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. 2011 Dec;2(12):1339-51.
doi: 10.18632/oncotarget.403.

T cell- but not tumor cell-produced TGF-β1 promotes the development of spontaneous mammary cancer

Affiliations

T cell- but not tumor cell-produced TGF-β1 promotes the development of spontaneous mammary cancer

Abira Sarkar et al. Oncotarget. 2011 Dec.

Abstract

During their development, tumors acquire multiple capabilities that enable them to proliferate, disseminate and evade immunosurveillance. A putative mechanism is through the production of the cytokine TGF-β1. We showed in our recent studies that T cell-produced TGF-β1 inhibits antitumor T cell responses to foster tumor growth raising the question of the precise function of TGF-β1 produced by tumor cells in tumor development. Here, using a transgenic model of mammary cancer, we report that deletion of TGF-β1 from tumor cells did not protect mice from tumor development. However, ablation of TGF-β1 from T cells significantly inhibited mammary tumor growth. Additionally, absence of TGF-β1 in T cells prevented tumors from advancing to higher pathological grades and further suppressed secondary tumor development in the lungs. These findings reveal T cells but not tumor cells as a critical source of TGF-β1 that promotes tumor development.

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Figures

Figure 1
Figure 1. Absence of TGF-β1 produced by mammary tumor cells does not affect tumor growth
(A) RT-PCR analysis of Tgfβ1 and Hprt expression from FACS-sorted tumor cells of control Tgfb1f/n PYMT mice, and from tumor cells and lymph node cells of Tgfb1f/n Mmtvcre-PYMT mice. LN; lymph node (B) Total tumor burden in all mammary glands of Tgfb1f/n Mmtvcre-PYMT (n=9) and control Tgfb1f/n PYMT (n=9) mice at 20 weeks of age. Tumor volume was calculated using the formula L x W2x 0.52 (where L is the longest diameter and W is the smallest diameter.) (C) The age at which Tgfb1f/n Mmtvcre-PYMT (n=9) and littermate control Tgfb1f/n PYMT mice (n=9) achieved the predetermined tumor burden of 2500 mm3. (D) Total pulmonary metastatic nodules in Tgfb1f/n Mmtvcre-PYMT (n=5) and control Tgfb1f/n PYMT (n=6) mice were assessed at a tumor burden of 2500 mm3. The p values between the two groups of tumor burden (B) age (C) and number of metastatic nodules (D) are shown (Students t-test).
Figure 2
Figure 2. Deficiency of T cell TGF-β1 inhibits mammary tumor development
(A) Total tumor burden in all mammary glands of Tgfb1f/n Cd4cre-PYMT (n=14) and control Tgfb1f/n PYMT (n=14) mice at 20 weeks of age. Tumor volume was calculated using the formula L x W2x 0.52 (where L is the longest diameter and W is the smallest diameter.) (B) The age at which Tgfb1f/n Cd4cre-PYMT (n=14) and littermate control Tgfb1f/n PYMT mice (n=14) achieved the predetermined tumor burden of 2500mm3. Tumor volume was calculated using the formula L x W2x 0.52 (where L is the longest diameter and W is the smallest diameter.) (C) Total pulmonary metastatic nodules in Tgfb1f/n Cd4cre-PYMT (n=9) and control Tgfb1f/n PYMT (n=9) mice were assessed at a tumor burden of 2500 mm3. The p values between the two groups of tumor burden (A) age (B) and number of metastatic nodules (C) are shown (Students t-test). * depicts statistically significant difference. (D) Histological analysis of sections of lungs of Tgfb1f/n Cd4cre-PYMT and Tgfb1f/n PYMT at a tumor burden of 2500 mm3. Sections of representative lungs from Tgfb1f/n PYMT and Tgfb1f/n Cd4cre-PYMT mice were stained with hematoxylin and eosin. Black arrows indicate metastatic nodules.

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