小细胞肺癌干细胞信号通路的研究进展

小细胞肺癌是具有高度侵袭性的肺肿瘤,其主要临床特征是化疗有效率高但易在短时间内复发转移,这一特点可能与肿瘤干细胞的存在有关。肿瘤干细胞被认为是恶性肿瘤发生发展、耐药、复发及转移的根源。目前多认为肿瘤干细胞与正常干细胞有着相同的信号通路,如Hedgehog、Notch、Wnt等通路。本文就这几条信号通路在小细胞肺癌干细胞中所起的作用以及针对这几条信号通路治疗药物的研究进展和可能的信号通路交互作用等方面进行综述。     

The role of nutraceuticals in the regulation of Wnt and Hedgehog signaling in cancer

Multiple cellular signaling pathways have been involved in the processes of cancer cell invasion and metastasis. Among many signaling pathways, Wnt and Hedgehog (Hh) signaling pathways are critically involved in embryonic development, in the biology of cancer stem cells (CSCs) and in the acquisition of epithelial to mesenchymal transition (EMT), and thus this article will remain focused on Wnt and Hh signaling. Since CSCs and EMT are also known to be responsible for cancer cell invasion and metastasis, the Wnt and Hedgehog signaling pathways are also intimately associated with cancer invasion and metastasis. Emerging evidence suggests the beneficial role of chemopreventive agents commonly known as nutraceutical in cancer. Among many such agents, soy isoflavones, curcumin, green tea polyphenols, 3,3′-diindolylmethane, resveratrol, lycopene, vitamin D, etc. have been found to prevent, reverse, or delay the carcinogenic process. Interestingly, these agents have also shown to prevent or delay the progression of cancer, which could in part be due to their ability to attack CSCs or EMT-type cells by attenuating the Wnt and Hedgehog signaling pathways. In this review, we summarize the current state of our knowledge on the role of Wnt and Hedgehog signaling pathways, and their targeted inactivation by chemopreventive agents (nutraceuticals) for the prevention of tumor progression and/or treatment of human malignancies.     

Drug discovery approaches to target Wnt signaling in cancer stem cells

Cancer stem cells (CSCs) represent a unique subset of cells within a tumor that possess self-renewal capacity and pluripotency, and can drive tumor initiation and maintenance. First identified in hematological malignancies, CSCs are now thought to play an important role in a wide variety of solid tumors such as NSCLC, breast and colorectal cancer. The role of CSCs in driving tumor formation illustrates the dysregulation of differentiation in tumorigenesis. The Wnt, Notch and Hedgehog (HH) pathways are developmental pathways that are commonly activated in many types of cancer. While substantial progress has been made in developing therapeutics targeting Notch and HH, the Wnt pathway has remained an elusive therapeutic target. This review will focus on the clinical relevance of the Wnt pathway in CSCs and tumor cell biology, as well as points of therapeutic intervention and recent advances in targeting Wnt/β-catenin signaling.     

Notch信号通路在肿瘤干细胞中的研究进展

肿瘤干细胞是一类具有自我更新分化能力,在移植动物宿主中具有致瘤性且对放化疗抵抗的细胞小亚群,是肿瘤复发转移的主要原因。Notch信号通路在进化中高度保守,具有调控细胞增殖、分化和凋亡的功能,且在维持肿瘤干细胞的干细胞特性方面发挥重要作用,在干细胞中与多个信号通路存在交互作用。通过抑制Notch信号通路靶向作用肿瘤干细胞的治疗策略已进入临床试验阶段,具有广阔的发展前景。全文就Notch信号通路在肿瘤干细胞中的作用及其与Wnt、TGF-β、Her-2信号通路的交互作用进行阐述与分析。     

Targeting a cornerstone of radiation resistance: cancer stem cell

In radiation oncology, cancer stem cells (CSCs) have become an important research field. In fact, it appears that most cancer types contain populations of cells that exhibit stem-cell properties. CSCs have the ability to renew indefinitely, which can drive tumor development and metastatic invasion. As those cells are classically resistant to conventional chemotherapy and to radiation therapy, they may contribute to treatment failure and relapse. Over past decades, preclinical research has highlighted that variations in the CSCs content within tumor could affect their radiocurability by interfering with mechanisms of DNA repair, redistribution in the cell cycle, tumor cells repopulation, and hypoxia. It is now possible to isolate particular cells expressing specific surface markers and thus better investigating CSCs pathways. Numerous inhibitory agents targeting these specific signaling pathways, such as Notch and Wnt/B-catenin, are currently evaluated in early clinical trials. By targeting CSCs, tumor radioresistance could be potentially overcome to improve outcome for patients with solid malignancies. Radiation therapy using ion particles (proton and carbon) may be also more effective than classic photon on CSCs. This review presents the major pathophysiological mechanisms involved in CSCs radioresistance and recent developments for targeted strategies.     

Hedgehog signalling as a target in cancer stem cells

Hedgehog (Hh) is one of the most important signalling pathways. Together with the Wnt, TGF-β/BMP and Notch pathways, it is involved in both embryonic development and adult tissue homeostasis. This is because Hh plays a central role in the proliferative control and differentiation of both embryonic stem cells and adult stem cells. In this way, an alteration in the Hh pathway, either by misexpression of components of that pathway or by changes in the expression of other cellular components that interfere with the Hh signalling system, may trigger the development of several types of cancer. This occurs because normal stem cells or their intermediaries toward differentiated mature cells are not part of the normal proliferative/differentiation balance and begin to expand without control, triggering the generation of the so-called cancer stem cells. In this review, we will focus on the molecular aspects and the role of Hh signalling in normal tissues and in tumour development.     

Cancer Stem Cells and Response to Therapy

The cancer stem cell (CSC) model states that cancers are organized in cellular hierarchies, which explains the functional heterogeneity often seen in tumors. Like normal tissue stem cells, CSCs are capable of self-renewal,either by symmetric or asymmetric cell division, and have the exclusive ability to reproduce malignant tumors indefinitely. Current systemic cancer therapies frequently fail to eliminate advanced tumors, which may be dueto their inability to effectively target CSC populations. It has been shown that embryonic pathways such as Wnt, Hedgehog, and Notch control self-renewal and cell fate decisions of stem cells and progenitor cells. These are evolutionary conserved pathways, involved in CSC maintenance. Targeting these pathways may be effective in eradicating CSCs and preventing chemotherapy or radiotherapy resistance.     

Notch signalling in cancer stem cells

A new theory about the development of solid tumours is emerging from the idea that solid tumours, like normal adult tissues, contain stem cells (called cancer stem cells) and arise from them. Genetic mutations encoding for proteins involved in critical signalling pathways for stem cells such as BMP, Notch, Hedgehog and Wnt would allow stem cells to undergo uncontrolled proliferation and form tumours. Taking into account that cancer stem cells (CSCs) would represent the real driving force behind tumour growth and that they may be drug resistant, new agents that target the above signalling pathways could be more effective than current anti-solid tumour therapies. In the present paper we will review the molecular basis of the Notch signalling pathway. Additionally, we will pay attention to their role in adult stem cell self-renewal, and cell fate specification and differentiation, and we will also review evidence that supports their implication in cancer.     

Biology of BMP signalling and cancer

In recent years, it has been proposed that tumours are not homogeneous but composed of several cellular types like normal tissues. A cellular subtype, which is though to be the origin of tumours as well as their malignant properties (i.e., capacity for regrowth and metastasis), are the cancer stem cells (CSCs). CSCs, like normal stem cells, have a nearly unlimited capacity to self-renew and to proliferate so that are responsible, besides their same auto-perpetuation giving rise to the features previously depicted, also for the generation of the bulk of more differentiated cells in tumour. The altered behaviour of CSCs may be caused by the malfunction of a number of signalling pathways involved in normal embryonic development and in tissue homeostasis in adulthood. Among these signalling pathways are Wnt, Hedgehog, Notch and BMP pathways. In this review, we will focus on the study of molecular aspects of BMP signalling as well as its involvement in cancer.     

Breast Cancer Stem Cells: A Novel Therapeutic Target

Breast cancer stem cells (BCSCs), characterized by the CD44⁺/CD24^?/low marker, are attributed with features that are demonstrated by the disease itself, such as growth of tumor, recurrence, metastases, and multiple drug resistance. This review concerns the emergence and expediency of BCSCs in treating relapse and advanced cases of breast cancer. One of the ideal ways of detecting and eliminating BCSCs would be to tweak certain molecular receptors in the desired pathway, which would require extensive and comprehensive knowledge about these cell signaling pathways. Although hedgehog (Hh), Notch, and Wnt signaling are of prime concern, governing tumorigenesis and cancer stem cell (CSC) renewal, designing chemotherapeutic or molecular targeted therapies is still a tricky arena to venture into, as these pathways play a vital role in normal mammary gland development. Thus selective inhibition of pathway receptors needs to be investigated in the future.     

Expression of Notch and Wnt pathway components and activation of Notch signaling in medulloblastomas from heterozygous patched mice

Summary Hedgehog (Hh), Notch, and Wingless (Wnt) signaling control normal development of the cerebellum, and dysregulation of these signaling pathways are associated with medulloblastoma (MB). As an initial step in the study of the role of interacting signaling pathways in MB pathogenesis, we demonstrate the expression of several components of the Notch and Wnt signaling pathways, and activation of Notch signaling in MB from Ptch ^+/− mice that have elevated Hh signaling. We also show a marked downregulation in the expression of Notch2, Jagged1, Hes1, mSfrp1, and mFrz7 in cerebella of developing mice with reduced Hh signaling, suggesting that Hh signaling regulates the expression of these genes. Together with recent published data, these findings indicate that Hh signaling might synergize simultaneously with Notch and Wnt signaling in MB development by controlling Notch and Wnt pathway ligand, receptor and/or target gene expression.     

Cancer stem cells: in the line of fire

Most tumours appear to contain a sub-population(s) of self-renewing and expanding stem cells known as cancer stem cells (CSCs). The CSC model proposes that CSCs are at the apex of a hierarchically organized cell population, somewhat akin to normal tissue organization. Selection pressures may also facilitate the stochastic clonal expansion of sub-sets of cancer cells that may co-exist with CSCs and their progeny, moreover the trait of stemness may be more fluid than hitherto expected, and cells may switch between the stem and non-stem cell state. A large body of evidence points to the fact that CSCs are particularly resistant to radiotherapy and chemotherapy. In this review we discuss the basis of such resistance that highlights the roles of ABC transporters, aldehyde dehydrogenase (ALDH) activity, intracellular signalling pathways, the DNA damage response, hypoxia and proliferative quiescence as being significant determinants. In the light of such observations, we outline strategies for the successful eradication of CSCs, including targeting the self-renewal controlling pathways (Wnt, Notch and Hedgehog), ALDH activity and ABC transporters, blocking epithelial mesenchymal transition (EMT), differentiation therapy and niche targeting.     

Notch inhibition suppresses nasopharyngeal carcinoma by depleting cancer stem-like side population cells

The cancer stem cell (CSC) is responsible for the initiation, proliferation and radiation resistance. Side population (SP) cells are a rare subset of cells enriched with CSCs. The targeting of key signaling pathways that are active in CSCs is a therapeutic approach to treating cancer. Notch signaling is important for the self-renewal and maintenance of stem cells. Our previous studies demonstrated that downregulation of Notch signaling could enhance radiosensitivity of nasopharyngeal carcinoma (NPC) cells. In this study, we found that Notch signaling was highly activated in SP cells compared with that of non-SP (NSP) cells of NPC. Therefore, Notch inhibition could reduce the proportion of SP cells. As SP cells decreased, proliferation, anti-apoptosis and tumorigenesis were also decreased. This study shows that Notch inhibition may be a promising clinical approach in CSC-targeting therapy for NPC.     

Targeting notch to eradicate pancreatic cancer stem cells for cancer therapy

Pancreatic cancer is the most aggressive malignant disease once it is diagnosed and it remains the fourth leading cause of cancer-related death in the U.S.A. Recent data indicates that the Notch signaling pathway plays an important role in the development and progression of pancreatic cancer. Emerging evidence also suggests that the activation of the Notch signaling pathway is mechanistically associated with molecular characteristics of cancer stem cells (CSCs) in pancreatic cancer. Moreover, CSCs are known to be highly drug-resistant, suggesting that targeted inactivation of Notch signaling would be useful for overcoming drug resistance and the elimination of CSCs. This review describes the roles of the Notch signaling pathway in pancreatic cancer with a special emphasis on its novel functions in the regulation of pancreatic CSC. Moreover, the review also proposes that targeting the Notch signaling pathway by natural agents may represent a novel strategy for overcoming drug resistance and the elimination of CSCs, which would be useful for the successful treatment of patients diagnosed with pancreatic cancer.     

Eradication of breast cancer cells in patients with distant metastasis: the finishing touches?

Cytotoxic agents are significantly active in breast cancer cells, but their usefulness has been limited in treating metastatic breast cancer (MBC). This has facilitated the development of an approach using molecular-targeted agents. Intrinsic subtypes including luminal A, luminal B, human epidermal growth factor receptor type 2 (HER2)-enriched, basal-like, and claudin-low tumors exhibit original drug responsiveness and clinical prognosis. Anti-HER2 treatments, trastuzumab or lapatinib, have demonstrated clinically significant efficacy. Poly ADP-ribose polymerase-1 inhibitors act against BRCA1-disabled breast cancer. Cancer stem cells could be the major obstacle to achieving a cure in systemic treatment. Extensive investigations are underway to develop novel agents that act on the genes or signaling of Hedgehog, Wnt, and Notch, which regulate cancer stem cells. Cancer cells undergo epithelial?Cmesenchymal transition (EMT) and acquire invasive properties. Breast cancer cells alter their phenotype in blood and bone marrow, e.g., circulating tumor cells or disseminated tumor cells. Cancer stem cells, like normal stem cells, may exist at niches in bone marrow. To achieve a cure for MBC, it is necessary to disrupt cancer stem cell?Cniche interactions or eradicate cancer stem cells. Traditional treatments with cytotoxic or endocrine agents require development in relation to intrinsic subtypes, stem cells, or EMT.