSCs受激活后丢失维甲酸呈现激活的肌成纤维细胞样。Chronopoulos
TGF-β是一种多效的细胞因子,在胚胎发育和组织稳态中起着重要作用。一方面,在正常组织和胰腺癌发生的早期,TGF-β可以抑制细胞增殖,反映出其抑瘤特性;另一方面,伴随着胰腺癌发展,TGF-β能够促进肿瘤细胞增殖、自我更新,发生间充质转换进而更加具有侵袭性,同时它是CAFs最为关键的活化因子。CAFs细胞膜上TGF-β受体活化后,会诱导Smad2、Smad3信号分子磷酸化,并与Smad4发生寡聚转移至细胞核内,诱导靶标基因转录促进ECM蛋白分
2014年FDA批准了TGF-β/Smad信号通路抑制剂吡非尼酮(perfenidone,PFD)用于特发性肺纤维化的治疗。近年来,越来越多的研究者认识到TGF-β/Smad信号通路抑制剂在基质丰富的胰腺癌治疗中的重要作用,致力于开发高效的纳米药物递送系统改善TGF-β/Smad信号通路抑制剂的生物相容性。Ji
此外,中药单体化合物在沉默CAFs方面展现出巨大的潜力,也成为TGF-β/Smad信号通路抑制的重要筛选对象。倒捻子素(α-mangostin,α-M)是从山竹果皮中分离出的天然黄酮类化合物,在体内外研究中显示出较好的CAFs沉默效果。Feng

Figure 3 α-mangostin (α-M) micelles promoting penetration of DiD labelled nanoparticles in pancreatic cance
Orthotopic pancreatic tumor bearing mice treatment of once, twice and thrice α-M (10 mg/kg) micelles and then injection of DiD labelled nanoparticles to investigate the intratumoral penetration and distribution through tail vein(Scale bars: 200 μm)
基因药物通过分子生物学方法将目的基因导入靶细胞以纠正基因异常引发的疾病,其需要选择合适的目标基因和作用靶点,并依托于适合的载体进行有效的递送。伴随着材料科学、生命科学的发展,以小干扰RNA、microRNA为代表的基因药物(
小干扰RNA(siRNA)是双链非编码RNA分子,长度通常在20 ~ 25个核苷酸,siRNA是基础生命科学领域研究基因功能的金标准,可以经由多种转染技术引入细胞内,与细胞质中RNA诱导沉默复合物(RISC)结合并解旋,正义链被降解,反义链结合在RISC上互补地和信使RNA结合诱发特定基因转录后沉
MicroRNA(miRNA)是内源性非编码单链RNA,通常长度在21 ~ 23个核苷酸,miRNA是信使RNA的互补序列,能够调控基因表达、细胞周期。在胰腺癌进程中,miRNA广泛参与CAFs的激

Figure 4 Anti-miR-210 inhibiting PSCs to enhance gene therapy and immune infiltratio
整合素α11β1是CAFs表面高表达的胶原受
嵌合抗原受体T细胞(chimeric antigen receptor T cells,CAR-T)疗法是指通过基因工程方法将具有特异性抗原识别结构域融合到T细胞受体信号域上,同时导入T细胞协同刺激分子的遗传物
Wang
胰腺癌基质高度纤维化,微血管密度高,高间质液压使瘤内血管皱缩,加剧了低血流灌注的局面,造成肿瘤组织高度乏氧和酸化。乏氧状态下,缺氧诱导因子-1(HIF-1)能保持稳定并诱导下游一系列基因的转录,刺激血管内皮生长因子(VEGF)和血小板衍生生长因子(PDGF)的表达,进一步促进非正常的血管新生。早在1970年,Folkma

Figure 5 Heterogeneous tumor vessel
然而,抗血管新生治疗策略在胰腺癌治疗一直是一个具有争议的话
近期,Katsuta
由于胰腺癌基质高度纤维化的特殊性,靶向肿瘤基质在改善抗肿瘤药物递送和延长患者生存期仍然是极具效力的策略。目前,以CAFs和ECM为靶标的胰腺癌基质治疗是较为热门且成熟的研究方向。从传统的靶向药物到免疫治疗如CAR-T都有CAFs的身影,其在胰腺癌治疗中的地位至关重要。越来越多的研究表明,对于CAFs的直接杀伤会使得胰腺癌细胞更具侵袭性且不利于患者生存期的改
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