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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 tumor invasiveness.(A and C)-Representative H&E staining of tumors formed by parental and TRβ-expressing SK and MDA cells inoculated in control and hypothyroid nude mice (left panels). Tumors originated in hypothyroid hosts were more invasive as illustrated by asterisks that denote sites of tumor invasion. The number of invasion fronts of the tumors was scored and is represented as mean±S.E in the right panels. (B and D)-Quantification of the percentage of animals with tumors infiltrating surrounding tissues such as muscle, blood and lymph vessels and skin or having long distance metastasis in lung, liver or bone. In the case of MDA cells, the number of tumor enveloped by a conspicuous gelatinous capsule was also scored.
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pone-0006428-g007: Hypothyroidism enhances tumor invasiveness.(A and C)-Representative H&E staining of tumors formed by parental and TRβ-expressing SK and MDA cells inoculated in control and hypothyroid nude mice (left panels). Tumors originated in hypothyroid hosts were more invasive as illustrated by asterisks that denote sites of tumor invasion. The number of invasion fronts of the tumors was scored and is represented as mean±S.E in the right panels. (B and D)-Quantification of the percentage of animals with tumors infiltrating surrounding tissues such as muscle, blood and lymph vessels and skin or having long distance metastasis in lung, liver or bone. In the case of MDA cells, the number of tumor enveloped by a conspicuous gelatinous capsule was also scored.

Mentions: Tumors originated from SK cells in normal nude mice are highly infiltrative, presenting an elevated number of invasion fronts. In contrast, tumors from SK-TRβ cells were less infiltrative, presenting a clearly detectable pseudocapsule of collagen and inflammatory cells, and a reduced number of invasion fronts (Figure 7A). This growth pattern was altered when SK-TRβ cells were inoculated into hypothyroid mice, since tumors acquired a more invasive phenotype with a significant increase in the number of invasion fronts. In addition, all hypothyroid animals injected with SK cells had tumors that infiltrated adjacent muscle, lymph and blood vessels or skin (Figure 7B), whereas some of the tumors from euthyroid animals did not invade these tissues. Furthermore, no tumors developed in normal mice caused the appearance of lung or liver metastasis, but such long distance metastasis in these tissues were present in 25% of the hypothyroid animals. In accordance with the less infiltrative pattern of SK-TRβ1 tumors, distant metastasis were not detected in either control or hypothyroid mice and invasion of surrounding tissues was strongly reduced, although it increased in hypothyroid mice (Figure 7B).


Hypothyroidism enhances tumor invasiveness and metastasis development.

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

Hypothyroidism enhances tumor invasiveness.(A and C)-Representative H&E staining of tumors formed by parental and TRβ-expressing SK and MDA cells inoculated in control and hypothyroid nude mice (left panels). Tumors originated in hypothyroid hosts were more invasive as illustrated by asterisks that denote sites of tumor invasion. The number of invasion fronts of the tumors was scored and is represented as mean±S.E in the right panels. (B and D)-Quantification of the percentage of animals with tumors infiltrating surrounding tissues such as muscle, blood and lymph vessels and skin or having long distance metastasis in lung, liver or bone. In the case of MDA cells, the number of tumor enveloped by a conspicuous gelatinous capsule was also scored.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0006428-g007: Hypothyroidism enhances tumor invasiveness.(A and C)-Representative H&E staining of tumors formed by parental and TRβ-expressing SK and MDA cells inoculated in control and hypothyroid nude mice (left panels). Tumors originated in hypothyroid hosts were more invasive as illustrated by asterisks that denote sites of tumor invasion. The number of invasion fronts of the tumors was scored and is represented as mean±S.E in the right panels. (B and D)-Quantification of the percentage of animals with tumors infiltrating surrounding tissues such as muscle, blood and lymph vessels and skin or having long distance metastasis in lung, liver or bone. In the case of MDA cells, the number of tumor enveloped by a conspicuous gelatinous capsule was also scored.
Mentions: Tumors originated from SK cells in normal nude mice are highly infiltrative, presenting an elevated number of invasion fronts. In contrast, tumors from SK-TRβ cells were less infiltrative, presenting a clearly detectable pseudocapsule of collagen and inflammatory cells, and a reduced number of invasion fronts (Figure 7A). This growth pattern was altered when SK-TRβ cells were inoculated into hypothyroid mice, since tumors acquired a more invasive phenotype with a significant increase in the number of invasion fronts. In addition, all hypothyroid animals injected with SK cells had tumors that infiltrated adjacent muscle, lymph and blood vessels or skin (Figure 7B), whereas some of the tumors from euthyroid animals did not invade these tissues. Furthermore, no tumors developed in normal mice caused the appearance of lung or liver metastasis, but such long distance metastasis in these tissues were present in 25% of the hypothyroid animals. In accordance with the less infiltrative pattern of SK-TRβ1 tumors, distant metastasis were not detected in either control or hypothyroid mice and invasion of surrounding tissues was strongly reduced, although it increased in hypothyroid mice (Figure 7B).

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