The Invasion Front of Human Colorectal Adenocarcinomas Shows Co-Localization of Nuclear β-Catenin, Cyclin D1, and p16INK4A and Is a Region of Low Proliferation

Jung, Andreas; Schrauder, Michael G.; Oswald, Ursula; Knoll, Claudia; Sellberg, Petter; Palmqvist, Richard; Niedobitek, Gerald; Brabletz, Thomas; Kirchner, Thomas

doi:10.1016/s0002-9440(10)63007-6

Cited by 208 publications

(200 citation statements)

References 23 publications

(30 reference statements)

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“…E-cadherin expression is decreased or undetected in tumour cells at the invasive front (Brabletz et al, 2001), whereas expression of laminin-5 g2 chain (Pyke et al, 1995;Hlubek et al, 2004), MMP7 (Brabletz et al, 1999) and SNAI2 (Shioiri et al, 2006) is increased. Additionally, cell proliferation (Ki-67 staining) is decreased at the invasive front (Brabletz et al, 2001;Jung et al, 2001). Consistent with these findings in carcinoma tissues, decreased E-cadherin and cell proliferation, and increased SNAI2, laminin a3 and g2 chains, and MMP7 defined spontaneous EMT of the carcinoids.…”

Section: Discussionsupporting

confidence: 76%

Frizzled-7 dictates three-dimensional organization of colorectal cancer cell carcinoids

et al. 2006

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Progression of colorectal cancer (CRC) involves spatial and temporal occurrences of epithelial-mesenchymal transition (EMT), whereby tumour cells acquire a more invasive and metastatic phenotype. Subsequently, the disseminated mesenchymal tumour cells must undergo a reverse transition (mesenchymal-epithelial transition, MET) at the site of metastases, as most metastases recapitulate the pathology of their corresponding primary tumours. Importantly, initiation of tumour growth at the secondary site is the rate-limiting step in metastasis. However, investigation of this dynamic reversible EMT and MET that underpins CRC morphogenesis has been hindered by a lack of suitable in vitro models. To this end, we have established a unique in vitro model of CRC morphogenesis, which we term LIM1863-Mph (morphogenetic). LIM1863-Mph cells spontaneously undergo cyclic transitions between two-dimensional monolayer (migratory, mesenchymal) and three-dimensional sphere (carcinoid, epithelial) states. Using RNAi, we demonstrate that FZD7 is necessary for MET of the monolayer cells as loss of FZD7 results in the persistence of a mesenchymal state (increased SNAI2/decreased E-cadherin). Moreover, FZD7 is also required for migration of the LIM1863-Mph monolayer cells. During development, FZD7 orchestrates either migratory or epithelialization events depending on the context. Our findings strongly implicate similar functional diversity for FZD7 during CRC morphogenesis.

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Section: Discussionsupporting

confidence: 76%

Frizzled-7 dictates three-dimensional organization of colorectal cancer cell carcinoids

et al. 2006

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“…The upregulation of p16 expression in association with cyclin D1 has also been described at the invasive front of colorectal carcinoma. 52,53 In summary, this study has shown that the immunoreactivity of cell cycle regulatory proteins in uterine low-grade endometrioid adenocarcinomas varies according to microanatomical distribution. Cyclin D1 and b-catenin are most uniformly expressed toward the peripheral or basal aspect of conventional tumor glands.…”

Section: Endometrial Carcinoma Invasionmentioning

confidence: 71%

Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

et al. 2009

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Endometrial adenocarcinomas may show a distinctive pattern of invasion characterized by the presence of microcystic, elongated and fragmented glands, often most evident along the advancing tumor margin. Earlier, we have shown that these changes appear restricted to low-grade endometrioid carcinomas, many of which show focal mucinous differentiation and lymphovascular space invasion. However, the molecular alterations associated with this morphological alteration are not known. In this study, we have examined immunoreactivity for the cell cycle regulatory proteins cyclin D1, p16 and b-catenin in 22 endometrial carcinomas, specifically comparing the results in conventional tumor areas and in foci in which the glands exhibited microcystic, elongated and fragmented appearances. The conventional neoplastic glands exhibited cyclin D1 and p16 expression in most cases, with 450% tumor cells positive in 8 cases and 11 tumors, respectively. Membranous expression of b-catenin was usually preserved, with variable cytoplasmic and nuclear staining. Cyclin D1 and b-catenin predominantly stained cells at the peripheral or basal aspect of the conventional glands, whereas p16 was more uniformly expressed centrally. Tumor foci composed of microcystic, fragmented and elongated glands showed strong expression of cyclin D1 and p16, sometimes in contrast to unstained contiguous or adjacent conventional neoplastic elements, and there was also loss or fragmentation of membranous b-catenin staining. Intravascular tumor cells also expressed cyclin D1 and p16 and therefore the immunostains often highlighted subtle foci of lymphovascular invasion. The heterogenous expression of cell cycle regulatory proteins within endometrial adenocarcinoma illustrates the importance of assessing microanatomical variations in immunoreactivity, particularly at the advancing margin of tumors. The upregulation of cyclin D1 and p16, together with loss of membranous b-catenin expression in microcystic, fragmented and elongated glands, is similar to epithelial-mesenchymal transitions observed in other malignancies and suggests that this pattern of invasion represents an active rather than a degenerative cellular process. Modern Pathology (2009) 22, 725-733; doi:10.1038/modpathol.2009 published online 6 March 2009 Keywords: endometrial; carcinoma; invasion; MELF; epithelial-mesenchymal transition; immunohistochemistry Endometrial carcinomas can be divided into two major groups on the basis of clinicopathological, immunohistological and molecular features. 1,2 The more common (type 1) subgroup accounts for 80-85% of cases and mainly comprises endometrioid adenocarcinomas of low-to-intermediate grade. These tumors typically occur in perimenopausal and younger postmenopausal patients, often arise in hyperestrogenic states and are associated with atypical endometrial hyperplasia/endometrial intraepithelial neoplasia. Frequently, type 1 carcinomas are confined to the uterine corpus at the time of diagnosis (stage 1), and the prognosis in such patients is generally ...

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“…On the one hand, this fits in with the observed differences in the cellular composition of these 2 areas and particularly our morphologic data, which indicates a decrease of hepatocytes and an increase of HSCs in the invasion front. On the other hand, at least cancer cells in the invasion front can be higher 55 as well as lower 56 in proliferation than their counterparts in the inner parts of the tumor, allowing them to concentrate on their specific roles in the process of invasion. This may hold true for some host cells as well but not for others (such as endothelial cells).…”

Section: Discussionmentioning

confidence: 99%

Global analysis of host tissue gene expression in the invasive front of colorectal liver metastases

Bandapalli

Geheeb

Kobelt

et al. 2005

Intl Journal of Cancer

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Host cell reactions are a crucial determinant for tumor invasion. We analyzed on a genomewide scale gene expression differences between microdissected tissues taken from unaffected liver tissue of a human colorectal tumor (LS174) growing in the livers of nude mice and tissue from the host part of the invasive front. Due to the low degree of interspecies cross‐hybridization of 15% as determined on Affymetrix microarrays, our xenograft model allowed for the distinction of genes of murine versus human origin even if the respective tissues could not be isolated separately. Using the gene ontology (GO) classification, we were able to determine patterns of up‐ and downregulated genes in the liver part of the invasive front. We observed a pronounced overrepresentation, e.g., of the GO terms “extracellular matrix,” “cell communication,” “response to biotic stimulus,” “structural molecule activity” and “cell growth,” indicating a very pronounced host cell response to tumor invasion. On the single gene level, hepatic stellate cell (HSC) activation markers were overrepresented in the liver part of the invasion front. Immunohistochemistry and qPCR confirmed an activation of HSC as well as an increased number of HSC in the invasive front as compared to the noninvaded liver tissue. In summary, our data demonstrate the feasibility of an interspecies differential gene expression approach on a genomewide scale. © 2005 Wiley‐Liss, Inc.

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The Invasion Front of Human Colorectal Adenocarcinomas Shows Co-Localization of Nuclear β-Catenin, Cyclin D1, and p16INK4A and Is a Region of Low Proliferation

Cited by 208 publications

References 23 publications

Frizzled-7 dictates three-dimensional organization of colorectal cancer cell carcinoids

Frizzled-7 dictates three-dimensional organization of colorectal cancer cell carcinoids

Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

Global analysis of host tissue gene expression in the invasive front of colorectal liver metastases

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