基于肿瘤干细胞分化差异的胰腺癌中医证候防治特点及其机制研究

Pancreatic cancer is one of the difficult treatment diseases in malignant tumors. The previous research showed that heat-dampness accumulation is the main pathogenesis in pancreatic cancer, and treatment by clearing up dampness-heat herbs, which showed good response in pancreatic cancer, could reduce the expression of pancreatic cancer stem cell surface markers and nuclear transcription factors (SOX-2,Nanog), and inhibit cancer stem cell proliferation and differentiation by the Sonic Hedgehog pathway. 8% of patients with advanced pancreatic cancer treated by QYHJ formula-based therapies have an over 5-year long term survival with tumor. It is reported the diversity of the proliferation and differentiation of cancer stem cells have the correlation to prognosis in this malignant tumors. It was also indicated that the prognosis of Traditional Chinese Medicine (TCM) syndromes is significant difference in the pancreatic cancer patients. Based on mentioned above, the questions as followed are urgently needed to be studied: 1. how is the correlation between the different syndromes of TCM and the differentiation and proliferation of cancer stem cells? 2. What are the characteristics of prevention and mechanism of TCM syndromes in clinical treatment from the perspective of pancreatic cancer stem cells? Consequently, we hypothesized that: A. The proliferation and differentiation of cancer stem cells in various TCM syndromes of pancreatic cancers is different and its changes depend on the kind of herbs. B. Syndromes changes in pancreatic cancer at different stages do not alter the nature of dampness-heat accumulation in the pathogenesis of pancreatic cancer. The QYHJ formula inhibits the growth of pancreatic cancer by suppressing the proliferation and differentiation of cancer stem cells. QYHJ formula, which reduce proliferation potential by inducing the pancreatic cancer stem cells, could enable the patients survive with tumor for long term by means of postponing tumor growth or alleviating the tumor load. The project intends to observe the difference of survival with tumor among different therapeutics by intervention situ pancreatic cancer and liver metastasis model, using the method to validate hypothesis A; then observe the difference of survival with tumor based on different syndromes nude mice model, and treated by different Chinese herbs based on different principles, e.g. dampness-heat, spleen deficiency, Yin deficiency, and blood stasis to validate hypothesis B. This study focuses mainly on the different TCM syndromes for pancreatic cancer and relationship between different herbal therapies and proliferation and differentiation of pancreatic cancer stem cells, to interpret clinical characteristics of the different herbs formula for the treatment of pancreatic cancer and its part of the mechanism..Project adopting the study on the pancreatic cancer syndrome tested by herbal formula. And by observing the different treatment responses to different herbal formula in pancreatic cancer in situ and liver metastasis model, the differences in tumor size and distant metastasis among the methods of clearing-up dampness-heat, reinforcing spleen and smooth qi, clearing-up heat and reinforcing yin, promoting blood circulation to remove blood stasis were recognized. Otherwise, we are going to make clear the ratio of pancreatic cancer stem cells and its related signaling pathways. From the perspective of pancreatic cancer stem cells, the characteristics of TCM treatment for pancreatic cancer and its mechanism will be explored.

胰腺癌是难治性恶性肿瘤之一。前期研究发现清热化湿中药治疗胰腺癌疗效显著，约8%晚期胰腺癌患者获得5年以上长期生存，相对于活血化瘀药、健脾理气药和化痰散结药，清热化湿药抗胰腺癌的作用更明显，且胰腺癌干细胞增殖分化差异与预后相关，不同中医证候胰腺癌患者预后也存在差异。因此，明确胰腺癌证候、不同中药治疗与胰腺癌干细胞之间关系成为亟待解决的临床课题。本研究重点在于明确不同胰腺癌中医证候以及不同中药治疗与胰腺癌干细胞增殖分化关系，诠释中医证候与不同中药在胰腺癌临床治疗中的防治特点及其部分机制。项目采用以方测证的胰腺癌证候研究，通过观察不同治则中药干预胰腺原位癌和肝转移模型后肿瘤大小和远处转移的差异，了解清热化湿、健脾理气、清热养阴和活血化瘀法不同中药治后胰腺癌原位肿瘤大小和远处转移的差异、胰腺癌干细胞比例以及胰腺癌干细胞相关信号通路变化，从胰腺癌干细胞角度探讨胰腺癌中医证候防治特点及部分机制。

胰腺癌是难治性恶性肿瘤之一，且胰腺癌干细胞增殖分化差异与预后相关，不同中医证候胰腺癌患者预后也存在差异，明确中药治疗与胰腺癌干细胞之间关系成为亟待解决的课题。结合方-证相关的现代生物学基础正在成为现代中医治则治法理论研究的热点领域，观察不同治则中药干预胰腺原位癌和肝转移模型后肿瘤大小和远处转移的差异，了解清热化湿、健脾理气、清热养阴和活血化瘀法不同中药治后胰腺癌原位肿瘤大小和远处转移的差异、胰腺癌干细胞比例以及胰腺癌干细胞相关信号通路变化，结果发现相对于活血化瘀药、健脾理气药和化痰散结药，清热化湿药抗胰腺癌干细胞的作用更明显，可能通过调控多种基因及相关信号通路发挥其作用，本研究可为后续的临床及基础研究提供新思路。