Carcinomas of the anal canal and anal margin differ in their expression of cadherin, cytokeratins and p53

Behrendt, G C; Ml, Hansmann

doi:10.1007/s004280100483

Cited by 14 publications

(7 citation statements)

References 20 publications

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“…5 We found that only 4% of our much larger sample set showed TP53 mutation in the mutation cluster region (exons 5-8), and to find a significant numbers of mutations outside the cluster region would appear unlikely. We found a higher frequency of nuclear TP53 accumulation (91%) than reported previously (37-71%) 6,8 and we predict the accumulated protein in most cases would be wild type.…”

Section: Discussioncontrasting

confidence: 53%

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Activation of AKT and nuclear accumulation of wild type TP53 and MDM2 in anal squamous cell carcinoma

Patel

Polanco-Echeverry

Segditsas

et al. 2007

Intl Journal of Cancer

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Human papilloma virus (HPV) infection is considered as an important aetiological factor for anal squamous cell carcinoma (ASCC) but is not sufficient for tumour progression. This carcinoma is poorly understood at the molecular level. Using the largest cohort of cases to date we investigated the molecular mechanisms underlying ASCC development, in particular the roles of TP53, MDM2 and AKT. Viral infection in our cohort occured at high frequency (73%, 94/128) with HPV16 accounting for the majority (86%, 81/94) of infected cases. Only 4% (5/119) of ASCCs showed TP53 (exons 5-8) mutations, but a high frequency (91%, 100/110) of nuclear protein expression of TP53 was observed. There was a significant association (p < 0.001) between nuclear accumulation of TP53 and MDM2 protein although no MDM2 mutations were found, and copy number was normal. Cellular accumulation of phosphorylated-AKT was observed in 66% (82/ 125) of ASCCs and an association demonstrated between nuclear accumulation of MDM2 and activated AKT (p < 0.001). We observed a high frequency of copy number gain at PIK3CA (47%), and some coding sequence mutations (4%). Amplification of PIK3CA was associated with presence of phosphorylated-AKT (p 5 0.008). There was no association between virus infection and TP53 nuclear accumulation (p 5 0.5). However, a significant association was found between infection and MDM2 nuclear staining, and between infection and activated AKT (p 5 0.04, p 5 0.01, respectively). We propose that activation of AKT, possibly through the PI3K-AKT pathway, is an important component of ASCC tumorigenesis that contributes to MDM2 and TP53 accumulation in the nucleus. ' 2007 Wiley-Liss, Inc.Key words: anal cancer; TP53; MDM2; AKT; HPV; ASCC The annual incidence of anal squamous cell carcinoma (ASCC) is 1.4-2 per 100,000 in the general, heterosexual population and accounts for approximately 300 cases per year in the UK and 3,500 in the USA.1,2 Sexually transmitted infection with mucosal high-risk human papillomavirus (HPV) causes anal intraepithelial neoplasia, which may progress from low-grade through to highgrade and finally to invasive neoplasia. 3,4 This process has distinct parallels with cervical intraepithelial neoplasia, including, origin within squamous epithelium and infection with some viral subtypes, such as HPV type 16, which appear to confer a significant risk of malignant transformation.ASCC is poorly understood at the molecular level and it remains to be documented whether mutational pathways in ASCC reflect those seen in cervical neoplasia, or whether there are parallels with colorectal cancer. The most common genetic alteration in human cancer is mutation of the TP53 tumour suppressor gene. To date, mutation of TP53 in ASCC has been examined in a single study that investigated only 9 tumours and found 3 coding sequence mutations.5 Whilst the frequency of TP53 mutation needs to be clarified, nuclear accumulation of TP53 protein has been shown in 37-71% of anal tumours. 6-8 Whether wild type or mutant TP53 protein can accou...

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Section: Discussioncontrasting

confidence: 53%

“…5 Whilst the frequency of TP53 mutation needs to be clarified, nuclear accumulation of TP53 protein has been shown in 37-71% of anal tumours. [6][7][8] Whether wild type or mutant TP53 protein can account for the observed nuclear staining is unclear.…”

mentioning

confidence: 99%

Activation of AKT and nuclear accumulation of wild type TP53 and MDM2 in anal squamous cell carcinoma

Patel

Polanco-Echeverry

Segditsas

et al. 2007

Intl Journal of Cancer

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“…It is also known that loss of E-cadherin has been associated with a less differentiated phenotype of squamous cell carcinoma. [28][29][30] Altered expression of keratin genes characterized by the absence of high-molecular-weight keratins, such as K1, has previously been shown to be related to malignant growth properties. 31 The absence of keratin pearls and loss of K1 expression in tumors generated with E-cadherin-deficient II-4 cells confirmed this relationship between the concomitant loss of cellcell adhesion and differentiation potential.…”

Section: Discussionmentioning

confidence: 99%

Loss of intercellular adhesion activates a transition from low‐ to high‐grade human squamous cell carcinoma

Margulis

Zhang

Alt-Holland

et al. 2005

Intl Journal of Cancer

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The relationship between loss of intercellular adhesion and the biologic properties of human squamous cell carcinoma is not well understood. We investigated how abrogation of E-cadherin-mediated adhesion influenced the behavior and phenotype of squamous cell carcinoma in 3D human tissues. Cell-cell adhesion was disrupted in early-stage epithelial tumor cells (HaCaT-II-4) through expression of a dominant-negative form of E-cadherin (H-2K dEcad). Three-dimensional human tissue constructs harboring either H-2K d -Ecad-expressing or control II-4 cells (pBabe, H-2K dEcadDC25) were cultured at an air-liquid interface for 8 days and transplanted to nude mice; tumor phenotype was analyzed 2 days and 2 and 4 weeks later. H-2Kd -Ecad-expressing tumors demonstrated a switch to a high-grade aggressive tumor phenotype characterized by poorly differentiated tumor cells that infiltrated throughout the stroma. This high-grade carcinoma revealed elevated cell proliferation in a random pattern, loss of keratin 1 and diffuse deposition of laminin 5 c2 chain. When II-4 cell variants were seeded into type I collagen gels as an in vitro assay for cell migration, we found that only E-cadherin-deficient cells detached, migrated as single cells and expressed N-cadherin. Functionblocking studies demonstrated that this migration was matrix metalloproteinase-dependent, as GM-6001 and TIMP-2, but not TIMP-1, could block migration. Gene expression profiles revealed that E-cadherin-deficient II-4 cells demonstrated increased expression of proteases and cell-cell and cell-matrix proteins. These findings showed that loss of E-cadherin-mediated adhesion plays a causal role in the transition from low-to high-grade squamous cell carcinomas and that the absence of E-cadherin is an important prognostic marker in the progression of this disease. ' 2005 Wiley-Liss, Inc.Key words: E-cadherin; squamous cell carcinoma; matrix metalloproteinase; laminin 5; tumor microenvironment E-cadherin is known to be a tumor suppressor gene since the loss of E-cadherin function in tumor progression during the advanced stages of carcinoma progression is well established [1][2][3] and has been linked to a poor clinical prognosis in vivo.4-6 Studies using 2D monolayer cultures have demonstrated the direct influence of E-cadherin function on the malignant properties of transformed cells at an advanced stage. For example, abrogation of E-cadherin-mediated adhesion 7-10 induced tumor cell invasion in vitro while restoration of E-cadherin function resulted in growth retardation and inhibition of invasive properties.3,9 However, the role that loss of E-cadherin-mediated adhesion may play in early stages of carcinoma progression is poorly understood, as studies have demonstrated either a reduction 11,12 or an increase 13,14 of E-cadherin function during the initial stages of epithelial cancer progression.Further elucidation of the impact of altered cell-cell adhesion on early events in squamous cell carcinoma progression has been limited by the inability of monolayer culture t...

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“…The altered mucosa was similar to that normally present in the anal squamocolumnar transition zone with areas akin to bronchial epithelium. Immunohistochemically, the former was CK5/6, CK7, and p63 positive, an immunophenotype described in normal anal transitional cell mucosa and carcinoma (6–8). The bronchial‐like epithelium showed a similar keratin profile, p63 positive basal cells, and was negative for thyroid transcription factor‐1 (a marker that occasionally shows basal cell nuclear positivity in typical bronchial epithelium).…”

Section: Discussionmentioning

confidence: 95%

Anal‐transitional and bronchial metaplasia within the ileostomy of a small bowel allograft: A case report

Talmon

Wisecarver

2011

Pediatric Transplantation

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Epithelial metaplasia is a phenomenon where a native mucosal cell type is replaced by another due to altered stem cell differentiation, usually as the result of long-standing injury or inflammation. It is common in ileostomies performed with native small bowels for both neoplastic and inflammatory conditions. We present a case of anal-transitional and bronchial epithelial metaplasia that occurred near the ileostomy of a small bowel allograft in a seven-month-old male transplanted for short bowel syndrome related to gastroschisis. The anal-transitional metaplastic mucosa had an immunophenotype (CK7- and p63-positive) similar to that of normal mucosa at the anal transition zone and a DNA STR profile consistent with the donor. To our knowledge, this represents the first report of this type of metaplasia occurring in ileostomies in the English literature. It is important for clinicians and pathologists to recognize these benign mucosal alterations to avoid diagnostic confusion.

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Carcinomas of the anal canal and anal margin differ in their expression of cadherin, cytokeratins and p53

Cited by 14 publications

References 20 publications

Activation of AKT and nuclear accumulation of wild type TP53 and MDM2 in anal squamous cell carcinoma

Activation of AKT and nuclear accumulation of wild type TP53 and MDM2 in anal squamous cell carcinoma

Loss of intercellular adhesion activates a transition from low‐ to high‐grade human squamous cell carcinoma

Anal‐transitional and bronchial metaplasia within the ileostomy of a small bowel allograft: A case report

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