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Comparative immunohistochemical analysis of ochratoxin A tumourigenesis in rats and urinary tract carcinoma in humans; mechanistic significance of p-S6 ribosomal protein expression.

Gazinska P, Herman D, Gillett C, Pinder S, Mantle P - Toxins (Basel) (2012)

Bottom Line: Examples of rat subcutaneous fibrosarcoma and testicular seminoma, as well as of normal renal tissue, showed no or very weak positive staining.In contrast to the animal model, human renal cell carcinoma, upper urinary tract transitional cell carcinoma from cases of Balkan endemic nephropathy, and a human angiosarcoma were negative for p-S6.The combined findings are reminiscent of constitutive changes in the rat tuberous sclerosis gene complex in the Eker strain correlated with renal neoplasms, Therefore rat renal carcinogenesis caused by OTA does not obviously mimic human urinary tract tumourigenesis.

View Article: PubMed Central - PubMed

Affiliation: Breakthrough Breast Cancer Research Unit, Guy's Hospital, King's Health Partners AHSC, King's College London School of Medicine, London SE1 9RT, UK. patrycja.gazinska@kcl.ac.uk

ABSTRACT
Ochratoxin A (OTA) is considered to be a possible human urinary tract carcinogen, based largely on a rat model, but no molecular genetic changes in the rat carcinomas have yet been defined. The phosphorylated-S6 ribosomal protein is a marker indicating activity of the mammalian target of rapamycin, which is a serine/threonine kinase with a key role in protein biosynthesis, cell proliferation, transcription, cellular metabolism and apoptosis, while being functionally deregulated in cancer. To assess p-S6 expression we performed immunohistochemistry on formalin-fixed and paraffin-embedded tumours and normal tissues. Marked intensity of p-S6 expression was observed in highly proliferative regions of rat renal carcinomas and a rare angiosarcoma, all of which were attributed to prolonged exposure to dietary OTA. Only very small OTA-generated renal adenomas were negative for p-S6. Examples of rat subcutaneous fibrosarcoma and testicular seminoma, as well as of normal renal tissue, showed no or very weak positive staining. In contrast to the animal model, human renal cell carcinoma, upper urinary tract transitional cell carcinoma from cases of Balkan endemic nephropathy, and a human angiosarcoma were negative for p-S6. The combined findings are reminiscent of constitutive changes in the rat tuberous sclerosis gene complex in the Eker strain correlated with renal neoplasms, Therefore rat renal carcinogenesis caused by OTA does not obviously mimic human urinary tract tumourigenesis.

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Contrasting findings on expression of p-S6 protein in renal, testicular and mammary tumours, and renal tissues, of rats treated with OTA. (A) (case 1) part of a small in situ renal tumour with engulfment of adjacent glomeruli and scattered foci staining intensely for p-S6 protein. (B) (case 5), consistent lack of p-S6 protein in both normal testicular seminiferous tubules (right) and in adjacent seminoma (left); (C) (case 3), similar absence of p-S6 protein in kidney cortex (right) and adenoma (left); (D) (case 7) tumour (right), partly adenoma (centre) partly surrounded by infiltrating carcinoma with p-S6 expression; contrast with normal kidney (left); (E) (case 4), mammary angiosarcoma with extensive evenly-distributed p-S6 positive elements; (F) (case 2), isolated intensely-stained elements in the non-tumour kidney (contralateral kidney had a tumour); (G) (cases 18 and 19), kidney after 6 months (left) and 16 months (right), showing changes in regional pattern revealed by p-S6 antibody; (H) (case 1), subcutaneous tumour (normal ageing pathology in occasional rats), above, unstained for p-S6 protein contrasting with the expression in adenoma-like regions of kidney tumour, below, but not in adjacent kidney.
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toxins-04-00643-f001: Contrasting findings on expression of p-S6 protein in renal, testicular and mammary tumours, and renal tissues, of rats treated with OTA. (A) (case 1) part of a small in situ renal tumour with engulfment of adjacent glomeruli and scattered foci staining intensely for p-S6 protein. (B) (case 5), consistent lack of p-S6 protein in both normal testicular seminiferous tubules (right) and in adjacent seminoma (left); (C) (case 3), similar absence of p-S6 protein in kidney cortex (right) and adenoma (left); (D) (case 7) tumour (right), partly adenoma (centre) partly surrounded by infiltrating carcinoma with p-S6 expression; contrast with normal kidney (left); (E) (case 4), mammary angiosarcoma with extensive evenly-distributed p-S6 positive elements; (F) (case 2), isolated intensely-stained elements in the non-tumour kidney (contralateral kidney had a tumour); (G) (cases 18 and 19), kidney after 6 months (left) and 16 months (right), showing changes in regional pattern revealed by p-S6 antibody; (H) (case 1), subcutaneous tumour (normal ageing pathology in occasional rats), above, unstained for p-S6 protein contrasting with the expression in adenoma-like regions of kidney tumour, below, but not in adjacent kidney.

Mentions: The following descriptions of immunohistochemical findings in tissues are best read in conjunction with rat case context detail and literature cross-referencing tabulated in Supplementary Data. Findings are also summarised in Table 1 and illustrated in Figure 1, Figure 2, Figure 3, Figure 4.


Comparative immunohistochemical analysis of ochratoxin A tumourigenesis in rats and urinary tract carcinoma in humans; mechanistic significance of p-S6 ribosomal protein expression.

Gazinska P, Herman D, Gillett C, Pinder S, Mantle P - Toxins (Basel) (2012)

Contrasting findings on expression of p-S6 protein in renal, testicular and mammary tumours, and renal tissues, of rats treated with OTA. (A) (case 1) part of a small in situ renal tumour with engulfment of adjacent glomeruli and scattered foci staining intensely for p-S6 protein. (B) (case 5), consistent lack of p-S6 protein in both normal testicular seminiferous tubules (right) and in adjacent seminoma (left); (C) (case 3), similar absence of p-S6 protein in kidney cortex (right) and adenoma (left); (D) (case 7) tumour (right), partly adenoma (centre) partly surrounded by infiltrating carcinoma with p-S6 expression; contrast with normal kidney (left); (E) (case 4), mammary angiosarcoma with extensive evenly-distributed p-S6 positive elements; (F) (case 2), isolated intensely-stained elements in the non-tumour kidney (contralateral kidney had a tumour); (G) (cases 18 and 19), kidney after 6 months (left) and 16 months (right), showing changes in regional pattern revealed by p-S6 antibody; (H) (case 1), subcutaneous tumour (normal ageing pathology in occasional rats), above, unstained for p-S6 protein contrasting with the expression in adenoma-like regions of kidney tumour, below, but not in adjacent kidney.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475221&req=5

toxins-04-00643-f001: Contrasting findings on expression of p-S6 protein in renal, testicular and mammary tumours, and renal tissues, of rats treated with OTA. (A) (case 1) part of a small in situ renal tumour with engulfment of adjacent glomeruli and scattered foci staining intensely for p-S6 protein. (B) (case 5), consistent lack of p-S6 protein in both normal testicular seminiferous tubules (right) and in adjacent seminoma (left); (C) (case 3), similar absence of p-S6 protein in kidney cortex (right) and adenoma (left); (D) (case 7) tumour (right), partly adenoma (centre) partly surrounded by infiltrating carcinoma with p-S6 expression; contrast with normal kidney (left); (E) (case 4), mammary angiosarcoma with extensive evenly-distributed p-S6 positive elements; (F) (case 2), isolated intensely-stained elements in the non-tumour kidney (contralateral kidney had a tumour); (G) (cases 18 and 19), kidney after 6 months (left) and 16 months (right), showing changes in regional pattern revealed by p-S6 antibody; (H) (case 1), subcutaneous tumour (normal ageing pathology in occasional rats), above, unstained for p-S6 protein contrasting with the expression in adenoma-like regions of kidney tumour, below, but not in adjacent kidney.
Mentions: The following descriptions of immunohistochemical findings in tissues are best read in conjunction with rat case context detail and literature cross-referencing tabulated in Supplementary Data. Findings are also summarised in Table 1 and illustrated in Figure 1, Figure 2, Figure 3, Figure 4.

Bottom Line: Examples of rat subcutaneous fibrosarcoma and testicular seminoma, as well as of normal renal tissue, showed no or very weak positive staining.In contrast to the animal model, human renal cell carcinoma, upper urinary tract transitional cell carcinoma from cases of Balkan endemic nephropathy, and a human angiosarcoma were negative for p-S6.The combined findings are reminiscent of constitutive changes in the rat tuberous sclerosis gene complex in the Eker strain correlated with renal neoplasms, Therefore rat renal carcinogenesis caused by OTA does not obviously mimic human urinary tract tumourigenesis.

View Article: PubMed Central - PubMed

Affiliation: Breakthrough Breast Cancer Research Unit, Guy's Hospital, King's Health Partners AHSC, King's College London School of Medicine, London SE1 9RT, UK. patrycja.gazinska@kcl.ac.uk

ABSTRACT
Ochratoxin A (OTA) is considered to be a possible human urinary tract carcinogen, based largely on a rat model, but no molecular genetic changes in the rat carcinomas have yet been defined. The phosphorylated-S6 ribosomal protein is a marker indicating activity of the mammalian target of rapamycin, which is a serine/threonine kinase with a key role in protein biosynthesis, cell proliferation, transcription, cellular metabolism and apoptosis, while being functionally deregulated in cancer. To assess p-S6 expression we performed immunohistochemistry on formalin-fixed and paraffin-embedded tumours and normal tissues. Marked intensity of p-S6 expression was observed in highly proliferative regions of rat renal carcinomas and a rare angiosarcoma, all of which were attributed to prolonged exposure to dietary OTA. Only very small OTA-generated renal adenomas were negative for p-S6. Examples of rat subcutaneous fibrosarcoma and testicular seminoma, as well as of normal renal tissue, showed no or very weak positive staining. In contrast to the animal model, human renal cell carcinoma, upper urinary tract transitional cell carcinoma from cases of Balkan endemic nephropathy, and a human angiosarcoma were negative for p-S6. The combined findings are reminiscent of constitutive changes in the rat tuberous sclerosis gene complex in the Eker strain correlated with renal neoplasms, Therefore rat renal carcinogenesis caused by OTA does not obviously mimic human urinary tract tumourigenesis.

Show MeSH
Related in: MedlinePlus