胰腺癌是一种恶性极高、预后差、易转移的肿瘤，其发病率与病死率的比值达到1∶0.99，五年总生存率低于5%。手术根治率低，术后5年的存活率只约13%。因此，了解其发病机理，寻找有效的治疗方法是当前亟待解决的问题。胰腺癌的主要病理特征是大规模的肿瘤结缔组织反应，当中胰腺星形细胞分泌的大量细胞外基质是导致结缔组织生成的主因，而这纤维化基质被认为能提供一个三维的微环境支持上皮间质转化(EMT)以助肿瘤发展和转移；基于此，胰腺星形细胞的活化，及其与癌细胞的相互讯息传递相信是肿瘤基质生成和促进EMT的重要过程。本课题组的研究发现SHH信号通路在胰腺星形细胞活化时呈激活状态，与胰腺癌的发生存在正相关。借著吉西他滨诱导细胞凋亡的优势，加上大黄酸对SHH信号通路的阻断效应，我们相信大黄酸/吉西他滨组合疗法能抑制胰腺星形细胞与癌细胞的相互作用，以控制肿瘤基质增长及EMT发展，从而有效的减低胰腺癌的发展及转移。

Pancreatic ductal adenocarcinoma (PDAC), accompanying with a 5-year survival rate of approximately 5%, is one of the most lethal malignancies among human cancers. Gemcitabine, an antimetabolite specifically interfering mitosis, is the standard first-line chemotherapy for PDAC but has limited efficacy due to inherent or rapidly developed resistance. The auxiliary use of Chinese medicinal compound can implement a beneficial approach for suppressing PDAC progression and/or metastasis. ..We propose a combinatory regimen targeting the relevant progressive signaling pathway, sonic hedgehog (SHH), which plays important roles in pancreatic stellate cell (PSC) activation, epithelial-to-mesenchymal transition (EMT), invasiveness and metastasis, to increase response to chemotherapy and suppress the progression of PDAC. ..Our combinatory regimen, comprising rhein and gemcitabine, is meant to work through diverse modes of actions and will be validated in mammalian PSC and PDAC cell lines, as well as a modified orthotopic pancreatic cancer mouse model. The regimen is anticipated to suppress the cellular interplay between PSCs and PDAC cells. The effects of our regimen will be examined in terms of reduction of extracellular matrix (ECM) proteins, EMT molecules, tumor size, invasiveness and metastases...Our previous studies demonstrated that rhein significantly down-regulated SHH activities in mice with pancreatic fibrosis and mammalian carcinoma cells. In the present preliminary trial, rhein inhibits expression levels of ECM proteins and EMT markers, and reduces migration when synergized with gemcitabine in PDAC cells and other kind of carcinoma cells. Thus, we propose that the natural anthraquinone rhein can be repurposed as a SHH signaling inhibitor and a combinatory component of an anti-cancer therapy for the management of PDAC. ..Under the attenuation of SHH signaling by rhein, we expect PDAC cells are more susceptible to gemcitabine-mediated tumor growth inhibition, and a gemcitabine-synergized suppression of PDAC progression and metastasis in vivo.