Metallothionein crypt-restricted immunopositivity indices (MTCRII) correlate with aberrant crypt foci (ACF) in mouse colon

Donnelly, Eilish; Bardwell, Helen; Thomas, G.A.; Williams, E. D.; Hoper, Margaret; Crowe, Paul; McCluggage, W Glenn; Stevenson, Michael; Phillips, David H.; Hewer, Alan; Osborne, Martin R.; Campbell, Frederick

doi:10.1038/sj.bjc.6602633

Cited by 8 publications

(4 citation statements)

References 19 publications

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“…MTimmunopositive crypt frequency has shown a dose response to three different chemical mutagens that further confirmed the evidence that it is a somatic mutation marker [13] .…”

Section: Stem Cell Mutationsupporting

confidence: 55%

Metallothionein: An overview

Thirumoorthy

Kumar²,

Sundar³

et al. 2007

WJG

190

135

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Metallothioneins (MTs) were discovered in 1957 by Margoshes and Vallee and identified as low-molecular weight and sulphydryl rich proteins. It is not surprising that most mammalian tissues contain age related basal levels of MTs since they are involved in metalloregulatory processes that include cell growth and multiplication. In an effort to understand the biology of this intriguing tumor, various biomarkers such as oncogenes, p53 tumor suppressor gene, waf 1 protein, proliferating cell nuclear antigen, telomerase, microsatellite markers and cytogenetic changes have been examined. One biomarker which has recently shown to be expressed in various human tumors but still less reported in carcinoma is MT. Immunohistochemical detection of MT proteins in cold acetone-fixed paraffin embedded liver sections was performed by the streptavidin-avidin-biotin immunoperoxidase complex method.

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“…MTimmunopositive crypt frequency has shown a dose response to three different chemical mutagens that further confirmed the evidence that it is a somatic mutation marker [13] .…”

Section: Stem Cell Mutationsupporting

confidence: 55%

Metallothionein: An overview

Thirumoorthy

Kumar²,

Sundar³

et al. 2007

WJG

190

135

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“…Furthermore, there was an even greater increase in relative number of MT-expressing crypts when T. cruzi infection was associated with nimesulide, suggesting that there may be a cumulative effect of T. cruzi infection and NSAID. The oncological relevance of MTEC is unclear but it has been recently shown that the relative number of MTECs correlates with the formation of aberrant crypt foci, that are well-recognized biomarkers of neoplastic transformation in the colon (15). Thus, it has been proposed that MTEC may be used as a relevant murine bioassay to study early stage colorectal tumorigenesis (15).…”

Section: Resultsmentioning

confidence: 99%

“…The oncological relevance of MTEC is unclear but it has been recently shown that the relative number of MTECs correlates with the formation of aberrant crypt foci, that are well-recognized biomarkers of neoplastic transformation in the colon (15). Thus, it has been proposed that MTEC may be used as a relevant murine bioassay to study early stage colorectal tumorigenesis (15).…”

Section: Resultsmentioning

confidence: 99%

Trypanosoma cruzi infection and/or administration of the nonsteroidal anti-inflammatory nimesulide increase the number of colonic crypts overexpressing metallothioneins in rat colon carcinogenesis

Escalante

Oliveira

Cunha

et al. 2006

Braz J Med Biol Res

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Trypanosoma cruzi infection and nonsteroidal anti-inflammatory drugs inhibit colorectal carcinogenesis by mechanisms not completely known and metallothionein proteins (MTs) may be involved in this process. Sixty-six male Wistar rats weighing 90 to 120 g were randomly divided into seven groups (GI to GVII). GI, GII and GIII animals were subcutaneously infected with 200,000 trypomastigote forms of the Y strain of T. cruzi. After 8 weeks, GI, GII, GIV, and GVI were injected with one weekly subcutaneous dose of 12 mg/kg dimethylhydrazine for 4 weeks. In sequence, GI, GIV and GV were treated with nimesulide (10 mg/kg per dose, five times per week for 8 weeks). Groups I, III, IV, and VI had 12 animals, and each of the other groups had 6 animals. All the animals were euthanized 8 weeks after the last dimethylhydrazine injection. The colons were fixed and processed for MT immunohistochemistry. The index of MT-overexpressing colonic crypts (MTEC) was estimated as the percentage of MT-stained crypts in relation to the total number of crypts scored. Five hundred crypts per animal were scored. Data were analyzed by the Kruskal-Wallis test followed by the Dunn test. There was an increase in MTEC index in the groups either infected with T. cruzi or treated with nimesulide or both infected and treated when compared to control (401, 809, and 1011%, respectively). We suggest that the increased formation of MTEC may be related to the protection against carcinogenesis provided both by T. cruzi infection and nimesulide.

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“…Aberrant crypt foci (ACF) were assessed as we have described previously (39). Briefly, colons were opened longitudinally, flushed with ice-cold phosphatebuffered saline, carefully pinned flat on a cork mat, painted with 0.2% methylene blue and left at room temperature for 10 min.…”

Section: Assay Of Colonic Aberrant Crypt Focimentioning

confidence: 99%

Apc MIN modulation of vitamin D secosteroid growth control

Xu¹,

Posner²,

Stevenson³

et al. 2010

Carcinogenesis

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A central paradox of vitamin D biology is that 1alpha,25-(OH)(2) D(3) exposure inversely relates to colorectal cancer (CRC) risk despite a capacity for activation of both pro- and anti-oncogenic mediators including osteopontin (OPN)/CD44 and E-cadherin, respectively. Most sporadic CRCs arise from adenomatous polyposis coli (APC) gene mutation but understanding of its effects on vitamin D growth control is limited. Here we investigate effects of the Apc(Min/+) genotype on 1alpha,25-(OH)(2) D(3) regulation of OPN/CD44/E-cadherin signalling and intestinal tumourigenesis, in vivo. In untreated Apc(Min/+) versus Apc(+/+) intestines, expression levels of OPN and its CD44 receptor were increased, whereas E-cadherin tumour suppressor signalling was attenuated. Treatment by 1alpha,25-(OH)(2) D(3) or rationally designed analogues (QW or BTW) enhanced OPN but inhibited expression of CD44, the OPN receptor implicated in cell growth. These treatments also enhanced E-cadherin tumour suppressor activity, characterized by inhibition of beta-catenin nuclear localization, T-cell factor 1 and c-myelocytomatosis protein expression in Apc(Min/+) intestine. All secosteroids suppressed Apc(Min/+)-driven tumourigenesis although QW and BTW had lower calcium-related toxicity. Taken together, these data indicate that the Apc(Min/+) genotype modulates vitamin D secosteroid actions to promote functional predominance of E-cadherin tumour suppressor activity within antagonistic molecular networks. APC heterozygosity may promote favourable tissue- or tumour-specific conditions for growth control by vitamin D secosteroid treatment.

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Metallothionein crypt-restricted immunopositivity indices (MTCRII) correlate with aberrant crypt foci (ACF) in mouse colon

Cited by 8 publications

References 19 publications

Metallothionein: An overview

Metallothionein: An overview

Trypanosoma cruzi infection and/or administration of the nonsteroidal anti-inflammatory nimesulide increase the number of colonic crypts overexpressing metallothioneins in rat colon carcinogenesis

Apc MIN modulation of vitamin D secosteroid growth control

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