Neuzillet Cindy, Tijeras-Raballand Annemilaï, Cros Jérôme, Faivre Sandrine, Hammel Pascal, Raymond Eric
Department of Medical Oncology (INSERM U728-PRES Paris 7 Diderot), Beaujon University Hospital, Assistance Publique-Hôpitaux de Paris, 100 boulevard du Général Leclerc, 92110, Clichy-La-Garenne, France.
Cancer Metastasis Rev. 2013 Dec;32(3-4):585-602. doi: 10.1007/s10555-013-9439-3.
Pancreatic ductal adenocarcinoma (PDAC) stands as the poorest prognostic tumor of the digestive tract, with a 5-year survival rate of less than 5%. Therapeutic options for unresectable PDAC are extremely limited and there is a pressing need for expanded therapeutic approaches to improve current options available with gemcitabine-based regimens. With PDAC displaying one of the most prominent desmoplastic stromal reactions of all carcinomas, recent research has focused on the microenvironment surrounding PDAC cells. Secreted protein acid and rich in cysteine (SPARC), which is overexpressed in PDAC, may display tumor suppressor functions in several cancers (e.g., in colorectal, ovarian, prostate cancers, and acute myelogenous leukemia) but also appears to be overexpressed in other tumor types (e.g., breast cancer, melanoma, and glioblastoma). The apparent contradictory functions of SPARC may yield inhibition of angiogenesis via inhibition of vascular endothelial growth factor, while promoting epithelial-to-mesenchymal transition and invasion through matrix metalloprotease expression. This feature is of particular interest in PDAC where SPARC overexpression in the stroma stands along with inhibition of angiogenesis and promotion of cancer cell invasion and metastasis. Several therapeutic strategies to deplete stromal tissue have been developed. In this review, we focused on key preclinical and clinical data describing the role of SPARC in PDAC biology, the properties, and mechanisms of delivery of drugs that interact with SPARC and discuss the proof-of-concept clinical trials using nab-paclitaxel.
胰腺导管腺癌（PDAC）是消化道预后最差的肿瘤，5年生存率低于5%。不可切除的PDAC的治疗选择极其有限，迫切需要扩展治疗方法以改善目前基于吉西他滨方案的现有选择。由于PDAC表现出所有癌症中最显著的促结缔组织增生性基质反应之一，最近的研究集中在PDAC细胞周围的微环境。在PDAC中过表达的富含半胱氨酸的酸性分泌蛋白（SPARC），在几种癌症（如结直肠癌、卵巢癌、前列腺癌和急性髓性白血病）中可能发挥肿瘤抑制功能，但在其他肿瘤类型（如乳腺癌、黑色素瘤和胶质母细胞瘤）中似乎也过表达。SPARC明显矛盾的功能可能通过抑制血管内皮生长因子来抑制血管生成，同时通过基质金属蛋白酶的表达促进上皮-间质转化和侵袭。这一特征在PDAC中特别令人关注，其中基质中SPARC的过表达与血管生成抑制以及癌细胞侵袭和转移的促进并存。已经开发了几种消耗基质组织的治疗策略。在这篇综述中，我们重点关注描述SPARC在PDAC生物学中的作用、与SPARC相互作用的药物的性质和递送机制的关键临床前和临床数据，并讨论使用纳米白蛋白结合型紫杉醇的概念验证临床试验。
