Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases

Muraoka, Rebecca S.; Dumont, Nancy; Ritter, Christoph A.; Dugger, Teresa C.; Brantley, Dana M.; Chen, Jin; Easterly, Evangeline; Roebuck, L. Renee; Ryan, Sarah; Gotwals, Philip J.; Koteliansky, Victor; Arteaga, Carlos L.

doi:10.1172/jci15234

Cited by 285 publications

(232 citation statements)

References 34 publications

Supporting

Mentioning

213

Contrasting

Unclassified

Order By: Relevance

“…Other groups have observed that 4T1 secretes significant amounts of TGF-␤, and that blocking TGF-␤ secretion by 4T1 enhanced the immune response primed by 4T1 (33,34). Increased IFN-␥ production by tumordraining lymph node cells was observed when mice were vaccinated with 4T1 transduced with an antisense TGF-␤ transgene (33).…”

Section: Discussionmentioning

confidence: 93%

Regression of a Mammary Adenocarcinoma in STAT6−/− Mice Is Dependent on the Presence of STAT6-Reactive T Cells

Jensen

Meijer²,

Kurt

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

Polarization of the immune response toward a type 1 cytokine profile has been posited to be associated with a therapeutic antitumor immune response. STAT6−/− mice are unable to generate a type 2 immune response, and instead mount an enhanced type 1 response. STAT6−/− mice are significantly more resistant to 4T1, a mammary adenocarinoma cell line, resisting a 10-fold higher tumor dose compared with wild-type (wt) BALB/c mice. An analysis of the T cells from tumor-bearing STAT6−/− mice revealed that they contained a population primed by a peptide (STAT6531–539) of the STAT6 protein expressed in 4T1. The adoptive transfer of T cells from STAT6531–539-vaccinated STAT6−/− mice significantly reduced the number of 4T1 pulmonary metastases in recipient mice. Additionally, the role of these STAT6531–539-reactive T cells against s.c. 4T1 tumor challenge was determined by tumor-challenging wt BALB/c mice reconstituted with STAT6−/− bone marrow, thereby assessing whether a polarized type 1 immune response in the absence of STAT6-reactive T cells was sufficient to reject a 4T1 tumor challenge. T cells from the STAT6−/− bone marrow chimeras failed to recognize the STAT6531–539, and these mice proved to be as susceptible as wt BALB/c mice to 4T1 challenge. This demonstrated that the absence of STAT6531–539-reactive T cells correlated with the inability to reject 4T1 challenge. Additionally, these data emphasize that the enhanced ability to mount a type 1-polarized immune response is inconsequential if a sufficient antitumor immune response is not primed by the tumor.

show abstract

Section: Discussionmentioning

confidence: 93%

Regression of a Mammary Adenocarcinoma in STAT6−/− Mice Is Dependent on the Presence of STAT6-Reactive T Cells

Jensen

Meijer²,

Kurt

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…MMTV-PymT transgenic mice develop mammary tumors with an average latency of 53 days and form lung metastases with 100% penetrance by 100 days of age (Muraoka et al, 2002). TRAMP transgenic mice develop prostate tumors with an average latency of 84 days and form lung metastases with 95% penetrance by 24 weeks of age (Gingrich et al, 1997).…”

Section: Resultsmentioning

confidence: 99%

PLCγ contributes to metastasis of in situ-occurring mammary and prostate tumors

et al. 2006

View full text Add to dashboard Cite

Phospholipase C-c (PLCc ) has been implicated in tumor cell motility required for invasiveness and metastasis. Diminished tumor dissemination has been demonstrated in xenograft models, but studies in naturally-occurring tumors are lacking, having been limited by the timing of the interventions. Therefore, we generated mice that express a doxycycline (DOX)-inducible dominantnegative fragment of PLCc, PLCz; this approach avoids the in utero lethality caused by the absence of PLCc. As we targeted two de novo-occurring carcinomas of the mammary (MMTV-driven polyoma middle T antigen model, PyVmT) and prostate (TRAMP model) glands, we limited expression to these epithelial cells by driving DOX transactivator from the prostatein C3 promoter. This avoids the confounding variable of potentially abrogating motility in stromal and endothelial cells. These mice developed normally in the presence of DOX, except for limited mammary development if treated before 6 weeks and immaturity of the prostate gland if treated before 2 weeks of age. DOX-mediated induction of PLCz from age 8 to 16 weeks in PyVmT mice decreased the number of lung metastases by >10-fold (Po0.06) without a detectable effect on in situ tumor cell proliferation or tumor size. Lung metastases were also significantly decreased in the TRAMP model in which the mice expressed the PLCz fragment (Po0.05). DOX treatment itself had no effect on tumor size or metastasis in control mice, nor did it affect tumor dissemination in nontransgenic littermates. In conclusion, abrogation of the PLCc signaling pathway can limit the metastatic potential of carcinomas.

show abstract

“…Successful use of various types of TGF-␤ antagonists has been reported in mouse pathological models. Recombinant soluble Fc-TGF-␤ type II receptor fusion protein was used to suppress breast cancer metastasis (Muraoka et al, 2002;Yang et al, 2002). Adenoviruses carrying cDNA encoding Smad7 were used to prevent pulmonary fibrosis induced by bleomycin administration (Nakao et al, 1999), although Smad7 also blocks BMP signaling.…”

Section: Use Of C-ski (Arpg) As An Antagonist Of Tgf-␤/activinmentioning

confidence: 99%

Interaction with Smad4 Is Indispensable for Suppression of BMP Signaling by c-Ski

Takeda

Mizuide

Oka³

et al. 2004

MBoC

View full text Add to dashboard Cite

c-Ski is a transcriptional corepressor that interacts strongly with Smad2, Smad3, and Smad4 but only weakly with Smad1 and Smad5. Through binding to Smad proteins, c-Ski suppresses signaling of transforming growth factor-␤ (TGF-␤) as well as bone morphogenetic proteins (BMPs). In the present study, we found that a mutant of c-Ski, termed c-Ski (ARPG) inhibited TGF-␤/activin signaling but not BMP signaling. Selectivity was confirmed in luciferase reporter assays and by determination of cellular responses in mammalian cells (BMP-induced osteoblastic differentiation of C2C12 cells and TGF-␤-induced epithelial-to-mesenchymal transdifferentiation of NMuMG cells) and Xenopus embryos. The ARPG mutant recruited histone deacetylases 1 (HDAC1) to the Smad3-Smad4 complex but not to the Smad1/5-Smad4 complex. c-Ski (ARPG) was unable to interact with Smad4, and the selective loss of suppression of BMP signaling by c-Ski (ARPG) was attributed to the lack of Smad4 binding. We also found that c-Ski interacted with Smad3 or Smad4 without disrupting Smad3-Smad4 heteromer formation. c-Ski (ARPG) would be useful for selectively suppressing TGF-␤/activin signaling. INTRODUCTIONCytokines of the transforming growth factor-␤ (TGF-␤) superfamily are multifunctional proteins that regulate growth, differentiation, apoptosis, and morphogenesis of a wide variety of cell types. TGF-␤ and related factors bind to two different types of serine/threonine kinase receptors, termed type I and type II (Derynck et al., 1998;Attisano and Wrana, 2000;Shi and Massagué, 2003). Type I receptor is activated by type II receptor upon ligand binding and transduces signals into cytoplasm through phosphorylation of receptorregulated Smads (R-Smads). Phosphorylated R-Smads interact with Co-Smad (Smad4) and translocate into the nucleus. Nuclear Smad complexes regulate transcription of target genes in cooperation with transcriptional activators/repressors as well as with coactivators/corepressors . Of the eight different mammalian Smad proteins, Smad1, Smad5, and Smad8 are R-Smads activated by BMP family members, whereas Smad2 and Smad3 are R-Smads activated by TGF-␤ and activin.Transcription of target genes by TGF-␤ is upregulated by binding of Smads to transcriptional coactivators, including p300 and CBP, which induce acetylation of histones and loosen chromatin structure (Massagué and Chen, 2000;Miyazono et al., 2001). In contrast, transcriptional corepressors, including TGIF, c-Ski, and SnoN, physically interact with Smads, and repress TGF-␤ signaling through recruitment of histone deacetylases (HDACs) (Massagué and Chen, 2000;Liu et al., 2001).c-Ski was originally identified as a cellular counterpart of a retroviral oncogene product, v-Ski (Li et al., 1986). c-Ski physically interacts with Smad2, Smad3, and Smad4, thus antagonizing signal transduction in the TGF-␤ pathway (Akiyoshi et al., 1999;Luo et al., 1999;Sun et al., 1999;Xu et al., 2000). Overexpression of c-Ski abolished TGF-␤-induced growth inhibition (Luo et al., 1999;Sun et al., 1999;Xu et al., 200...

show abstract

Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases

Cited by 285 publications

References 34 publications

Regression of a Mammary Adenocarcinoma in STAT6−/− Mice Is Dependent on the Presence of STAT6-Reactive T Cells

Regression of a Mammary Adenocarcinoma in STAT6−/− Mice Is Dependent on the Presence of STAT6-Reactive T Cells

PLCγ contributes to metastasis of in situ-occurring mammary and prostate tumors

Interaction with Smad4 Is Indispensable for Suppression of BMP Signaling by c-Ski

Contact Info

Product

Resources

About