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Hypothyroidism enhances tumor invasiveness and metastasis development.

Martínez-Iglesias O, García-Silva S, Regadera J, Aranda A - PLoS ONE (2009)

Bottom Line: In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRbeta-expressing cells were injected into euthyroid nude mice.Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs.On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas y Universidad Autónoma de Madrid, Madrid, Spain.

ABSTRACT

Background: Whereas there is increasing evidence that loss of expression and/or function of the thyroid hormone receptors (TRs) could result in a selective advantage for tumor development, the relationship between thyroid hormone levels and human cancer is a controversial issue. It has been reported that hypothyroidism might be a possible risk factor for liver and breast cancer in humans, but a lower incidence of breast carcinoma has been also reported in hypothyroid patients

Methodology/principal findings: In this work we have analyzed the influence of hypothyroidism on tumor progression and metastasis development using xenografts of parental and TRbeta1-expressing human hepatocarcinoma (SK-hep1) and breast cancer cells (MDA-MB-468). In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRbeta-expressing cells were injected into euthyroid nude mice. Whereas tumor growth was retarded when cells were inoculated into hypothyroid hosts, tumors had a more mesenchymal phenotype, were more invasive and metastatic growth was enhanced. Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs.

Conclusions/significance: These results show that changes in the stromal cells secondary to host hypothyroidism can modulate tumor progression and metastatic growth independently of the presence of TRs on the tumor cells. On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer.

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Hypothyroidism enhances the mesenchymal phenotype of tumors.(A)-Immunohistochemical staining for vimentin, cytokeratin 8/18 and β-catenin showed that tumors from inoculated parental SK and MDA cells, as well as from cells expressing TRβ1, showed an increase of the mesenchymal marker and a reduction of epithelial markers. (B)-Quantification of the percentage of cells from the different tumors expressing cytokeratin 8/18 and vimentin. (C)- Cytokeratin 8/18 expression analyzed by immunofluorescence in explants obtained from tumors excised after 25 days of inoculation of SK and SK-TRβ cells into control and hypothyroid mice.
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pone-0006428-g006: Hypothyroidism enhances the mesenchymal phenotype of tumors.(A)-Immunohistochemical staining for vimentin, cytokeratin 8/18 and β-catenin showed that tumors from inoculated parental SK and MDA cells, as well as from cells expressing TRβ1, showed an increase of the mesenchymal marker and a reduction of epithelial markers. (B)-Quantification of the percentage of cells from the different tumors expressing cytokeratin 8/18 and vimentin. (C)- Cytokeratin 8/18 expression analyzed by immunofluorescence in explants obtained from tumors excised after 25 days of inoculation of SK and SK-TRβ cells into control and hypothyroid mice.

Mentions: We have previously observed that TRβ1 causes a partial mesenchymal to epithelial transition in the hepatocarcinoma and breast cancer tumors, decreasing the levels of the mesenchymal marker vimentin and increasing the epithelial marker cytokeratin 8/18. Other epithelial marker, β-catenin, was absent in xenografts from MDA cells, but it was expressed in xenografts from TRβ1-expressing SK cells [22]. As shown in Figure 6A, when cells were inoculated in hypothyroid mice, tumors from both parental and TRβ1-expressing SK and MDA cells had a more mesenchymal phenotype with a strong reduction of keratin 8/18 and β-catenin and a concomitant increase in vimentin. Quantification of the percentage of cells positive for these markers confirmed a strong reduction in the expression of the epithelial marker and a significant increase in the expression of the mesenchymal marker in tumors grown in hypothyroid hosts (Figure 6B). In addition, a strong reduction in cytokeratin 8/18 levels was observed by immunofluorescence in explants derived from hepatocarcinoma SK and SK-TRβ tumors originated in the hypothyroid mice (Figure 6C). These results show that hypothyroidism confers a less differentiated phenotype to the tumors independently of the presence of the receptor in the cancer cells.


Hypothyroidism enhances tumor invasiveness and metastasis development.

Martínez-Iglesias O, García-Silva S, Regadera J, Aranda A - PLoS ONE (2009)

Hypothyroidism enhances the mesenchymal phenotype of tumors.(A)-Immunohistochemical staining for vimentin, cytokeratin 8/18 and β-catenin showed that tumors from inoculated parental SK and MDA cells, as well as from cells expressing TRβ1, showed an increase of the mesenchymal marker and a reduction of epithelial markers. (B)-Quantification of the percentage of cells from the different tumors expressing cytokeratin 8/18 and vimentin. (C)- Cytokeratin 8/18 expression analyzed by immunofluorescence in explants obtained from tumors excised after 25 days of inoculation of SK and SK-TRβ cells into control and hypothyroid mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2712768&req=5

pone-0006428-g006: Hypothyroidism enhances the mesenchymal phenotype of tumors.(A)-Immunohistochemical staining for vimentin, cytokeratin 8/18 and β-catenin showed that tumors from inoculated parental SK and MDA cells, as well as from cells expressing TRβ1, showed an increase of the mesenchymal marker and a reduction of epithelial markers. (B)-Quantification of the percentage of cells from the different tumors expressing cytokeratin 8/18 and vimentin. (C)- Cytokeratin 8/18 expression analyzed by immunofluorescence in explants obtained from tumors excised after 25 days of inoculation of SK and SK-TRβ cells into control and hypothyroid mice.
Mentions: We have previously observed that TRβ1 causes a partial mesenchymal to epithelial transition in the hepatocarcinoma and breast cancer tumors, decreasing the levels of the mesenchymal marker vimentin and increasing the epithelial marker cytokeratin 8/18. Other epithelial marker, β-catenin, was absent in xenografts from MDA cells, but it was expressed in xenografts from TRβ1-expressing SK cells [22]. As shown in Figure 6A, when cells were inoculated in hypothyroid mice, tumors from both parental and TRβ1-expressing SK and MDA cells had a more mesenchymal phenotype with a strong reduction of keratin 8/18 and β-catenin and a concomitant increase in vimentin. Quantification of the percentage of cells positive for these markers confirmed a strong reduction in the expression of the epithelial marker and a significant increase in the expression of the mesenchymal marker in tumors grown in hypothyroid hosts (Figure 6B). In addition, a strong reduction in cytokeratin 8/18 levels was observed by immunofluorescence in explants derived from hepatocarcinoma SK and SK-TRβ tumors originated in the hypothyroid mice (Figure 6C). These results show that hypothyroidism confers a less differentiated phenotype to the tumors independently of the presence of the receptor in the cancer cells.

Bottom Line: In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRbeta-expressing cells were injected into euthyroid nude mice.Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs.On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas y Universidad Autónoma de Madrid, Madrid, Spain.

ABSTRACT

Background: Whereas there is increasing evidence that loss of expression and/or function of the thyroid hormone receptors (TRs) could result in a selective advantage for tumor development, the relationship between thyroid hormone levels and human cancer is a controversial issue. It has been reported that hypothyroidism might be a possible risk factor for liver and breast cancer in humans, but a lower incidence of breast carcinoma has been also reported in hypothyroid patients

Methodology/principal findings: In this work we have analyzed the influence of hypothyroidism on tumor progression and metastasis development using xenografts of parental and TRbeta1-expressing human hepatocarcinoma (SK-hep1) and breast cancer cells (MDA-MB-468). In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRbeta-expressing cells were injected into euthyroid nude mice. Whereas tumor growth was retarded when cells were inoculated into hypothyroid hosts, tumors had a more mesenchymal phenotype, were more invasive and metastatic growth was enhanced. Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs.

Conclusions/significance: These results show that changes in the stromal cells secondary to host hypothyroidism can modulate tumor progression and metastatic growth independently of the presence of TRs on the tumor cells. On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer.

Show MeSH
Related in: MedlinePlus