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.     

Prostate cancer and Hedgehog signalling pathway

The Hedgehog (Hh) family of intercellular signalling proteins have come to be recognised as key mediators in many fundamental processes in embryonic development. Their activities are central to the growth, patterning and morphogenesis of many different regions within the bodies of vertebrates. In some contexts, Hh signals act as morphogens in the dose-dependent induction of distinct cell fates within a target field, in others as mitogens in the regulation of cell proliferation or as inducing factors controlling the form of a developing organ. These diverse functions of Hh proteins raise many intriguing questions about their mode of action. Various studies have now demonstrated the function of Hh signalling in the control of cell proliferation, especially for stem cells and stem-like progenitors. Abnormal activation of the Hh pathway has been demonstrated in a variety of human tumours. Hh pathway activity in these tumours is required for cancer cell proliferation and tumour growth. Recent studies have uncovered the role for Hh signalling in advanced prostate cancer and demonstrated that autocrine signalling by tumour cells is required for proliferation, viability and invasive behaviour. Thus, Hh signalling represents a novel pathway in prostate cancer that offers opportunities for prognostic biomarker development, drug targeting and therapeutic response monitoring. Supported by an unrestricted educational grant from Pfizer.     

Hedgehog信号转导通路与肺癌

Hedgehog(Hh)信号通路在胚胎发育期起关键作用,调节细胞的增殖、分化,协调组织器官如皮肤、脑、神经管、肠、附肢及肺等发育过程中的关键步骤.在成年期,Hh通路调控干细胞的增殖,此时Hh通路受到严格的时空限制.近年来研究表明Hh信号通路异常激活与包括肺癌在内的多种肿瘤的发生、发展密切相关,因此可能会成为肿瘤治疗的一个新靶点.现对Hh信号通路的特性及其在肺癌中的研究现状作一综述.     

Hedgehog signalling in colorectal tumour cells: induction of apoptosis with cyclopamine treatment

Hedgehog (Hh) signalling controls many aspects of development. It also regulates cell growth and differentiation in adult tissues and is activated in a number of human malignancies. Hh and Wnt signalling frequently act together in controlling cell growth and tissue morphogenesis. Despite the fact that the majority of colorectal tumours have a constitutively activated canonical Wnt pathway, few previous studies have investigated the expression of Hh signalling components in colorectal tumours. We describe here epithelial cell lines derived from both nonmalignant colorectal adenomas and colorectal adenocarcinomas that express both Sonic and Indian Hh. Interestingly, these cells also express the Hh receptor Patched and the downstream signalling components Smoothened and Gli1, suggesting autocrine Hh signalling in these cells. To test whether autocrine Hh signalling contributes to cell survival, we treated colorectal tumour cells with cyclopamine, a known inhibitor of Hh signalling. Cyclopamine treatment induced apoptosis in both adenoma- and carcinoma-derived cell lines, which could be partially rescued by further stimulation of Hh signalling. These data suggest that autocrine Hh signalling can increase aberrant cell survival in colorectal tumour cells and may be a novel target for colon cancer therapy using drugs such as cyclopamine.     

Hedgehog信号转导通路与肺癌

 【摘要】　Hedgehog（Hh）信号通路在胚胎发育期起关键作用,调节细胞的增殖、分化,协调组织器官如皮肤、脑、神经管、肠、附肢及肺等发育过程中的关键步骤。在成年期,Hh通路调控干细胞的增殖,此时Hh通路受到严格的时空限制。近年来研究表明Hh信号通路异常激活与包括肺癌在内的多种肿瘤的发生、发展密切相关,因此可能会成为肿瘤治疗的一个新靶点。现对Hh信号通路的特性及其在肺癌中的研究现状作一综述。     

Hedgehog信号转导通路与肺癌

Hedgehog(Hh)信号通路在胚胎发育期起关键作用,调节细胞的增殖、分化,协调组织器官如皮肤、脑、神经管、肠、附肢及肺等发育过程中的关键步骤.在成年期,Hh通路调控干细胞的增殖,此时Hh通路受到严格的时空限制.近年来研究表明Hh信号通路异常激活与包括肺癌在内的多种肿瘤的发生、发展密切相关,因此可能会成为肿瘤治疗的一个新靶点.现对Hh信号通路的特性及其在肺癌中的研究现状作一综述.     

The utility of hedgehog signaling pathway inhibition for cancer

The Hedgehog (Hh) signaling pathway has been implicated in tumor initiation and metastasis across different malignancies. Major mechanisms by which the Hh pathway is aberrantly activated can be attributed to mutations of members of Hh pathway or excessive/inappropriate expression of Hh pathway ligands. The Hh signaling pathway also affects the regulation of cancer stem cells, leading to their capabilities in tumor formation, disease progression, and metastasis. Preliminary results of early phase clinical trials of Hh inhibitors administered as monotherapy demonstrated promising results in patients with basal cell carcinoma and medulloblastoma, but clinically meaningful anticancer efficacy across other tumor types seems to be lacking. Additionally, cases of resistance have been already observed. Mutations of SMO, activation of Hh pathway components downstream to SMO, and upregulation of alternative signaling pathways are possible mechanisms of resistance development. Determination of effective Hh inhibitor-based combination regimens and development of correlative biomarkers relevant to this pathway should remain as clear priorities for future research.     

Lung cancer stem cells: Progress and prospects

Epithelial stem cells are critical for tissue generation during development and for repair following injury. In both gestational and postnatal stages, the highly branched and compartmentalized organization of the lung is maintained by multiple, resident stem/progenitor cell populations that are responsible for the homeostatic maintenance and injury repair of pulmonary epithelium. Though lung epithelial injury in the absence of oncogenic mutation is more commonly expressed as chronic lung disease, lung cancer is the most common form of death worldwide and poses a highly significant risk to human health. Cancer is defined by the cell of origin, responsible for initiating the disease. The Cancer Stem Cell Hypothesis proposes that cancer stem cells, identified by stem-like properties of self-renewal and generation of differentiated progeny, are responsible for propagating growth and spread of the disease. In lung cancer, it is hypothesized that cancer stem cells derive from several possible cell sources. The stem cell-like resistance to injury and proliferative potentials of bronchioalveolar stem cells (BASCs) and alveolar epithelial type II cells (AEC2), as well as cells that express the cancer stem cell marker glycoprotein prominin-1 (CD133) or markers for side populations make them potential reservoirs of lung cancer stem cells. The abnormal activation of pathways that normally regulate embryonic lung development, as well as adult tissue maintenance and injury repair, including the Wnt, Hedgehog (Hh) and Notch pathways, has also been identified in lung tumor cells. It is postulated that therapies for lung cancer that specifically target stem cell signaling pathways utilized by lung cancer stem cells could be beneficial in combating this disease.     

Wnt signalling and cancer stem cells

Intracellular signalling mediated by secreted Wnt proteins is essential for the establishment of cell fates and proper tissue patterning during embryo development and for the regulation of tissue homeostasis and stem cell function in adult tissues. Aberrant activation of Wnt signalling pathways has been directly linked to the genesis of different tumours. Here, the components and molecular mechanisms implicated in the transduction of Wnt signal, along with important results supporting a central role for this signalling pathway in stem cell function regulation and carcinogenesis will be briefly reviewed.     

Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways

Tumor relapse and metastasis remain major obstacles for improving overall cancer survival, which may be due at least in part to the existence of cancer stem cells (CSCs). CSCs are characterized by tumorigenic properties and the ability to self-renew, form differentiated progeny, and develop resistance to therapy. CSCs use many of the same signaling pathways that are found in normal stem cells, such as Wnt, Notch, and Hedgehog (Hh). The origin of CSCs is not fully understood, but data suggest that they originate from normal stem or progenitor cells, or possibly other cancer cells. Therapeutic targeting of both CSCs and bulk tumor populations may provide a strategy to suppress tumor regrowth. Development of agents that target critical steps in the Wnt, Notch, and Hh pathways will be complicated by signaling cross-talk. The role that embryonic signaling pathways play in the function of CSCs, the development of new anti-CSC therapeutic agents, and the complexity of potential CSC signaling cross-talk are described in this Review.     

Targeting hedgehog in cancer stem cells: how a paradigm shift can improve treatment response

The integration of developmental biology and cancer therapeutics has revolutionized the understanding of tumor proliferation. Cell-signaling pathways first recognized for their importance in embryogenesis have begun to inspire the scientific community to investigate new avenues in cancer initiation and growth. Other ground-breaking discoveries provided evidence for a revisit to the theory of cancer stem cells, which has long-term implications for the efficient and lasting elimination of cancer. This paradigm shift involves a change from viewing the malignant tumor as a perpetually mutating mass of clonogenic cells to seeing it as an organ mistakenly created by mutations that disrupt cell-signaling pathways in stem cells. As researchers find more evidence of the essential involvement of these signaling pathways in cancer formation and maintenance, the link between tumorigenesis and aberrant stem cell activation can be more clearly drawn. One such pathway is the hedgehog (Hh)-signaling pathway, which is important in growth and differentiation during embryogenesis and for proper functioning in many adult tissues. Investigation of this pathway and its involvement in cancer has already led to drug development that could eradicate basal cell carcinoma, the most common type of cancer in humans. Future research focused on Hh and related signaling pathways involved in cancer might improve treatment response in malignancies resistant to traditional therapy.     

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.     

Locally advanced and metastatic basal cell carcinoma: molecular pathways,treatment options and new targeted therapies

The hedgehog (Hh) signaling pathway has been identified as important to normal embryonic development in living organisms and it is implicated in processes including cell proliferation, differentiation and tissue patterning. Aberrant Hh pathway has been involved in the pathogenesis and chemotherapy resistance of different solid and hematologic malignancies. Basal cell carcinoma (BCC) and medulloblastoma are two well-recognized cancers with mutations in components of the Hh pathway. Vismodegib has recently approved as the first inhibitor of one of the components of the Hh pathway (smoothened). This review attempts to provide current data on the molecular pathways involved in the development of BCC and the therapeutic options available for the treatment of locally advanced and metastatic BCC, and the new targeted therapies in development.     

Targeting the Hedgehog pathway in cancer

The Hedgehog (Hh) pathway is a major regulator of many fundamental processes in vertebrate embryonic development including stem cell maintenance, cell differentiation, tissue polarity and cell proliferation. Constitutive activation of the Hh pathway leading to tumorigenesis is seen in basal cell carcinomas and medulloblastoma. A variety of other human cancers, including brain, gastrointestinal, lung, breast and prostate cancers, also demonstrate inappropriate activation of this pathway. Paracrine Hh signaling from the tumor to the surrounding stroma was recently shown to promote tumorigenesis. This pathway has also been shown to regulate proliferation of cancer stem cells and to increase tumor invasiveness. Targeted inhibition of Hh signaling may be effective in the treatment and prevention of many types of human cancers. The discovery and synthesis of specific Hh pathway inhibitors have significant clinical implications in novel cancer therapeutics. Several synthetic Hh antagonists are now available, several of which are undergoing clinical evaluation. The orally available compound, GDC-0449, is the farthest along in clinical development. Initial clinical trials in basal cell carcinoma and treatment of select patients with medulloblastoma have shown good efficacy and safety. We review the molecular basis of Hh signaling, the current understanding of pathway activation in different types of human cancers and we discuss the clinical development of Hh pathway inhibitors in human cancer therapy.     

Hedgehog信号通路与肿瘤的关系

 Hedgehog(Hh)信号通路在脊椎动物胚胎发育过程中起核心作用,参与调控多个基本生命过程,包括细胞增殖、分化和组织塑形。在正常成人该通路涉及干细胞维持、组织修复和再生等过程。目前越来越多的证据表明Hh信号通路与人类肿瘤的增殖、生存能力等有相关性。     

Androgens regulate Hedgehog signalling and proliferation in androgen-dependent prostate cells

Prostate cancer (PCa) is androgen sensitive in its development and progression to metastatic disease. Hedgehog (Hh) pathway activation is important in the initiation and growth of various carcinomas including PCa. We and others have observed aberrations of Hh pathway during the progression of PCa to the castration-resistant state. The involvement of androgen signalling in Hh pathway activation, however, remains largely elusive. Here we investigate the direct role of androgen signalling on Hh pathway. We examined the effect of Dihydrosterone (DHT), antiandrogen, bicalutamide, and Hh pathway inhibitor, KAAD-cyclopamine in four human prostate cell lines (two cancerous: LNCaP, VCaP, and two normal: PNT2 and PNT2-ARm which harbours a mutant version of androgen receptor (AR) that is commonly found in LNCaP). Cell proliferation as well as Hh pathway members (SHH, IHH, DHH, GLI, PTCH) mRNA expression levels were assessed. We showed that KAAD-cyclopamine decreased cell proliferation of DHT-stimulated LNCaP, VCaP and PNT2-ARm cells. SHH expression was found to be downregulated by DHT in all AR posititve cells. The negative effect of DHT on SHH expression was counteracted when cells were treated by bicalutamide. Importantly, KAAD-cyclopamine treatment seemed to inhibit AR activity. Moreover, bicalutamide as well as KAAD-cyclopamine treatments induced GLI and PTCH expression in VCaP and PNT2-ARm. Our results suggest that Hh pathway activity can be regulated by androgen signalling. Specifically, we show that the DHT-induced inhibition of Hh pathway is AR dependent. The mutual interaction between these two pathways might be important in the regulation of cell proliferation in PCa.     

Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer

The Hedgehog (Hh) signaling pathway functions as an organizer in embryonic development. Genetic analysis has demonstrated a critical role for the Hh pathway in mammary gland morphogenesis. Disruption of Patched1, a component of the Hh pathway, results in abnormal growth of mammary duct. Recent studies have shown constitutive activation of the Hh pathway in various types of malignancies. However, it remains unclear whether this pathway is activated in human breast cancer. Here, we determined the expression of the components, including Sonic Hh, Patched1, and Gli1, of the Hh pathway by immunohistochemical staining in a series of 52 human breast carcinomas. All of 52 tumors display staining of high intensity for Gli1 when compared with adjacent normal tissue. The nuclear staining ratio of Gli1 correlates with expression of estrogen receptor and histologic type. Exposure to cyclopamine, a steroidal alkaloid that blocks the Hh pathway, suppresses expression of Gli1 and the growth of the Hh pathway-activated breast carcinoma cells. These data indicate that the Hh pathway is a new candidate for therapeutic target of breast cancer.     

Inhibition of osteosarcoma cell proliferation by the Hedgehog-inhibitor cyclopamine

Osteosarcomas (OS) are the most frequent primary malignant bone tumors in humans. Even though OS are chemosensitive, about 30% of patients must be considered poor responders and consequently have a dismal long term prognosis. The Hedgehog (Hh) gene is crucial in the signalling pathways of proliferation and differentiation during embryonic development. There is evidence that uncontrolled activation of this pathway results in specific types of cancer and that inhibition of Hh signalling is able to suppress tumour growth and to induce apoptosis of neoplastic cells. This study investigates the impact of the steroidal alkaloid and Hh-inhibitor cyclopamine on osteosarcoma cells. Thus we demonstrate the drug's impact on cellular proliferation, cell cycle cell death as well as the cells' metabolism. We here demonstrate that cyclopamine exhibits a high efficacy against the osteosarcoma cell lines HOS, SaOS and OS-KA, a self-established primary osteosarcoma cell line. In particular, cyclopamine is able to inhibit proliferation and to promote cell death. Our results provide evidence for the potency of the Hh-inhibitor cyclopamine as a future treatment of osteosarcomas.