The Hedgehog and Wnt signalling pathways in cancer

Taipale, Jussi; Beachy, Philip A.

doi:10.1038/35077219

Cited by 1,289 publications

(962 citation statements)

References 65 publications

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“…It has become increasingly common to view cancer as a "stem cell" disease (see [39]). In the colon, loss of TCF4 or Dkk over-expression promotes loss of stem cells in the colon crypt, indicating that Wnt signaling is required for maintenance of the stem cell compartment [40][41][42].…”

Section: Wnt Signaling In Cancer and Human Diseasementioning

confidence: 99%

Wnt signaling in disease and in development

2005

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ABSCTACTThe highly conserved Wnt secreted proteins are critical mediators of cell-to-cell signaling during development of animals. Recent biochemical and genetic analyses have led to significant insight into understanding how Wnt signals work. The catalogue of Wnt signaling components has exploded. We now realize that multiple extracellular, cytoplasmic, and nuclear components modulate Wnt signaling. Moreover, receptor-ligand specificity and multiple feedback loops determine Wnt signaling outputs. It is also clear that Wnt signals are required for adult tissue maintenance. Perturbations in Wnt signaling cause human degenerative diseases as well as cancer.

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Section: Wnt Signaling In Cancer and Human Diseasementioning

confidence: 99%

Wnt signaling in disease and in development

2005

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“…Thus, it is not surprising that several genes that control normal stem-cell self-renewal can cause cancer when deregulated by mutations. WNT signaling pathway regulates proliferation and self-renewal of different organs whereas activating mutations of WNT proteins have been identified in a variety of cancers [63][64][65] .…”

Section: Disruption Of Critical Self-renewal Pathwaysmentioning

confidence: 99%

“…Other signaling pathways involved in stem cell selfrenewal include Notch, Sonic hedgehog (Shh), phosphatidylinositol-3 kinase (PIK3), and Homeobox (HOX) and Polycomb families, all of which are deregulated in hematopoietic and epithelial tumors 64,[66][67][68][69][70][71][72] . A crucial task for investigators is to search for genetic and functional similarities and differences between normal and cancer stem cell self-renewal pathways.…”

Section: Disruption Of Critical Self-renewal Pathwaysmentioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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“…It has been shown that multiple pathways are involved in the self-renewal and tumor progression of CSCs, including Notch, Wnt, Hedgehog and phosphatidyl-inositol-3 kinase (PI3K) etc (Taipale and Beachy, 2001;Reya and Clevers, 2005;Farnie and Clarke, 2007;Dubrovska et al, 2009;Zhao et al, 2009). The ERBB2 (HER2) gene is amplified in approximately 20-30% of human breast and gastric cancers, in which it is associated with aggressive disease and early development of metastasis (Slamon et al, 1989;Tanner et al, 2005;Yano et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

et al. 2011

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Identification and characterization of cancer stem cells (CSCs) in gastric cancer are difficult owing to the lack of specific markers and consensus methods. In this study, we show that cells with the CD90 surface marker in gastric tumors could be enriched under non-adherent, serumfree and sphere-forming conditions. These CD90 þ cells possess a higher ability to initiate tumor in vivo and could re-establish the cellular hierarchy of tumors from singlecell implantation, demonstrating their self-renewal properties. Interestingly, higher proportion of CD90 þ cells correlates with higher in vivo tumorigenicity of gastric primary tumor models. In addition, it was found that ERBB2 was overexpressed in about 25% of the gastric primary tumor models, which correlates with the higher level of CD90 expression in these tumors. Trastuzumab (humanized anti-ERBB2 antibody) treatment of hightumorigenic gastric primary tumor models could reduce the CD90 þ population in tumor mass and suppress tumor growth when combined with traditional chemotherapy. Moreover, tumorigenicity of tumor cells could also be suppressed when trastuzumab treatment starts at the same time as cell implantation. Therefore, we have identified a CSC population in gastric primary tumors characterized by their CD90 phenotype. The finding that trastuzumab targets the CSC population in gastric tumors suggests that ERBB2 signaling has a role in maintaining CSC populations, thus contributing to carcinogenesis and tumor invasion. In conclusion, the results from this study provide new insights into the gastric tumorigenic process and offer potential implications for the development of anticancer drugs as well as therapeutic treatment of gastric cancers.

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The Hedgehog and Wnt signalling pathways in cancer

Cited by 1,289 publications

References 65 publications

Wnt signaling in disease and in development

Wnt signaling in disease and in development

Somatic stem cells and the origin of cancer

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

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