Hedgehog signalling in foregut malignancy

Watkins, D. Neil; Peacock, Craig D.

doi:10.1016/j.bcp.2004.04.025

Cited by 70 publications

(59 citation statements)

References 70 publications

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“…Thus, the levels of these transcripts are often used as surrogate markers of HH pathway activity (33). However, recent studies suggested that other less-understood mechanisms also influence the levels of PTCH and GLI1 transcripts.…”

Section: Discussionmentioning

confidence: 99%

Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

Li¹,

Che²,

Yanhua³

et al. 2012

Chin. J. Cancer Res.

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Section: Discussionmentioning

confidence: 99%

Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

Li¹,

Che²,

Yanhua³

et al. 2012

Chin. J. Cancer Res.

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“…However, the significance of high expression in these neoplastic lesions is evident from several previous studies on the role of unregulated and persistent Shh activation in the connection between chronic tissue injury and cancer. 8,23,24 Persistent Shh activation related to chronic injury is required for tumorigenesis, instead of the transient activation induced by acute injury. This continuous Shh activation induces expansion in a pool of activated stem cells.…”

Section: Discussionmentioning

confidence: 99%

“…While the significance of this observation is still elusive, the reason is inferred from the dual function of Shh, that is, one, to increase the stem cell number during regeneration, and the other, to provide a polarizing signal in asymmetrical differentiation of gastric mucosa to the gastric pit and glandular components. 8,23,24 Therefore, Shh expression is absent in simple metaplasia where asymmetrical differentiation was lost, but increased in inflammation and regeneration-associated metaplasia related to the intense proliferation of tissue stem cells.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions

et al. 2006

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The hedgehog (Hh) signaling pathway plays an important role in foregut development, and its activity is increased in various tumors, including those of the digestive tract. Our objective in the present study was to determine the pattern and extent of Sonic hedgehog (Shh) expression in gastric cancer and related lesions as well as the methylation status of its promoter region, in an attempt to clarify the regulatory mechanism of Shh expression. A total of 237 gastric cancers and related lesions (89 carcinomas, 22 high-grade dysplasia, 21 lowgrade dysplasia, 47 intestinal metaplasia, 38 chronic gastritis, and 20 normal epithelia) were subjected to immunohistochemical analysis with the Shh monoclonal antibody. The methylation status of Shh was determined by methylation-specific PCR (MS PCR), involving bisulfate treatment of DNA from 150 tissues followed by amplification using specific primer pairs designed by our group. Shh was completely absent in the upper part of normal gastric epithelia (gastric pit cells), and no significant differences were observed among the lower parts of normal epithelia, chronic gastritis, and intestinal metaplasia. However, Shh expression was significantly elevated in neoplastic lesions, such as carcinoma and high low-grade dysplasia, compared to nonneoplastic lesions. In carcinomas, Shh expression was associated with clinical stage, direct tumor invasion, and differentiation of tumor cells. Methylation of the Shh promoter region was frequent in normal gastric pit cells (11/18, 61.1%), but very rare in gastritis (0/18), intestinal metaplasia (0/19), dysplasia (0/10), and carcinoma (1/63, 1.6%), and correlated significantly with expression (Po0.001). Our results suggested that the increased and constitutive Shh expression is implicated in gastric carcinogenesis, and that promoter methylation may be an important regulatory mechanism of Shh expression.

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“…The mechanism of abnormal Hh pathway activation in such ''non-Gorlin'' tumors remains unclear; however, growth of a significant proportion of these cancers is inhibited by cyclopamine, suggesting that events leading to SMO activation contribute to the malignant phenotype of these tumors (21). Genetic mouse models suggest that Hh signaling may contribute to the initiation and expansion of an aberrant progenitor population (22,23), which is then maintained in cancer as a tumor ''stem cell.''…”

mentioning

confidence: 99%

Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma

Peacock

Wang

Gesell

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

444

351

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The cancer stem cell hypothesis suggests that malignant growth depends on a subset of tumor cells with stem cell-like properties of self-renewal. Because hedgehog (Hh) signaling regulates progenitor cell fate in normal development and homeostasis, aberrant pathway activation might be involved in the maintenance of such a population in cancer. Indeed, mutational activation of the Hh pathway is associated with medulloblastoma and basal cell carcinoma; pathway activity is also critical for growth of other tumors lacking such mutations, although the mechanism of pathway activation is poorly understood. Here we study the role and mechanism of Hh pathway activation in multiple myeloma (MM), a malignancy with a well defined stem cell compartment. In this model, rare malignant progenitors capable of clonal expansion resemble B cells, whereas the much larger tumor cell population manifests a differentiated plasma cell phenotype that pathologically defines the disease. We show that the subset of MM cells that manifests Hh pathway activity is markedly concentrated within the tumor stem cell compartment. The Hh ligand promotes expansion of MM stem cells without differentiation, whereas the Hh pathway blockade, while having little or no effect on malignant plasma cell growth, markedly inhibits clonal expansion accompanied by terminal differentiation of purified MM stem cells. These data reveal that Hh pathway activation is heterogeneous across the spectrum of MM tumor stem cells and their more differentiated progeny. The potential existence of similar relationships in other adult cancers may have important biologic and clinical implications for the study of aberrant Hh signaling.cancer stem cells ͉ cancer therapy ͉ cyclopamine

show abstract

Hedgehog signalling in foregut malignancy

Cited by 70 publications

References 70 publications

Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions

Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma

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