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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 retards tumor growth.(A)-Tumor incidence in euthyroid and hypothyroid nude mice injected heterotopically into both flanks with parental (SK) and TRβ1-expressing (SK-TRβ) hepatocarcinoma cells. (B)-Tumor volume was measured at different time points after inoculation in the same experimental groups. (C)-MDA and MDA-TRβ cells were inoculated orthotopically into the mammary fat pad of both groups of mice and tumor appearance was followed. (D)-Tumor volume in xenografts of parental and TRβ-expressing MDA cells. Data are mean±S.E.
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pone-0006428-g002: Hypothyroidism retards tumor growth.(A)-Tumor incidence in euthyroid and hypothyroid nude mice injected heterotopically into both flanks with parental (SK) and TRβ1-expressing (SK-TRβ) hepatocarcinoma cells. (B)-Tumor volume was measured at different time points after inoculation in the same experimental groups. (C)-MDA and MDA-TRβ cells were inoculated orthotopically into the mammary fat pad of both groups of mice and tumor appearance was followed. (D)-Tumor volume in xenografts of parental and TRβ-expressing MDA cells. Data are mean±S.E.

Mentions: Nude mice were made hypothyroid by treatment with anti-thyroidal drugs 4 weeks before inoculation of tumor cells (Figure 1). This treatment significantly retarded the growth of the animals that at the end of the experiments showed a decreased weight in comparison with the untreated controls, strongly reduced the levels of circulating thyroxine, and also markedly decreased transcript levels for deiodinase 1 in liver, a sensitive marker for tissue hypothyroidism [35]. SK and SK-TRβ cells were inoculated subcutaneously into the flanks of control and hypothyroid nude mice and tumor growth was followed (Figure 2). In agreement with our previous observations [22], in euthyroid animals expression of TRβ retarded the detection of palpable tumors (Figure 2A) and significantly reduced tumor volume during the first weeks (Figure 2B). Furthermore, hypothyroidism retarded tumor growth in mice inoculated with both SK and SK-TRβ cells, although the reduction was more marked in the case of the TRβ-expressing cells. When MDA cells were inoculated orthotopically in the mammary gland, tumor appearance was slightly retarded in hypothyroid animals in both parental and TRβ-expressing cells (Figure 2C) and tumor volume was also smaller (Figure 2D), although differences were less marked than those observed with hepatocarcinoma cells and were only statistically significant at 9 weeks post-inoculation of MDA-TRβ cells.


Hypothyroidism enhances tumor invasiveness and metastasis development.

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

Hypothyroidism retards tumor growth.(A)-Tumor incidence in euthyroid and hypothyroid nude mice injected heterotopically into both flanks with parental (SK) and TRβ1-expressing (SK-TRβ) hepatocarcinoma cells. (B)-Tumor volume was measured at different time points after inoculation in the same experimental groups. (C)-MDA and MDA-TRβ cells were inoculated orthotopically into the mammary fat pad of both groups of mice and tumor appearance was followed. (D)-Tumor volume in xenografts of parental and TRβ-expressing MDA cells. Data are mean±S.E.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2712768&req=5

pone-0006428-g002: Hypothyroidism retards tumor growth.(A)-Tumor incidence in euthyroid and hypothyroid nude mice injected heterotopically into both flanks with parental (SK) and TRβ1-expressing (SK-TRβ) hepatocarcinoma cells. (B)-Tumor volume was measured at different time points after inoculation in the same experimental groups. (C)-MDA and MDA-TRβ cells were inoculated orthotopically into the mammary fat pad of both groups of mice and tumor appearance was followed. (D)-Tumor volume in xenografts of parental and TRβ-expressing MDA cells. Data are mean±S.E.
Mentions: Nude mice were made hypothyroid by treatment with anti-thyroidal drugs 4 weeks before inoculation of tumor cells (Figure 1). This treatment significantly retarded the growth of the animals that at the end of the experiments showed a decreased weight in comparison with the untreated controls, strongly reduced the levels of circulating thyroxine, and also markedly decreased transcript levels for deiodinase 1 in liver, a sensitive marker for tissue hypothyroidism [35]. SK and SK-TRβ cells were inoculated subcutaneously into the flanks of control and hypothyroid nude mice and tumor growth was followed (Figure 2). In agreement with our previous observations [22], in euthyroid animals expression of TRβ retarded the detection of palpable tumors (Figure 2A) and significantly reduced tumor volume during the first weeks (Figure 2B). Furthermore, hypothyroidism retarded tumor growth in mice inoculated with both SK and SK-TRβ cells, although the reduction was more marked in the case of the TRβ-expressing cells. When MDA cells were inoculated orthotopically in the mammary gland, tumor appearance was slightly retarded in hypothyroid animals in both parental and TRβ-expressing cells (Figure 2C) and tumor volume was also smaller (Figure 2D), although differences were less marked than those observed with hepatocarcinoma cells and were only statistically significant at 9 weeks post-inoculation of MDA-TRβ 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