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Sheppard D 《Cancer metastasis reviews》2005,24(3):395-402
Members of the integrin family recognize a variety of spatially-restricted extracellular ligands. Classically, ligation of
integrins activates cytoplasmic signals in the integrin-expressing cell and contributes to cell adhesion, migration, proliferation
and survival. At least two members of this family, αvβ6 and αvβ8 perform an additional function, activation of latent complexes
of transforming growth factor β. In effect, this process allows integrins on one cell to activate signals on adjacent (in
the case of αvβ6) or nearby cells (in the case of αvβ8). Integrin-mediated TGFβ activation has been shown to play important
roles in modulating tissue fibrosis, acute lung injury and pulmonary emphysema. Given the important roles that TGFβ plays
in modulating epithelial cell growth, epithelial-to-mesenchymal transformation and tumor invasion and metastasis, integrin-mediated
TGFβ activation is likely to play important roles in tumor growth ad metastasis. 相似文献
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Summary Recently, several in vitro studies have demonstrated production of the potent immunosuppressive cytokine transforming growth factor β (TGF-β)2 in glioblastoma cell lines. Systematic studies of the concentration of TGF-β isoforms in the plasma of patients harboring intracerebral tumors do not exist.In the present study, the concentrations of TGF-β1 and TGF-β2 in platelet-poor plasma of 21 patients with glioblastoma before and after extensive resection were measured by specific ELISA systems and related to survival.The plasma concentrations of latent TGF-β1 of patients with glioblastoma prior to surgery were significantly higher in comparison to healthy control probands, but not to patients with multiple sclerosis (MS). Furthermore, latent TGF-β2 was found to be significantly increased in the plasma of patients with glioblastoma in comparison to healthy control probands and patients with MS. After extensive resection of the tumor, the value of latent TGF-β2 evidently decreased.Interestingly, the concentration of latent TGF-β2 prior to surgery was correlated with survival and a strong relationship was found between the survival and the difference of latent TGF-β2 levels prior to surgery minus the TGF-β2 concentrations 7 days after surgery. A higher difference in these plasma concentrations >6 ng/ml vs. <6 ng/ml clearly correlates with a longer survival time. In conclusion, this study suggests that glioblastoma does secret TGF-β2 in vivo and that TGF-β2 may play an important role in glioblastoma patients. 相似文献
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The transforming growth factor-β1 (TGF-β1) signaling pathway is important in human oral squamous cell carcinoma (OSCC). Accordingly, the aims of this study were to evaluate the effect of antisense TGF-β1 oligonucleotides (ODNs) on OSCC in cell culture and in a xenograft model, as well as to evaluate any effects ODNs have on proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-2 (MMP-2) expression in the xenograft model. We performed real-time cell electronic sensing (RT-CES) to determine the effect of antisense TGF-β1 ODNs on SCC-9?cell growth. To examine the in?vivo effect of antisense TGF-β1 ODN therapy, SCC-9?cells were grafted into nude mice. Antisense ODNs were injected into the mass daily. Tumor size, body weight and duration of survival were assessed daily. Specimens from the main mass were used for immunohistochemical staining to analyze PCNA and MMP-2 expression. In?vitro treatment with antisense TGF-β1 ODNs decreased TGF-β1 expression and growth of SCC-9?cells. In the xenograft model, the antisense TGF-β1 ODN group exhibited a significantly decreased tumor growth rate compared to the control, which received Dulbecco's modified Eagle's medium (DMEM) (P=0.022). However, mean survival time and body weights were not significantly different between the groups (P>0.05). Immunohistochemistry showed that tumors from animals that received antisense TGF-β1 ODNs had significantly lower expression levels of PCNA and MMP-2 compared to tumors from animals in the DMEM group (P<0.05). In conclusion, antisense TGF-β1 ODN therapy significantly inhibits tumor growth compared to controls, however, there are no significant differences between groups with respect to changes in body weight. 相似文献
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Gastrointestinal (GI) cancer, including esophageal, gastric, and colorectal cancer, is one of the most prevalent types of malignant carcinoma and the leading cause of cancer-related deaths. Despite significant advances in therapeutic strategies for GI cancers in recent decades, drug resistance with various mechanisms remains the prevailing cause of therapy failure in GI cancers. Accumulating evidence has demonstrated that the transforming growth factor (TGF)-β signaling pathway has crucial, complex roles in many cellular functions related to drug resistance. This review summarizes current knowledge regarding the role of the TGF-β signaling pathway in the resistance of GI cancers to conventional chemotherapy, targeted therapy, immunotherapy, and traditional medicine. Various processes, including epithelial-mesenchymal transition, cancer stem cell development, tumor microenvironment alteration, and microRNA biogenesis, are proposed as the main mechanisms of TGF-β-mediated drug resistance in GI cancers. Several studies have already indicated the benefit of combining antitumor drugs with agents that suppress the TGF-β signaling pathway, but this approach needs to be verified in additional clinical studies. Moreover, the identification of potential biological markers that can be used to predict the response to TGF-β signaling pathway inhibitors during anticancer treatments will have important clinical implications in the future. 相似文献
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Objective: To investigate the expression of angiogenic factors, basic fibroblast, growth factor (bFGF) and transforming growth
factor (TGF)-β1 in osteosarcoma, its association with neovascularization and prognosis. Methods: The expression of bFGF, β1 and their receptors, as well as intratumoral microvessel count (MVD) were studied in 80 osteosarcomas by immunohistochemical
staining and morphometry. The relationship between the angiogenic factors expression and prognosis was evaluated by a multivariate
analysis using Cox proportion hazard model. Results: Among 80 cases of osteosarcoma, 46 cases were positive for TGF/TGF-β
(57.5%), and 31 cases for β1, (RI)(38.8%) respectively. The MVD and bFGF, TGFβ1
1 were important indicators to predict the prognosis of patients with osteosarcoma by the Cox proportion hazard model analysis.
Conclusion: The angiogenic factors bFGF and TGF-β1 are involved in the angiogenesis of osteosarcoma, and the angiogenesis influences the prognosis. Also they may be useful
in the evaluation of the prognosis of patients with osteosarcoma.
This work was supported by a grant from the Youth Scientific Research Foundation of the 9th Five-year Plan of the PLA. 相似文献
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This review examines the apparently paradoxical conversion of transforming growth factor 's (TGF) regulatory role as a growth inhibitor among normal glial cells to that of a progression factor among glioblastomas (GM). In vitro, TGF functions as an autocrine growth inhibitor of near-diploid gliomas of any grade. In contrast, hyperdiploid glioblastoma multiforme (HD-GM) cultures proliferate in response to TGF, which is mediated by induction of platelet-derived growth factor B chain (PDGF-BB). The dominant hypothesis of TGF's pathogenetic association with malignant transformation has been predicated upon acquisition of resistance to its growth inhibitory effects. However, the lack of obvious correlation with TGF receptor (TR) expression (or loss) between the HD-GM and the TGF-inhibited GM cultures suggests the existence of intrinsically opposed regulatory mechanisms influenced by TGF. The mechanism of conversion might be explained either by the loss of a putative tumor suppressor gene (TSG) which mediates TGF's inhibition of growth or by enhancement of an active oncogenic pathway among the HD-GM. The frequency of mutations within glioma-associated TSG, such as TP53 and RB, suggests that defects in TGF's inhibitory signaling pathway may have analogous effects in the progression to HD-GM, and TGF's conversion to a mitogen. Alternative sites of inactivation which might explain the loss of TGF's inhibitory effect include inactivating mutation/loss of the TR type II, alterations in post-receptor signal transmission or the cyclin/cyclin dependent kinase system which regulates the phosphorylation of pRB. Loss or inactivation of a glial TSG with a consequent failure of inhibition appears to allow TGF's other constitutive effects, such as induction of c-sis, to become functionally dominant. Mechanistically, TGF's conversion from autocrine inhibitor to mitogen promotes 'clonal dominance' by conferring a Darwinian advantage to the hyperdiploid subpopulations through qualitative and quantitative differences in its modulation of PDGF-A and c-sis, with concomitant paracrine inhibition of competing, near-diploid elements. Abbreviations: transforming growth factor (TGF) and receptor (TR); retinoblastoma gene (RB) and protein (pRB); platelet-derived growth factor (PDGF) and receptor (PDGFR); epidermal growth factor (EGF) and receptor (EGFR); fibroblast growth factor (FGF); malignant glioma (MG), astrocytoma (AST), anaplastic astrocytoma (AAST), glioblastoma (GM); hyperdiploid glioblastoma (HD-GM); glioblastoma multiforme (GM); normal rat kidney (NRK); tumor suppressor gene (TSG); loss of heterozygosity (LOH); TP53 wild type (TP53wt); TP53 mutant (TP53m) 相似文献
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Bone metastasis is a frequent complication of advanced breast cancer. On the basis of functional and molecular evidence, signaling mediated by the binding of platelet-derived growth factor (PDGF)-BB and -DD to PDGF receptor β (PDGFRβ) is critical for the survival and growth of metastatic breast cancer cells within the bone microenvironment. In this study, we propose a new approach to blocking PDGFRβ signaling using soluble PDGFRβ (sPDGFRβ) as a decoy receptor for PDGF-BB and -DD secreted from tumor cells and bone marrow stromal cells. A bone-seeking TNBCT/Bo cell line was established by in vivo selection from TNBCT human breast cancer cells, which are negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 protein expression. The TNBCT/Bo cells were transfected with a mammalian expression vector encoding the extracellular domain of PDGFRβ. A stable transfectant (TNBCT/Bo-sPDGFRβ) grew at a similar rate to that of control cells under normal culture conditions, although growth stimulation of human fibroblasts with PDGF-BB was neutralized by the culture medium from TNBCT/Bo-sPDGFRβ cells. Intratibial injection of TNBCT/Bo-sPDGFRβ cells into athymic nude mice resulted in a significant decrease in tumor incidence compared with control mice (P < 0.01). This attenuated growth correlated with decreased cancer cell proliferation, angiogenesis, and recruitment of stromal cells, and with an increase in the number of apoptotic cells. These findings suggest that sPDGFRβ is useful for the treatment of breast cancer bone metastasis. 相似文献
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Overexpression of platelet-derived growth factor receptor α in breast cancer is associated with tumour progression
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Introduction
Receptor tyrosine kinases have been extensively studied owing to their frequently abnormal activation in the development and progression of human cancers. Platelet-derived growth factor receptors (PDGFRs) are receptors with intrinsic tyrosine kinase activity that regulate several functions in normal cells and are widely expressed in a variety of malignancies. After the demonstration that gastrointestinal stromal tumours without c-Kit mutations harbour PDGFR-α-activating mutations and that PDGFR-α is also a therapeutic target for imatinib mesylate, the interest for this receptor has increased considerably. Because breast cancer is one of the most frequent neoplasias in women worldwide, and only one study has reported PDGFR-α expression in breast carcinomas, the aim of this work was to investigate the potential significance of PDGFR-α expression in invasive mammary carcinomas. 相似文献13.
Li FF Liu JJ Liu DW Lin B Hao YY Cong JP Zhu LC Gao S Zhang SL Iwamori M 《International journal of oncology》2012,40(4):1196-1202
LeY (Lewis Y) is a difucosylated oligosaccharide carried by glycoconjugates on the cell surface. Elevation of LeY is frequently observed in epithelial-derived cancers and is correlated to pathological staging and prognosis. To study the role of LeY on cancer cells, a stably LeY-overexpressing cell line, RMG-I-H, was developed previously by transfection of the α1,2-fucosyltransferase gene, a key enzyme that catalyzes the synthesis of LeY, into ovarian carcinoma-derived RMG-I cells. Our studies have shown that LeY is involved in the changes in biological behavior of RMG-I-H cells. However, the mechanism is still largely unknown. In this study, we determined the structural relationship and co-localization between LeY and TβRI/TβRII, respectively, and the potential cellular signaling mechanism was also investigated. We found that both TβRI and TβRII contain the LeY structure, and the level of LeY in TβRI and TβRII in RMG-I-H cells was significantly increased. Overexpression of LeY up-regulates the phosphorylation of ERK, Akt and down-regulates the phosphorylation of Smad2/3. In addition, the phosphorylation intensity was attenuated significantly by LeY monoantibody. These findings suggest that LeY is involved in the changes in biological behavior through TGF?β receptors via Smad, ERK/MAPK and PI3K/Akt signaling pathways. We suggest that LeY may be an important composition of growth factor receptors and could be an attractive candidate for cancer diagnosis and treatment. 相似文献
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Massabeau C Sigal-Zafrani B Belin L Savignoni A Richardson M Kirova YM Cohen-Jonathan-Moyal E Mégnin-Chanet F Hall J Fourquet A 《Breast cancer research and treatment》2012,132(1):259-266
There is evidence that aspirin use reduces the risk of breast cancer. Increased mammographic density is known to be associated
with increased breast cancer risk. Little is known about the association between mammographic density and aspirin or other
non-steroidal anti-inflammatory drug (NSAID) use, but it is possible that the association between aspirin use and breast cancer
risk might be due to the effect of aspirin on mammographic density. Multiple linear regression was used to investigate the
association between measures of mammographic density and the use, frequency, and duration of aspirin and other NSAIDs such
as paracetamol (acetaminophen), arthritis medication, and other over-the-counter or doctor-prescribed pain medications in
3286 women from the Australian Mammographic Density Twins and Sisters Study and the Genes Behind Endometriosis Study. We found
no association between either dense area or percent dense area with any of the NSAIDs examined (all P > 0.06). If aspirin is reducing the breast cancer risk in women, it is likely doing so via a different pathway other than
mammographic density measures that predict breast cancer risk. 相似文献
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Jen-Eing Jeng Meng-Feng Tsai Hey-Ru Tsai Lea-Yea Chuang Zu-Yau Lin Min-Yuh Hsieh Shinn-Chern Chen Wan-Lung Chuang Liang-Yen Wang Min-Lung Yu Chia-Yen Dai Jung-Fa Tsai 《Tumour biology》2014,35(4):3689-3698
This case–control study aimed to evaluate the diagnostic application of urinary transforming growth factor (TGF) α and serum α-fetoprotein (AFP) in hepatocellular carcinoma (HCC). TGFα and AFP were determined in 90 pairs of age- and gender-matched patients with cirrhotic HCC and patients with cirrhosis alone and 60 healthy controls. The results indicated that TGFα and AFP levels in patients with HCC were higher than in those with cirrhosis alone or healthy controls (each P?=?0.0001). Multivariate analysis indicated that TGFα (odds ratio (OR) 1.03, 95 % confidence interval (CI) 1.05–1.16) and AFP (OR 1.03, 95 % CI 1.01–1.06) were closely associated, in a dose-related fashion, with the development of HCC. The optimal cutoff values, determined with the receiver operating characteristic (ROC) curves, were 29 μg/g creatinine for TGFα and 100 ng/ml for AFP, respectively. The areas under ROC curve (AUC) were 0.74 for TGFα and 0.78 for AFP, respectively. Both biomarkers showed the same sensitivity (52.2 %), high specificity, high positive predictive value, and moderate positive likelihood ratio. Determination of both markers in parallel significantly increased the AUC (0.91) and diagnostic accuracy (92.2 %), with a high sensitivity (86.7 %), specificity (97.8 %), positive predictive value (PPV; 97.5 %), and moderate positive likelihood ratio (PLR; 39.4). Among 31 cirrhotic HCC with AFP?≤?20 ng/ml, the calculated AUC for TGFα was 0.79, with a sensitivity of 64.5 %, specificity of 96.7 %, PPV of 87.0 %, and PLR of 19.5. In conclusion, urinary TGFα and serum AFP are complementary tumor markers for detection of HCC with low AFP production. 相似文献
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Despite a primary tumor suppressor role, there is compelling evidence suggesting that TGF-β can promote tumor growth, invasion and metastasis in advanced stages of colorectal cancer. Blocking these tumor-promoting effects of TGF-β provides a potentially important therapeutic strategy for the treatment of colorectal cancer. However, little is known about how the inhibitors of TGF-β receptor kinases affect colorectal carcinogenesis in vivo. Here, we have observed that a novel dual kinase inhibitor of TGF-β type I and type II receptors, LY2109761, inhibits TGF-β-mediated activation of Smad and non-Smad pathways in CT26 colon adenocarcinoma cells having K-Ras mutation. The inhibitor attenuates the oncogenic effects of TGF-β on cell migration, invasion and tumorigenicity of CT26 cells. Furthermore, LY2109761 decreases liver metastases and prolongs survival in an experimental metastasis model. These findings suggest that the dual kinase inhibitor LY2109761 has potential therapeutic value for metastatic colorectal cancer. 相似文献
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Song S Christova T Perusini S Alizadeh S Bao RY Miller BW Hurren R Jitkova Y Gronda M Isaac M Joseph B Subramaniam R Aman A Chau A Hogge DE Weir SJ Kasper J Schimmer AD Al-awar R Wrana JL Attisano L 《Cancer research》2011,71(24):7628-7639
Excessive signaling from the Wnt pathway is associated with numerous human cancers. Using a high throughput screen designed to detect inhibitors of Wnt/β-catenin signaling, we identified a series of acyl hydrazones that act downstream of the β-catenin destruction complex to inhibit both Wnt-induced and cancer-associated constitutive Wnt signaling via destabilization of β-catenin. We found that these acyl hydrazones bind iron in vitro and in intact cells and that chelating activity is required to abrogate Wnt signaling and block the growth of colorectal cancer cell lines with constitutive Wnt signaling. In addition, we found that multiple iron chelators, desferrioxamine, deferasirox, and ciclopirox olamine similarly blocked Wnt signaling and cell growth. Moreover, in patients with AML administered ciclopirox olamine, we observed decreased expression of the Wnt target gene AXIN2 in leukemic cells. The novel class of acyl hydrazones would thus be prime candidates for further development as chemotherapeutic agents. Taken together, our results reveal a critical requirement for iron in Wnt signaling and they show that iron chelation serves as an effective mechanism to inhibit Wnt signaling in humans. 相似文献