The hedgehog signalling pathway in tumorigenesis and development

Wicking, Carol; Smyth, Ian; Bale, Allen E.

doi:10.1038/sj.onc.1203282

Cited by 154 publications

(111 citation statements)

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“…It is thus reasonable to suspect that similar pathways may be altered in both of these neoplasias. However, contrary to our data, PTC mutations are found in 12-38% of sporadic BCCs and overexpression of PTC is observed in these tumours (Wicking et al, 1999). The expression of PTC mRNA in normal urothelium, the absence of PTC mutations and the decreased expression of PTC mRNA in UCs, all argue for a different regulation of the PTC/SHH pathway in bladder than in skin.…”

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confidence: 55%

“…To our knowledge, such an occurrence has not been reported for the PTC gene. On the other hand, increased PTC expression has been reported in cancers such as BCCs and medulloblastomas even in the presence of PTC LOH (Wicking et al, 1999;Zurawel et al, 2000). Various studies have suggested that any disruption in the equilibrium between PTC, SHH and SMO can lead to tumour formation.…”

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confidence: 99%

“…A second gene located in the 9q22 minimal region of deletion is the PTC gene (Hahn et al, 1996;Johnson et al, 1996). First described in the drosophila, PTC is part of an important pathway involved in developmental patterning (Chen and Struhl, 1996;Goodrich et al, 1996;Wicking et al, 1999). According to current hypotheses, the PTC protein acts as a repressor of the pathway that is mediated through binding of the secreted protein Sonic Hedgehog (SHH).…”

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Alteration of the PATCHED locus in superficial bladder cancer

et al. 2003

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Chromosome 9 alterations are the most frequently encountered cytologic anomalies in urothelial carcinoma (UC). We previously screened 139 low-stage UCs for loss of heterozygosity on chromosome 9, and identified five distinct regions likely to harbour tumour-suppressor genes. The present study focused on deletion mapping in the 9q22 region with 11 additional microsatellite markers. New deletions in the 9q22 region were found in five tumours. Deletion mapping allowed us to identify a 0.5 CM common minimal region of deletion between markers D9S280 and D9S1809, encompassing PATCHED (PTC), a gene identified as a tumour suppressor in basal cell carcinoma and in medulloblastoma. A marker located in the first intron of this gene showed the highest percentage of deletion (45%). cDNA sequencing in 15 tumours with deletion of PTC showed no mutation in the remaining allele. However, average expression of PTC mRNA measured by semiquantitative RT-PCR was significantly decreased in tumours with LOH in the 9q22 region, compared to normal urothelium (P ¼ 0.04), while it showed marked fluctuations in tumours without deletion. Our results suggest that the PTC gene is a putative suppressor at the 9q22 locus and that haploinsufficiency of this gene may be an early event in the development of papillary bladder tumours.

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Alteration of the PATCHED locus in superficial bladder cancer

et al. 2003

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“…Loss of regulation in this pathway has been implicated in several human cancers 10,11 . Thus in order to determine the potential role of SHH misexpression in the adult human pancreas, pancreata from transgenic mice (gift of H. Edlund) in which Shh misexpression was driven by the pancreatic-specific Pdx-1 promoter were histologically and immunohistochemically analysed.…”

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Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Thayer

Magliano

Heiser

et al. 2003

Nature

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Hedgehog signalling-an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer-may also be an important mediator in human pancreatic carcinoma [1][2][3][4][5][6][7][8] . Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx-Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.Sonic hedgehog (SHH) is misexpressed in human adenocarcinoma and its precursor lesions. SHH expression was determined using in situ hybridization to detect SHH messenger RNA and immunohistochemistry (IHC) to detect the protein with an antibody directed against Competing interests statementThe authors declare that they have no competing financial interests. . Pancreatic tissues were obtained from 20 specimens resected for pancreatic cancer. Control pancreatic tissues with no evidence of abnormality or autolysis upon histological evaluation were obtained from autopsy specimens or from pancreatic resections for trauma. In normal adult human pancreata, no SHH was detected in the islets, acini or ductal epithelium (Fig. 1a). However, evaluation of pancreata from patients with adenocarcinoma reveals that SHH is aberrantly expressed in 70% of specimens. Normal ductal epithelium does not express detectable levels of SHH (Fig. 1b); however, as the ductal epithelium shows increasing degrees of atypia, PanIN-1 to -3 ( Fig. 1c-e), a higher expression of SHH is observed. SHH expression is also detected in the malignant epithelium of adenocarcinoma samples (Fig. 1f). This expression pattern was also confirmed by our in situ hybridization for SHH mRNA ( Supplementary Fig. 1). NIH Public AccessLoss of regulation in this pathway has been implicated in several human cancers 10,11 . Thus in order to determine the potential role of SHH misexpression in the adult human pancreas, pancreata from transgenic mice (gift of H. Edlund) in which Shh misexpression was driven by the pancreatic-specific Pdx-1 promoter were histologically and immunohistochemically analysed.A total of four pancreata from three-week-old Pdx-Shh mice were histologically evaluated by a gastro...

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“…The secreted molecule sonic hedgehog (Shh) is essential for many developmental processes in vertebrates, including the induction of motor neurons (reviewed in Ingham, 1998;Wicking et al, 1999). Three hedgehog genes, shh (Krauss et al, 1993), tiggy-winkle hedgehog (twhh; Ekker et al, 1995) and echidna hedgehog (ehh; Currie and Ingham, 1996) are expressed in various tissues in zebrafish embryos.…”

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confidence: 99%