The Utility of Hedgehog Signaling Pathway Inhibition for Cancer

Sahebjam, Solmaz; Siu, Lillian L.; Razak, Albiruni Abdul

doi:10.1634/theoncologist.2011-0450

Cited by 45 publications

(30 citation statements)

References 106 publications

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“…This phenomenon had been previously observed in various cancers 53. In cancers of the GI tract, SHH is often upregulated, thereby contributing to tumour formation and progression 44.…”

Section: The Hedgehog Dependence Receptors As Original Regulator Of Crcsupporting

confidence: 53%

Dependence receptors and colorectal cancer

Mehlen

Tauszig-Delamasure

2014

Gut

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The research on colorectal cancer (CRC) biology has been leading the oncology field since the early 1990s. The search for genetic alterations has allowed the identification of the main tumour suppressors or oncogenes. Recent work obtained in CRC has unexpectedly proposed the existence of novel category of tumour suppressors, the so-called 'dependence receptors'. These transmembrane receptors behave as Dr Jekyll and Mr Hyde with two opposite sides: they induce a positive signalling (survival, proliferation, differentiation) in presence of their ligand, but are not inactive in the absence of their ligand and rather trigger apoptosis when unbound. This trait confers them a conditional tumour suppressor activity: they eliminate cells that grow abnormally in an environment offering a limited quantity of ligand. This review will describe how receptors such as deleted in colorectal carcinoma (DCC), uncoordinated 5 (UNC5), rearranged during transfection (RET) or TrkC constrain CRC progression and how this dependence receptor paradigm may open up therapeutical perspectives.

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“…This phenomenon had been previously observed in various cancers 53. In cancers of the GI tract, SHH is often upregulated, thereby contributing to tumour formation and progression 44.…”

Section: The Hedgehog Dependence Receptors As Original Regulator Of Crcsupporting

confidence: 53%

Dependence receptors and colorectal cancer

Mehlen

Tauszig-Delamasure

2014

Gut

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“…vismodegib, BMS-833293/XL139, IPI-926, LDE225, PF-04449913, LEQ 506, and TAK-441) either alone or in combination with chemotherapy for a variety of solid tumors (30). In 63 patients with locally advanced basal cell carcinoma, vismodegib led to a partial response in 22% of patients and a complete response in 21% of patients (31).…”

Section: Discussionmentioning

confidence: 99%

CD44 Expression Denotes a Subpopulation of Gastric Cancer Cells in Which Hedgehog Signaling Promotes Chemotherapy Resistance

Yoon¹,

Park²,

Schmidt

et al. 2014

Clinical Cancer Research

169

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Purpose Gastric cancers (GC) may harbor a small subset of cells with cancer stem cell (CSC) properties including chemotherapy (CT) resistance. The Hedgehog (HH) pathway is a key developmental pathway that can be subverted by CSCs during tumorigenesis. Here we examine the role of HH signaling in CD44(+) GC cells. Experimental Design GC cell lines, tumor xenografts, and patient tumors were examined. Results GC cell lines AGS, MKN-45, and NCI-N87 grown as spheroids or sorted for CD44(+) were found to have upregulation of HH pathway proteins. HH inhibition using Smo shRNA or vismodegib (VIS) decreased spheroid formation and colony formation. CD44(+) cells, compared to unselected cells, were also resistant to 5-fluorouracil and cisplatin CT, and this resistance was reversed in vitro and in xenografts with Smo shRNA or VIS. CD44(+) cells also had significantly more migration, invasion, and anchorage-independent growth, and these properties could all be blocked with HH inhibition. Clinical tumor samples from a phase II trial for advanced GC of CT with or without VIS were analyzed for CD44 expression. In the CT alone group, high CD44 expression was associated with decreased survival, while in the CT plus VIS group, high CD44 expression was associated with improved survival. Conclusions HH signaling maintains CSC phenotypes and malignant transformation phenotypes in CD44(+) GC cells, and HH inhibition can block CT resistance in CD44(+) cells. GC is a heterogeneous disease, and the strategy of combining CT with HH inhibition may only be effective in the subset with high CD44 levels.

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“…They found that IL-23 signaling promotes tumor growth and progression, and the development of tumoral IL-17 response, resulting in an additional aggravation of disease progression (60). Efforts to target pathogenic Hedgehog signaling have steadily progressed from the laboratory to the clinic, and the recent approval of vismodegib for patients with advanced basal cell carcinoma represents an important milestone (61)(62)(63)(64)(65)(66). However, in a recent phase II study, vismodegib did not add to the efficacy of standard first-line treatment for metastatic colorectal cancer (67).…”

Section: Discussionmentioning

confidence: 99%

A Functional Germline Variant in GLI1 Implicates Hedgehog Signaling in Clinical Outcome of Stage II and III Colon Carcinoma Patients

Szkandera

Pichler²,

Absenger

et al. 2014

Clinical Cancer Research

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Purpose: Cumulating evidence indicates that germline variants in the Wnt, Notch, and Hedgehog pathways are involved in colon carcinoma progression and metastasis. We investigated germline polymorphisms in a comprehensive panel of Wnt, Notch, and Hedgehog pathway genes to predict time to recurrence (TTR) and overall survival in patients with stage II and III colon carcinoma.Experimental Design: A total of 742 consecutively collected patients with stage II and III colon carcinoma were included in this retrospective study. Genomic DNA was analyzed for 18 germline polymorphisms in Wnt, Notch, and Hedgehog pathway genes (SFRP, DKK 2 and 3, AXIN2, APC, MYC, TCF7L2, NOTCH2, and GLI1) by TaqMan 5 0 -exonuclease assays. Results: In univariate analysis, the homozygous mutant variant of GLI1 rs2228226 G>C was significantly associated with decreased TTR in a recessive genetic model after adjustment for multiple testing [HR ¼ 2.35; confidence interval (95% CI), 1.48-3.74; P < 0.001] and remained significant in multivariate analysis including clinical stage, lymphovascular-, vascular-, and perineural-invasion (HR ¼ 2.43; CI 95%, 1.52-3.87; P < 0.001). In subanalyses, the association was limited to patients with surgery alone (HR ¼ 3.21; CI 95%, 1.59-6.49; P ¼ 0.001), in contrast with patients with adjuvant chemotherapy (HR ¼ 0.82; CI 95%, 0.35-1.95; P ¼ 0.657). When the subgroup of patients with "high-risk" GLI1 rs2228226 C/C genotype was analyzed, no benefit of adjuvant 5-fluorouracil-based chemotherapy could be found.Conclusion: This is the first study identifying GLI1 rs2228226 G>C as an independent prognostic marker in patients with stage II and III colon carcinoma. Prospective studies are warranted to validate our findings.

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The Utility of Hedgehog Signaling Pathway Inhibition for Cancer

Abstract: ABSTRACT

Cited by 45 publications

References 106 publications

Dependence receptors and colorectal cancer

Dependence receptors and colorectal cancer

CD44 Expression Denotes a Subpopulation of Gastric Cancer Cells in Which Hedgehog Signaling Promotes Chemotherapy Resistance

A Functional Germline Variant in GLI1 Implicates Hedgehog Signaling in Clinical Outcome of Stage II and III Colon Carcinoma Patients

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