Fitzgerald Timothy L, Lertpiriyapong Kvin, Cocco Lucio, Martelli Alberto M, Libra Massimo, Candido Saverio, Montalto Giuseppe, Cervello Melchiorre, Steelman Linda, Abrams Stephen L, McCubrey James A
Department of Surgery, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
Department of Comparative Medicine, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
Adv Biol Regul. 2015 Sep;59:65-81. doi: 10.1016/j.jbior.2015.06.003. Epub 2015 Jul 17.
Pancreatic cancer is currently the fourth most common cancer, is increasing in incidence and soon will be the second leading cause of cancer death in the USA. This is a deadly malignancy with an incidence that approximates the mortality with 44,000 new cases and 36,000 deaths each year. Surgery, although only modestly successful, is the only curative option. However, due the locally aggressive nature and early metastasis, surgery can be performed on less than 20% of patients. Cytotoxic chemotherapy is palliative, has significant toxicity and improves survival very little. Thus new treatment paradigms are needed desperately. Due to the extremely high frequency of KRAS gene mutations (>90%) detected in pancreatic cancer patients, the roles of the epidermal growth factor receptor (EGFR), Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTORC1/GSK-3 pathways have been investigated in pancreatic cancer for many years. Constitutively active Ras can activate both of these pathways and there is cross talk between Ras and EGFR which is believed to be important in driving metastasis. Mutant KRAS may also drive the expression of GSK-3 through Raf/MEK/ERK-mediated effects on GSK-3 transcription. GSK-3 can then regulate the expression of NF-kappaB which is important in modulating pancreatic cancer chemoresistance. While the receptors and many downstream signaling molecules have been identified and characterized, there is still much to learn about these pathways and how their deregulation can lead to cancer. Multiple inhibitors to EGFR, PI3K, mTOR, GSK-3, Raf, MEK and hedgehog (HH) have been developed and are being evaluated in various cancers. Current research often focuses on the role of these pathways in cancer stem cells (CSC), with the goal to identify sites where therapeutic resistance may develop. Relatively novel fields of investigation such as microRNAs and drugs used for other diseases e.g., diabetes, (metformin) and malaria (chloroquine) have provided new information about therapeutic resistance and CSCs. This review will focus on recent advances in the field and how they affect pancreatic cancer research and treatment.
胰腺癌目前是第四大常见癌症，其发病率正在上升，很快将成为美国癌症死亡的第二大主要原因。这是一种致命的恶性肿瘤，发病率与死亡率相近，每年有44000例新发病例和36000例死亡。手术虽然成功率不高，但却是唯一的治愈选择。然而，由于其局部侵袭性和早期转移的特性，只有不到20%的患者能够接受手术。细胞毒性化疗具有姑息作用，毒性显著，对提高生存率的作用甚微。因此，迫切需要新的治疗模式。由于在胰腺癌患者中检测到极高频率的KRAS基因突变（>90%），表皮生长因子受体（EGFR）、Ras/Raf/MEK/ERK和PI3K/PTEN/Akt/mTORC1/GSK-3信号通路在胰腺癌中的作用已经被研究多年。持续激活的Ras可以激活这两条信号通路，并且Ras与EGFR之间存在相互作用，这被认为在驱动转移中起重要作用。突变的KRAS还可能通过Raf/MEK/ERK介导的对GSK-3转录的影响来驱动GSK-3 的表达。然后，GSK-3可以调节NF-κB的表达，这在调节胰腺癌化疗耐药性中很重要。虽然已经鉴定并表征了这些信号通路的受体和许多下游信号分子，但关于这些信号通路以及它们的失调如何导致癌症，仍有许多需要了解的地方。已经开发了多种针对EGFR、PI3K、mTOR、GSK-3、Raf、MEK和刺猬蛋白（HH）的抑制剂，并正在各种癌症中进行评估。当前的研究通常集中在这些信号通路在癌症干细胞（CSC）中的作用，目标是确定可能产生治疗耐药性的位点。相对较新的研究领域，如微小RNA以及用于其他疾病（如糖尿病的二甲双胍和疟疾的氯喹）的药物，已经提供了关于治疗耐药性和癌症干细胞的新信息。本综述将重点关注该领域的最新进展以及它们如何影响胰腺癌的研究和治疗。
