TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases

Buijs, Jeroen T.; Stayrook, Keith R.; Guise, Theresa A.

doi:10.1007/s12307-011-0075-6

Cited by 67 publications

(51 citation statements)

References 195 publications

(204 reference statements)

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“…The overexpression of certain tumorigenesis-related factors such as VEGF-C, ICAM-1 and TGF-β has been observed in numerous tumors, indicating that these factors may play important roles in tumor initiation, growth, and development (Roskoski, 2007;Buijs et al, 2011;Kotteas et al, 2014). VEGF-C regulates angiogenesis, an indispensable mechanism in living organisms that controls proliferation, development, and reproduction in normal tissue as well as cancer tissue.…”

Section: Journal Of Agricultural Sciencementioning

confidence: 99%

“…Moreover, various tumorigenesis-related factors such as transforming growth factor beta (TGF-β), vascular endothelial growth factor-C (VEGF-C), and intracellular cell adhesion molecule-1 (ICAM-1) have been shown to participate in tumor growth and dissemination (Roskoski, 2007;Buijs et al, 2011;Kotteas et al, 2014). de Jong et al, have demonstrated that TGF-β expression levels correlated with angiogenesis and prognosis of breast cancer patients (de Jong et al, 1998).…”

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confidence: 99%

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Suppressive Effects of Puerariae Radix on the Breast Tumor Incidence in Rats Treated with DMBA

Chen¹,

Wu²,

Tseng³

et al. 2017

JAS

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Puerariae Radix (PR) is the root of Pueraria lobata, an herb widely used in traditional Chinese medicine and as a food seasoning. Owing to its potential anti-oxidative ability, the effects of PR on the inhibition of breast tumors were investigated in this study using the 7,12-dimethylbenz[a]anthracene (DMBA)-treated rat model. Thirty-two female Sprague-Dawley rats were randomly assigned to one of four different treatment groups, with or without PR and/or DMBA administration. At the age of 177 days, all rats were sacrificed, the number and size of tumors were recorded, and blood and tissue samples were collected for assessment of hematological parameters, redox status, and tumorigenesis-related factors. We found that PR supplementation decreased tumor incidence and WBC count but increased the IgM levels, and significantly altered the redox status, elevated serum TGF-β levels, and reduced serum VEGF-C and ICAM-1 levels. The mechanism by which PR decreased the incidence of DMBA-induced rat breast tumors might include ameliorating immunity, enhancing the antioxidant status, increasing the hepatic excretion of carcinogenic metabolites of DMBA, and influencing the expression of tumorigenesis-related factors.

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Section: Journal Of Agricultural Sciencementioning

confidence: 99%

mentioning

confidence: 99%

Suppressive Effects of Puerariae Radix on the Breast Tumor Incidence in Rats Treated with DMBA

Chen¹,

Wu²,

Tseng³

et al. 2017

JAS

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“…It is a potent inducer of epithelial-mesenchymal transition of cancer cells, an event thought to be critical for tumor dissemination, and also mediates communication of cancer cells with other tumor components during metastasis of cancer cells to various organs (4)(5)(6)50). TGF-β is of particular importance in bone metastasis because of its abundance in bone matrix and its pivotal role in the osteolytic vicious cycle (3,51). The pathway has been reported to regulate other prominent pathways, such as PI3K, MAPK, Rho/RAC1, NF-κB, Notch, and TNF-α (52).…”

Section: Dlc1 Expression Is Negatively Associated With Pthlh and Bonementioning

confidence: 99%

“…TGF-β signaling is a critical regulator of breast cancer metastasis to the bone, which is a rich reservoir of various growth factors, such as TGF-β, IGF, and EGF (2,3). TGF-β binds to and activates a pair of cell surface receptors, which in turn phosphorylate SMAD2 and SMAD3.…”

Section: Introductionmentioning

confidence: 99%

DLC1-dependent parathyroid hormone–like hormone inhibition suppresses breast cancer bone metastasis

Wang¹,

Rong²,

Zhuang³

et al. 2014

J. Clin. Invest.

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Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-β signaling; however, little is known about how the TGF-β pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-β-induced expression of parathyroid hormone-like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho-TGF-β crosstalk in osteolytic bone metastasis.

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“…For example, tumor cell and bone cell secretion of TGF-b has been associated with immunosuppression in the tumor microenvironment. Apart from its well-known role in promoting bone resorption during the 'viscous cycle', 50 TGF-b suppresses the immune response by repressing the production of effector molecules such as perforin, granzymes, Fas-ligand and IFN-g by cytotoxic immune cells 51 and by downregulating the expression of the NKG2D receptor on NK cells in numerous human cancers. 52 Additionally, TGF-b targets the maturation of DCs and the antitumor functionality of macrophages and neutrophils.…”

Section: Indirect Effects On the Immune Milieumentioning

confidence: 99%

Bone specific immunity and its impact on metastasis

Baschuk¹,

Rautela²,

Parker³

2015

BoneKEy Reports

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Bone is one of the most common sites of metastasis in solid malignancy. Contributing to this osteotropism are the dynamic interactions between tumor cells and the numerous cell types resident in the normal bone, particularly osteoclasts and osteoblasts, which create a tumor supporting microenvironment. However, disseminated cells are detected in the bone marrow long before evidence of metastatic outgrowth, and it is likely that prolonged survival is also reliant on immunoescape. Compared with other peripheral organs such as the lung and spleen, the bone marrow constitutes a unique immune cell compartment that likely provides an immune privileged niche for disseminated tumor cells. This includes the large proportions of immunosuppressive cells, including myeloid derived suppressor cells and regulatory T cells, that blunt the activity of cytotoxic lymphocytes involved in tumor immunosurveillance. This review highlights key aspects of the osteoimmune landscape and emerging mechanisms by which tumor cells create or co-opt an immunosuppressed niche to support their outgrowth in bone. Future studies in this field are likely to shed light on the differences in immunoregulation between the bone and other sites including the primary tumor, and the potential for immunotherapeutics in treating disseminated disease in the bone. However, more immunocompetent models, that recapitulate tumor heterogeneity and bone metastasis need to be developed to accelerate this field.

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TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases

Cited by 67 publications

References 195 publications

Suppressive Effects of Puerariae Radix on the Breast Tumor Incidence in Rats Treated with DMBA

Suppressive Effects of Puerariae Radix on the Breast Tumor Incidence in Rats Treated with DMBA

DLC1-dependent parathyroid hormone–like hormone inhibition suppresses breast cancer bone metastasis

Bone specific immunity and its impact on metastasis

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