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S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma.

Zou M, Al-Baradie RS, Al-Hindi H, Farid NR, Shi Y - Br. J. Cancer (2005)

Bottom Line: However, in MNG coexistent with PTC, moderate focal staining could be found in 11 of 15 MNG adjacent to PTC.The S100A4 was stained more intensely in invading fronts than in central portions of both T and M.Real-time RT-PCR analysis of primary tumours and their matched lymph node metastasis demonstrated that significantly higher S100A4 transcripts were present in metastatic tumours as compared to the primary tumours (P<0.01).

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Saudi Arabia.

ABSTRACT
Tumour cell invasion and metastasis are the hallmark of malignant neoplasm. S100A4 is a member of small calcium-binding protein family and is involved in the cell proliferation and cancer progression. S100A4 is capable of inducing metastasis in animal models and is associated with aggressive phenotype of human tumours. We previously identified S100A4 as a candidate gene involved in anaplastic thyroid cancer metastasis by microarray analysis. To further determine whether S100A4 overexpression is associated with thyroid tumour invasion and metastasis, in the present study, we examined S100A4 gene expression in six benign multinodular goitres (MNG) and 28 matched samples of adjacent normal thyroid tissue (N), primary (T) and metastatic (M) papillary thyroid carcinomas (PTC) by immunohistochemistry and real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. This gave us the advantage of directly comparing levels of S100A4 expression within the same genetic background. Using immunohistochemistry, we found that high levels of S100A4 were detected in 24 of 28 (86%) PTC specimens and their local regional lymph node or distant metastases. No S100A4 staining was observed in normal thyroid tissues and simple MNG. However, in MNG coexistent with PTC, moderate focal staining could be found in 11 of 15 MNG adjacent to PTC. The S100A4 was stained more intensely in invading fronts than in central portions of both T and M. Real-time RT-PCR analysis of primary tumours and their matched lymph node metastasis demonstrated that significantly higher S100A4 transcripts were present in metastatic tumours as compared to the primary tumours (P<0.01). These data suggest that overexpression of S100A4 is associated with thyroid tumour invasion and metastasis and it may be a potential target for therapeutic intervention.

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Focal S100A4 immunostaining of thyroid follicular cells in a multinodular goitre coexisted with papillary thyroid carcinoma. Moderate focal cytoplasmic and nuclear labelling of thyroid follicular cells can be seen in a multinodular goitre (upper panel: A, × 100; B, × 200), which is adjacent to papillary thyroid carcinoma. Strong labelling was shown in thyroid papillary carcinoma cells at the invading front from the same patient (upper panel: C, × 100; D, × 200). The lower panel shows the conventional haematoxylin and eosin staining of the corresponding areas shown in the upper panel.
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fig4: Focal S100A4 immunostaining of thyroid follicular cells in a multinodular goitre coexisted with papillary thyroid carcinoma. Moderate focal cytoplasmic and nuclear labelling of thyroid follicular cells can be seen in a multinodular goitre (upper panel: A, × 100; B, × 200), which is adjacent to papillary thyroid carcinoma. Strong labelling was shown in thyroid papillary carcinoma cells at the invading front from the same patient (upper panel: C, × 100; D, × 200). The lower panel shows the conventional haematoxylin and eosin staining of the corresponding areas shown in the upper panel.

Mentions: We demonstrated previously the S100A4 overexpression in advanced stage of thyroid carcinomas by Northern blot and real-time RT–PCR analysis. To examine the expression of S100A4 at the cellular level, we performed immunohistochemical analyses using histochemical preparations of formalin-fixed paraffin-embedded surgical specimens. Normal thyroid follicular cells were not stained with the S100A4 antibody (Figure 1A). No immunostaining was found in samples incubated with the secondary antibodies in the absence of primary antibodies (Figure 1C). Strong immunostaining was present in some lymphocytes, dendritic cells, and fibroblast-like reactive stroma cells in the thyroid tissues and lymph nodes usually surrounding the germinal centres (Figure 1E and F), which served as an internal positive control as previously reported (Rudland et al, 2000; Rosty et al, 2002). As shown in Table 1, S100A4 immunostaining was detected in 24 out of 28 (86%) PTC specimens: 21 with diffuse staining (staining was present in more than 25% of tumour cells) and three with focal staining (staining was present in <25% of tumour cells). In these S100A4-positive PTC samples, stronger staining was often observed at the tumour-invading front (Figure 2B and E) as compared to the central region (Figure 2A and D). In general, metastatic PTC samples had stronger staining (Figure 2C and F) when compared with their matched primary tumours (Figure 2A and D). There are two cases where positive staining was found in the metastatic lymph nodes and negative staining in the primary tumours. Therefore, 26 metastatic PTCs were S100A4 positive. We next compared the intensity of S100A4 staining between primary and metastatic PTCs. In all, 17 out of 24 (71%) metastatic PTCs were found to have stronger immunostaining than their matched primary PTC samples: 14 with local regional lymph node metastasis and three with distant metastases (one metastasised to the nose 8 years after treatment, and the other two metastasised to the lung and brain frontal lobe, respectively at the time of diagnosis) (Figure 3). Equal intensity of staining was found in the remaining seven metastatic tumours as compared to the primary tumours. S100A4 staining was mainly cytoplasmic, heterogeneous in some tumours with tendency to more intense staining in invading fronts than in central portions of the tumour samples. Striking nuclear staining was found in five tumour samples: three with distant metastasis to nose, lung or brain frontal lobe (TNM stage IV), and the other two with stage III tumours, indicating that nuclear staining may be associated with aggressive behaviour of the cancer (Figure 3). Among the four primary PTC samples with negative S100A4 staining, strong staining was observed in two matched lymph node metastasis tumour tissues. Interestingly, in 11 out of 15 cases where MNG were next to PTC, focal moderate cytoplasmic and nuclear staining could be found in MNG (Figure 4, upper panels A and B) as compared to the stronger staining in PTC (Figure 4, upper panels C and D). Examination of the same MNG area stained by haematoxylin and eosin failed to show the diagnostic nuclear features of PTC such as clearing of the nucleoplasm, peripheral margination of chromatin, or nuclear grooves, although subtle nuclear atypia manifesting as nucleomegaly and slight irregularity of the nuclear membrane was evident (Figure 4, lower panels A and B). These features were, however, present in the PTC area of the same patient (Figure 4, lower panels C and D). However, in the six cases with simple MNG, none of them labelled by S100A4 (Figure 1B).


S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma.

Zou M, Al-Baradie RS, Al-Hindi H, Farid NR, Shi Y - Br. J. Cancer (2005)

Focal S100A4 immunostaining of thyroid follicular cells in a multinodular goitre coexisted with papillary thyroid carcinoma. Moderate focal cytoplasmic and nuclear labelling of thyroid follicular cells can be seen in a multinodular goitre (upper panel: A, × 100; B, × 200), which is adjacent to papillary thyroid carcinoma. Strong labelling was shown in thyroid papillary carcinoma cells at the invading front from the same patient (upper panel: C, × 100; D, × 200). The lower panel shows the conventional haematoxylin and eosin staining of the corresponding areas shown in the upper panel.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361511&req=5

fig4: Focal S100A4 immunostaining of thyroid follicular cells in a multinodular goitre coexisted with papillary thyroid carcinoma. Moderate focal cytoplasmic and nuclear labelling of thyroid follicular cells can be seen in a multinodular goitre (upper panel: A, × 100; B, × 200), which is adjacent to papillary thyroid carcinoma. Strong labelling was shown in thyroid papillary carcinoma cells at the invading front from the same patient (upper panel: C, × 100; D, × 200). The lower panel shows the conventional haematoxylin and eosin staining of the corresponding areas shown in the upper panel.
Mentions: We demonstrated previously the S100A4 overexpression in advanced stage of thyroid carcinomas by Northern blot and real-time RT–PCR analysis. To examine the expression of S100A4 at the cellular level, we performed immunohistochemical analyses using histochemical preparations of formalin-fixed paraffin-embedded surgical specimens. Normal thyroid follicular cells were not stained with the S100A4 antibody (Figure 1A). No immunostaining was found in samples incubated with the secondary antibodies in the absence of primary antibodies (Figure 1C). Strong immunostaining was present in some lymphocytes, dendritic cells, and fibroblast-like reactive stroma cells in the thyroid tissues and lymph nodes usually surrounding the germinal centres (Figure 1E and F), which served as an internal positive control as previously reported (Rudland et al, 2000; Rosty et al, 2002). As shown in Table 1, S100A4 immunostaining was detected in 24 out of 28 (86%) PTC specimens: 21 with diffuse staining (staining was present in more than 25% of tumour cells) and three with focal staining (staining was present in <25% of tumour cells). In these S100A4-positive PTC samples, stronger staining was often observed at the tumour-invading front (Figure 2B and E) as compared to the central region (Figure 2A and D). In general, metastatic PTC samples had stronger staining (Figure 2C and F) when compared with their matched primary tumours (Figure 2A and D). There are two cases where positive staining was found in the metastatic lymph nodes and negative staining in the primary tumours. Therefore, 26 metastatic PTCs were S100A4 positive. We next compared the intensity of S100A4 staining between primary and metastatic PTCs. In all, 17 out of 24 (71%) metastatic PTCs were found to have stronger immunostaining than their matched primary PTC samples: 14 with local regional lymph node metastasis and three with distant metastases (one metastasised to the nose 8 years after treatment, and the other two metastasised to the lung and brain frontal lobe, respectively at the time of diagnosis) (Figure 3). Equal intensity of staining was found in the remaining seven metastatic tumours as compared to the primary tumours. S100A4 staining was mainly cytoplasmic, heterogeneous in some tumours with tendency to more intense staining in invading fronts than in central portions of the tumour samples. Striking nuclear staining was found in five tumour samples: three with distant metastasis to nose, lung or brain frontal lobe (TNM stage IV), and the other two with stage III tumours, indicating that nuclear staining may be associated with aggressive behaviour of the cancer (Figure 3). Among the four primary PTC samples with negative S100A4 staining, strong staining was observed in two matched lymph node metastasis tumour tissues. Interestingly, in 11 out of 15 cases where MNG were next to PTC, focal moderate cytoplasmic and nuclear staining could be found in MNG (Figure 4, upper panels A and B) as compared to the stronger staining in PTC (Figure 4, upper panels C and D). Examination of the same MNG area stained by haematoxylin and eosin failed to show the diagnostic nuclear features of PTC such as clearing of the nucleoplasm, peripheral margination of chromatin, or nuclear grooves, although subtle nuclear atypia manifesting as nucleomegaly and slight irregularity of the nuclear membrane was evident (Figure 4, lower panels A and B). These features were, however, present in the PTC area of the same patient (Figure 4, lower panels C and D). However, in the six cases with simple MNG, none of them labelled by S100A4 (Figure 1B).

Bottom Line: However, in MNG coexistent with PTC, moderate focal staining could be found in 11 of 15 MNG adjacent to PTC.The S100A4 was stained more intensely in invading fronts than in central portions of both T and M.Real-time RT-PCR analysis of primary tumours and their matched lymph node metastasis demonstrated that significantly higher S100A4 transcripts were present in metastatic tumours as compared to the primary tumours (P<0.01).

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Saudi Arabia.

ABSTRACT
Tumour cell invasion and metastasis are the hallmark of malignant neoplasm. S100A4 is a member of small calcium-binding protein family and is involved in the cell proliferation and cancer progression. S100A4 is capable of inducing metastasis in animal models and is associated with aggressive phenotype of human tumours. We previously identified S100A4 as a candidate gene involved in anaplastic thyroid cancer metastasis by microarray analysis. To further determine whether S100A4 overexpression is associated with thyroid tumour invasion and metastasis, in the present study, we examined S100A4 gene expression in six benign multinodular goitres (MNG) and 28 matched samples of adjacent normal thyroid tissue (N), primary (T) and metastatic (M) papillary thyroid carcinomas (PTC) by immunohistochemistry and real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. This gave us the advantage of directly comparing levels of S100A4 expression within the same genetic background. Using immunohistochemistry, we found that high levels of S100A4 were detected in 24 of 28 (86%) PTC specimens and their local regional lymph node or distant metastases. No S100A4 staining was observed in normal thyroid tissues and simple MNG. However, in MNG coexistent with PTC, moderate focal staining could be found in 11 of 15 MNG adjacent to PTC. The S100A4 was stained more intensely in invading fronts than in central portions of both T and M. Real-time RT-PCR analysis of primary tumours and their matched lymph node metastasis demonstrated that significantly higher S100A4 transcripts were present in metastatic tumours as compared to the primary tumours (P<0.01). These data suggest that overexpression of S100A4 is associated with thyroid tumour invasion and metastasis and it may be a potential target for therapeutic intervention.

Show MeSH
Related in: MedlinePlus