Kobet Robert A, Pan Xiaoping, Zhang Baohong, Pak Stephen C, Asch Adam S, Lee Myon-Hee
Department of Medicine, Department of Oncology, Division of Hematology/Oncology, Brody School of Medicine, East Carolina University, Greenville, NC 27834.
Department of Biology, East Carolina University, Greenville, NC 27858.
Biomol Ther (Seoul). 2014 Sep;22(5):371-83. doi: 10.4062/biomolther.2014.084. Epub 2014 Sep 30.
The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer.
线虫秀丽隐杆线虫（C. elegans）因其遗传易处理性和明确的发育谱系，为生物学和基础医学研究提供了独特的机会。它还为人类疾病相关基因的遗传、分子和细胞分析提供了一个特殊的模型。最近，秀丽隐杆线虫已被用作体内药物（或小分子）鉴定和功能分析的理想模型。在这篇综述中，我们描述了保守的致癌信号通路（Wnt、Notch和Ras）及其在癌症干细胞发育中的潜在作用。在秀丽隐杆线虫生殖系发育过程中，这些信号通路调节多种细胞过程，如生殖系干细胞微环境的特化、生殖系干细胞的维持以及生殖细胞命运的特化。因此，这些信号通路的异常调节可导致生殖系干细胞的丧失或特定细胞类型的过度增殖，从而导致不育。这种不育表型使我们能够通过高通量筛选鉴定出可直接或间接调节致癌信号通路的药物。目前的体内或体外筛选方法主要集中在特定的核心信号成分上。然而，这种基于表型的筛选将鉴定出可能靶向核心信号通路上游或下游的药物，并排除毒性作用。尽管基于表型的药物筛选很理想，但鉴定药物靶点是一个重大挑战。我们在此介绍一种新技术，称为药物亲和力响应靶点稳定性（DARTS）。这种创新方法能够鉴定出已鉴定药物的靶点。重要的是，秀丽隐杆线虫中的信号通路及其调节因子在包括人类在内的大多数脊椎动物中高度保守。因此，秀丽隐杆线虫将为鉴定治疗药物及其靶点以及理解癌症形成的潜在机制提供一个绝佳的机会。
