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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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Renal tumour pathology (case 12, Supplementary Table S1) of the largest compression tumour found in all ochratoxin A (OTA) studies at Imperial College [6,8,10,11,12] illustrating adenoma histology. (A) formalin-fixed tumour, splitting functional (right) and necrotic (left) kidney tissue to opposite poles, with associated peri-renal fat. (B) divided spherical adenoma showing areas of haemorrhage. (C) section (H & E stained) from functional kidney showing small tangential tumourfragment (arrow). (D) section just beyond tumour edge, with expanded detail showing karyomegaly diagnosing outer medulla. (E) central tumour in formalin-fixed kidney, (F) separate micro-tumour with expanded detail of tumour-kidney junction; carcinoma bottom left, medulla with karyomegaly top right. (G) main tumour edge showing adenoma (left) bounded by stretched kidney cortex with distorted glomerulus (see immunohistochemical staining in Figure 2B).
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toxins-04-00643-f004: Renal tumour pathology (case 12, Supplementary Table S1) of the largest compression tumour found in all ochratoxin A (OTA) studies at Imperial College [6,8,10,11,12] illustrating adenoma histology. (A) formalin-fixed tumour, splitting functional (right) and necrotic (left) kidney tissue to opposite poles, with associated peri-renal fat. (B) divided spherical adenoma showing areas of haemorrhage. (C) section (H & E stained) from functional kidney showing small tangential tumourfragment (arrow). (D) section just beyond tumour edge, with expanded detail showing karyomegaly diagnosing outer medulla. (E) central tumour in formalin-fixed kidney, (F) separate micro-tumour with expanded detail of tumour-kidney junction; carcinoma bottom left, medulla with karyomegaly top right. (G) main tumour edge showing adenoma (left) bounded by stretched kidney cortex with distorted glomerulus (see immunohistochemical staining in Figure 2B).

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)

Renal tumour pathology (case 12, Supplementary Table S1) of the largest compression tumour found in all ochratoxin A (OTA) studies at Imperial College [6,8,10,11,12] illustrating adenoma histology. (A) formalin-fixed tumour, splitting functional (right) and necrotic (left) kidney tissue to opposite poles, with associated peri-renal fat. (B) divided spherical adenoma showing areas of haemorrhage. (C) section (H & E stained) from functional kidney showing small tangential tumourfragment (arrow). (D) section just beyond tumour edge, with expanded detail showing karyomegaly diagnosing outer medulla. (E) central tumour in formalin-fixed kidney, (F) separate micro-tumour with expanded detail of tumour-kidney junction; carcinoma bottom left, medulla with karyomegaly top right. (G) main tumour edge showing adenoma (left) bounded by stretched kidney cortex with distorted glomerulus (see immunohistochemical staining in Figure 2B).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

toxins-04-00643-f004: Renal tumour pathology (case 12, Supplementary Table S1) of the largest compression tumour found in all ochratoxin A (OTA) studies at Imperial College [6,8,10,11,12] illustrating adenoma histology. (A) formalin-fixed tumour, splitting functional (right) and necrotic (left) kidney tissue to opposite poles, with associated peri-renal fat. (B) divided spherical adenoma showing areas of haemorrhage. (C) section (H & E stained) from functional kidney showing small tangential tumourfragment (arrow). (D) section just beyond tumour edge, with expanded detail showing karyomegaly diagnosing outer medulla. (E) central tumour in formalin-fixed kidney, (F) separate micro-tumour with expanded detail of tumour-kidney junction; carcinoma bottom left, medulla with karyomegaly top right. (G) main tumour edge showing adenoma (left) bounded by stretched kidney cortex with distorted glomerulus (see immunohistochemical staining in Figure 2B).
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