Hedgehog signaling and therapeutics in pancreatic cancer

Kelleher, Fergal C.

doi:10.1093/carcin/bgq280

Cited by 108 publications

(78 citation statements)

References 39 publications

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“…22 Activation of the Hh pathway is detected in stem cell-like subpopulation in pancreatic adenocarcinoma. [23][24][25] Hh pathway inhibitors cyclopamine, 26 IPI-269609 27 have effect in pancreatic cancer mouse model. Combination of Hh pathway inhibitor IPI-926 and gemcitabine, 28 SMO antagonist SANT-1 and histone deacetylase inhibitor SAHA, 29 Hh pathway inhibitor cyclopamine and inhibitor of epidermal growth factor receptor (EGFR) Iressa 30 inhibit tumor cells in pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Activation of the hedgehog pathway in gastroesophageal cancers

Yang

Xie²,

Su³

2011

JST

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The hedgehog pathway is a major regulator for cell differentiation, tissue polarity and cell proliferation in embryonic development and homeostasis in adult tissue. Studies from many laboratories reveal activation of this pathway in a variety of human cancer, including basal cell carcinomas, medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast and prostate cancers. It is thus believed that targeted inhibition of hedgehog signaling may be effective in treatment and prevention of human cancer. Even more exciting is the discovery and synthesis of specific signaling antagonists for the hedgehog pathway, which have significant clinical implications in novel cancer therapeutics. In this review, we will summarize major advances in the last two years in our understanding of hedgehog signaling activation in human gastroesophageal cancer, and their potential in clinical treatment with hedgehog pathway inhibitors.

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Section: Introductionmentioning

confidence: 99%

Activation of the hedgehog pathway in gastroesophageal cancers

Yang

Xie²,

Su³

2011

JST

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“…These findings suggested that the hedgehog pathway was frequently activated or deregulated in human HCCs (14)(15)(16)(17)21). In vitro, certain authors considered that some hedgehog signal-responsive progenitor cells function as cancer stem cells, leading to carcinogenesis (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

“…Cyclopamine may affect the mRNA expression. The key target factor of the Shh pathway in the inhibition of cancer remains controversial (24,33,34). Interference with Shh-Gli-1 signaling may inhibit the proliferation of prostate cancer cells (35).…”

Section: Discussionmentioning

confidence: 99%

Blockade of the sonic hedgehog pathway effectively inhibits the growth of hepatoma in mice: An in vivo study

et al. 2012

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Abstract. Hepatocellular carcinoma (HCC), a worldwide malignancy, is prevalent in Asian countries. For individuals with unresectable HCC, the effect of chemotherapy or the present target therapy is limited. There is an urgent need to find innovative new therapies. It is believed that sonic hedgehog (Shh) pathway activation may be essential for hepatocarcinogenesis. In the present study, we conducted an in vivo animal study using an Shh pathway inhibitor to elucidate the effect of treatment upon mice with HCC. Eighty C57BL/6 mice were divided into 4 groups (groups A, B, C and D, with group A serving as a control; n=20 for each). We injected mouse hepatoma Mistheton Lectin-1 cells (5xl0 6 cells/20 µl) into the left liver of each mouse in groups B, C and D. In the second week, we analyzed each mouse to assess the tumor growth status. Following the tumor injection, group B did not receive any additional intraperitoneal (i.p.) injection, group C received cyclopamine 10 mg/kg/day i.p. and group D received cyclopamine 30 mg/kg/day i.p. every day for 10 days. After an interval of 4 weeks, harvesting and analysis of the liver was performed for each mouse. Tumor size measurement and real-time PCR of Shh pathway factors (Shh, Ptch-1, Gli-1 and Smoh) for livers of group A and tumors of group B, C and D were undertaken. The decrease in the tumor size of group D was found to be statistically significant (P= 0.047) when compared with groups B or C. The decrease of Shh mRNA of both groups C and D had borderline significance when compared with group B. However, Gli-1 mRNA of group D has statistically significant difference (P=0.044) when compared with group A, B or C. Inhibition of the Shh pathway significantly decreases the size and Gli-1 mRNA expression of the tumor. The Shh pathway may be an effective treatment target for HCC in the future.

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“…It is beyond the scope of this chapter to discuss each pathway in detail, other than to note that the consequences of their disruption likely mimic, enhance, or synergize with K-ras mutations to drive transformation and cancer progression. Involvement of Notch and hedgehog signaling deserves special mention, as these critical pathways are best known for maintaining cells in an undifferentiated state during development (Kelleher, 2011, Ristorcelli & Lombardo, 2010. In the adult organism, these pathways are involved in tissue homeostasis via maintenance of tissue stem cell populations.…”

Section: Mutational Activation Of Other Proto-oncogenic Signaling Patmentioning

confidence: 99%