Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease

Shull, Marcia M.; Ormsby, Ilona; Kier, Ann B.; Pawlowski, Sharon A.; Diebold, Ronald J.; Yin, Moying; Allen, Ruth D.; Sidman, Charles L.; Proetzel, Gabriele; Calvin, Dawn; Annunziata, Nikki; Doetschman, Thomas

doi:10.1038/359693a0

Cited by 2,815 publications

(1,844 citation statements)

References 51 publications

(34 reference statements)

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“…TGF-␤1 gene disrupted mice displayed defects in hematopoiesis and vasculogenesis in 50% of homozygous embryos at E10.5 (Martin et al, 1995) and massive inflammatory cell infiltration was observed in TGF-␤1 null mice after weaning (Shull et al, 1992). The lack of effect of TGF-␤1 null genotype on lung morphogenesis and epithelial cell differentiation may be related to the compensation by other TGF-␤ isoforms present in the lung.…”

Section: Discussionmentioning

confidence: 97%

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

Zeng

Gray

Stahlman

et al. 2001

Developmental Dynamics

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Members of the transforming growth factor ␤ (TGF-␤) family of polypeptides have been implicated in morphogenesis and differentiation in numerous tissues, including the lung. In order to further define effects of TGF-␤ signaling in lung morphogenesis, a constitutively active form of TGF-␤1 was expressed in respiratory epithelial cells of the fetal mouse lung in vivo. Expression of TGF-␤1 arrested lung morphogenesis in the pseudoglandular stage of development, inhibiting synthesis of differentiation-dependent proteins, SP-B, SP-C, and CCSP, and maintaining embryonic patterns of staining for thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear factor-3␤ (HNF-3␤). The pulmonary mesenchyme was thickened and vascular density was increased by TGF-␤1. TGF-␤1 decreased expression of vascular endothelial growth factor-A (VEGF-A) mRNA and protein, and the abundance of Flk-1 mRNA in the lung mesenchyme. Distribution of platelet-endothelial cell adhesion molecule (PECAM)-1, a marker of pulmonary blood vessels, was altered, and ultrastructural studies demonstrated that TGF-␤1 inhibited vascular development in the fetal lung. TGF-␤1 perturbed both epithelial cell differentiation and formation of the pulmonary vasculature, supporting the concept that precise control of signaling via the TGF-␤ receptor pathway is critical for normal lung morphogenesis.

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Section: Discussionmentioning

confidence: 97%

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

Zeng

Gray

Stahlman

et al. 2001

Developmental Dynamics

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“…These animals had widespread inflammatory leukocyte infiltration into multiple organs and died prematurely [72][73][74]. High levels of TGF-β1 are produced by various tumor types including breast, colon, stomach, liver [75] and fibroblasts [64].…”

Section: Role Of Transforming Growth Factor-β In Til Hyporesponsivenessmentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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“…Thus, we investigated whether expression of the neutralizing ligand trap could blunt TGF-b-induced expression of these two factors. Vector control (VC) or Fc:TbRII(ECD)-expressing MDA-MB-231 breast cancer cells were allowed to condition serum free media for 48 h and subsequently incubated in the absence or presence of TGF-b1 for a further 3 h. Quantitative Loss or reduction of TGF-b1 levels in host-derived tissue prevents the efficient establishment of breast cancer cells in bone To specifically interrogate the importance of bonederived TGF-b1 on the ability of breast cancer cells to form osteolytic lesions, we used TGF-b1-deficient mice that were bred onto a RAG2-deficient background (Engle et al, 1999), which rescues the early lethality observed in TGF-b1-null mice due to widespread inflammatory disease (Shull et al, 1992;Kulkarni et al, 1993). To ensure that the RAG2À/À mice permitted xenografting of human breast cancer cells, we injected an MDA-MB-231 variant that aggressively metastasizes to bone (1833-TR cells) into mammary fat pads of RAG2À/À mice (Kang et al, 2003;Minn et al, 2005).…”

Section: Tgf-b-neutralizing Ligand Trap Impairs Signaling Induced Bymentioning

confidence: 99%

Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

Mourskaia

Dong

et al. 2008

Oncogene

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Transforming growth factor (TGF)-b signaling is a potent modulator of the invasive and metastatic behavior of breast cancer cells. Indeed, breast tumor responsiveness to TGF-b is important for the development of osteolytic bone metastases. However, the specific TGF-b isoforms that promote breast cancer outgrowth in bone is unknown. We demonstrate that expression of a TGF-b ligand trap, which neutralizes TGF-b1 and TGF-b3, in MDA-MB-231 breast cancer cells diminished their outgrowth in bone and reduced the severity of osteolytic lesion formation when compared with controls. We further show that a reduction or loss of TGF-b1 expression within the bone microenvironment of TGF-b1 þ /À and TGF-b1À/À mice significantly reduced the incidence of breast tumor outgrowth compared with wild-type animals. Interestingly, those tumors capable of growing within the tibiae of TGF-b1-deficient mice had upregulated expression of all three TGF-b isoforms. Finally, breast cancer cells expressing the TGF-b ligand trap showed a pronounced reduction in their ability to form osteolytic lesions when injected into the tibiae of TGF-b1 þ /À mice. Thus, our studies show that both host-and tumor-derived TGF-b expression plays a critical role during the establishment and outgrowth of breast cancer cells in bone.

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Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease

Abstract: Transforming growth factor-β1 (TGF-

Cited by 2,815 publications

References 51 publications

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

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