Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev

Diabetes Center, Department of Medicine, University of California, San Francisco, California 94143, USA.
Genes & Development (Impact Factor: 10.8). 11/2006; 20(22):3161-73. DOI: 10.1101/gad.1470806
Source: PubMed


Pancreatic ductal adenocarcinoma (PDA) constitutes a lethal disease that affects >30,000 people annually in the United States. Deregulation of Hedgehog signaling has been implicated in the pathogenesis of PDA. To gain insights into the role of the pathway during the distinct stages of pancreatic carcinogenesis, we established a mouse model in which Hedgehog signaling is activated specifically in the pancreatic epithelium. Transgenic mice survived to adulthood and developed undifferentiated carcinoma, indicating that epithelium-specific Hedgehog signaling is sufficient to drive pancreatic neoplasia but does not recapitulate human pancreatic carcinogenesis. In contrast, simultaneous activation of Ras and Hedgehog signaling caused extensive formation of pancreatic intraepithelial neoplasias, the earliest stages of human PDA tumorigenesis, and accelerated lethality. These results indicate the cooperation of Hedgehog and Ras signaling during the earliest stages of PDA formation. They also mark Hedgehog pathway components as relevant therapeutic targets for both early and advanced stages of pancreatic ductal neoplasia.

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Available from: Marina Pasca di Magliano, Dec 15, 2014
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    • "Notch and Hh signaling were shown to induce survival and multidrug resistance. induced activation of the EGFR/AKT pathway and vice versa [44]. Combined activation of Hh and EGFR signaling led to synergistic oncogenic transformation in multiple cell types [69]. "
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    ABSTRACT: The Hedgehog (Hh) pathway is aberrantly activated in a number of tumors. In medulloblastoma, basal cell carcinoma, and rhabdomyosarcoma, mutations in Hh pathway genes lead to ligand-independent pathway activation. In many other tumor types, ligand-dependent activation of Hh signaling is potentiated through crosstalk with other critical molecular signaling pathways. Among such pathways, RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch are of particular interest because agents that selectively inhibit these pathways are available and can be readily combined with agents such as vismodegib, sonidegib (LDE225), and BMS-833923, which target smoothened—a key Hh pathway regulator. Numerous preclinical studies have revealed the ways in which Hh intersects with each of these pathways, and combination therapies have resulted in improved antitumor efficacy and survival in animal models. Hh also plays an important role in hematopoiesis and in the maintenance of BCR-ABL–driven leukemic stem cells. Thus, combined inhibition of the Hh pathway and BCR-ABL has emerged as a promising potential therapeutic strategy in chronic myeloid leukemia (CML). A number of clinical trials evaluating combinations of Hh inhibitors with other targeted agents are now underway in CML and a variety of solid tumors. This review highlights these trials and summarizes preclinical evidence of crosstalk between Hh and four other actionable pathways—RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch—as well as the role of Hh in the maintenance of BCR-ABL–driven leukemic stem cells.
    Cancer Treatment Reviews 07/2014; 40(6). DOI:10.1016/j.ctrv.2014.02.003 · 7.59 Impact Factor
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    • "As a result, clinical excitement over hedgehog inhibition has waned. Additionally, given the relationship between the RAS/MAPK and Hedgehog signaling pathways in PDAC, it has been suggested that synergistic targeting of both the RAS and Hedgehog pathways may represent a new therapeutic strategy for the treatment of PDAC (Pasca di Magliano et al., 2006; Koorstra et al., 2008; Mimeault and Batra, 2010; LoRusso et al., 2011). "
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in both men and women in the United States, carrying a 5-year survival rate of approximately 5%, which is the poorest prognosis of any solid tumor type. Given the dismal prognosis associated with PDAC, a more thorough understanding of risk factors and genetic predisposition has important implications not only for cancer prevention, but also for screening techniques and the development of personalized therapies. While screening of the general population is not recommended or practicable with current diagnostic methods, studies are ongoing to evaluate its usefulness in people with at least 5- to 10-fold increased risk of PDAC. In order to help identify high-risk populations who would be most likely to benefit from early detection screening tests for pancreatic cancer, discovery of additional pancreatic cancer susceptibility genes is crucial. Thus, specific gene-based, gene-product, and marker-based testing for the early detection of pancreatic cancer are currently being developed, with the potential for these to be useful as potential therapeutic targets as well. The goal of this review is to provide an overview of the genetic basis for PDAC with a focus on germline and familial determinants. A discussion of potential therapeutic targets and future directions in screening and treatment is also provided.
    Frontiers in Physiology 03/2014; 5:87. DOI:10.3389/fphys.2014.00087 · 3.53 Impact Factor
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    • "Once Hh binds to PTCH, SMO will be released to activate the GLI (glioma-associated oncogene homologue) to be an active form of transcription factor. The Hh signaling pathway alone is sufficient to drive pancreatic neoplasia [12], and it is known that the activation of the Hh-GLI pathway is associated with tumor proliferation and pancreatic cancer-related fibroblasts [13]. "
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    ABSTRACT: Background Recent cancer studies revealed, the interaction between pancreatic cancer cells and pancreatic stellate cells is of importance in the cancer progression. The activation of stellate cells is mediated by some growth factors and cytokines secreted by the cancer cells. In turn, the activated stellate cells will synthesize and secrete multiple growth factors to continuously stimulate the growth of surrounding cancer cells through paracrine pathways. The mechanism behind the evolution of stellate cells from quiescent state to a cancer-associated phenotype is still not well understood. Results To systematically investigate the interaction between cancer cells and stellate cells, we constructed a multicellular discrete value model, which is composed of several intracellular and intercellular signaling pathways that are frequently mutated in the pancreatic cancer, to study the cell cycle progression and angiogenesis. We, then, introduced and applied a formal verification technique, Symbolic Model Checking, to automatically analyze the cells' proliferation, angiogenesis and apoptosis in the proposed signal transduction model of tumor microenvironment. Conclusions Our studies predicted some important temporal logic properties and dynamic behaviors in the pancreatic cancer cells and stellate cells. The verification technique identified several signaling components, including the RAS, RAGE, AKT, IKK, DVL, RB and PTEN, whose mutation or loss of function can promote cell growth and inhibit apoptosis, some of which have been confirmed by existing experiments. Our formal studies demonstrated that, the bidirectional interaction between cancer cells and stellate cells could significantly increase cell proliferation, inhibit apoptosis, induce tumor angiogenesis, and promote cancer metastasis.
    BMC Systems Biology 10/2013; 7(3). DOI:10.1186/1752-0509-7-S3-S5 · 2.44 Impact Factor
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