Expression of transforming growth factor ? in renal cell carcinoma and matched non-involved renal tissue

Mitropoulos, Dionisios; Kiroudi, Aspasia; Christelli, Evangelia; Serafetinidis, Efraim; Zervas, Anastasios; Anastasiou, Ioannis; Dimopoulos, C

doi:10.1007/s00240-003-0360-z

Cited by 36 publications

(27 citation statements)

References 26 publications

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“…(7) In RCC, TGF-␤1 expression directly correlates with tumor stage and grade, suggesting its importance in tumor progression. (8) In line with these findings, TGF-␤1 levels are significantly elevated in patients with metastatic disease. (9) Here we present the first evidence that TGF-␤1 promotes the growth of RCC bone metastasis and subsequent bone destruction.…”

supporting

confidence: 53%

TGF-β Promotes the Establishment of Renal Cell Carcinoma Bone Metastasis

Kominsky

Doucet

Brady

et al. 2007

Journal of Bone and Mineral Research

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Bone metastases develop in ∼30% of patients with RCC, and the mechanisms responsible for this phenomenon are unknown. We found that TGF-␤1 stimulation of RCC bone metastasis cells promotes tumor growth and bone destruction possibly by stimulating paracrine interactions between tumor cells and the bone.Introduction: Bone metastasis is a frequent complication and causes marked morbidity in patients with renal cell carcinoma (RCC). Surprisingly, the specific mechanisms of RCC interaction with bone have been scarcely studied despite the inability to prevent or effectively treat bone metastasis. Bone is a reservoir for various growth factors including the pleiotropic cytokine TGF-␤1. TGF-␤1 has been shown to have tumor-supportive effects on advanced cancers and evidence suggests its involvement in promoting the development of breast cancer bone metastasis. Here, we studied the potential role of TGF-␤1 in the growth of RCC bone metastasis (RBM). Materials and Methods:To inhibit TGF-␤1 signaling, RBM cells stably expressing a dominant-negative (DN) TGF-␤RII cDNA were generated. The in vivo effect of TGF-␤1 on RBM tumor growth and osteolysis was determined by histological and radiographic analysis, respectively, of athymic nude mice after intratibial injection of parental, empty vector, or DN RBM cells. The in vitro effect of TGF-␤1 on RBM cell growth was determined after TGF-␤1 treatment by MTT assay. Results: TGF-␤1 and the TGF-␤ receptors I and II (TGF-␤RI/II) were consistently expressed in both RBM tissues and cell lines. Inhibition of TGF-␤1 signaling in RBM cells significantly reduced tumor establishment and osteolysis observed in vivo after injection into the murine tibia, although no effect on tumor establishment was observed after injection of RBM cells subcutaneously or into the renal subcapsule. Treatment of five RBM cell lines with TGF-␤1 in vitro either had no effect (2/5) or resulted in a significant inhibition (3/5) of cell growth, suggesting that TGF-␤1 may promote RBM tumor growth indirectly in vivo. Conclusions: TGF-␤1 stimulation of RBM cells plays a role in promoting tumor growth and subsequent osteolysis in vivo, likely through the initiation of tumor-promoting paracrine interactions between tumor cells and the bone microenvironment. These data suggest that inhibition of TGF-␤1 signaling may be useful in the treatment of RBM.

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supporting

confidence: 53%

TGF-β Promotes the Establishment of Renal Cell Carcinoma Bone Metastasis

Kominsky

Doucet

Brady

et al. 2007

Journal of Bone and Mineral Research

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“…To note, breast cancer is well-known for its ability to produce and secrete TGFand intriguingly, RCC also is one of the representative cancers known to produce TGF- (Arteaga et al 1993). Elevated serum TGF-levels in the patients with RCC before surgery and elevated levels in the RCC tissues compared with the normal kidney have been documented, which is consistent with our data (Junker et al 2000;Mitropoulos et al 2004). A potent inhibitor of epithelial proliferation, resistance of RCC to the growth suppressive properties of this cytokine as we have conWrmed is also well-known (Ramp et al 1997).…”

Section: Discussionsupporting

confidence: 80%

Transforming growth factor-β downregulates interleukin-2-induced phosphorylation of signal transducer and activator of transcription 5 in human renal cell carcinoma

Song

Jun

Hong

et al. 2007

J Cancer Res Clin Oncol

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“…The TGFb signaling pathway is known to be involved in cell proliferation, differentiation, apoptosis, and EMT in various cancer cell types (25). In ccRCC cells, although the precise regulatory mechanism remains largely unknown, TGFb expression correlates with pathologic stages and grades, and TGFb promotes the establishment of bone metastasis in RCC (26,27). Moreover, the TGFb signaling pathway has been reported to upregulate both integrin a5 (28) and LOXL2 expression (29).…”

Section: Discussionmentioning

confidence: 99%

LOXL2 Status Correlates with Tumor Stage and Regulates Integrin Levels to Promote Tumor Progression in ccRCC

Hase

Jingushi

Ueda

et al. 2014

Molecular Cancer Research

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Clear cell renal cell carcinoma (ccRCC) is the most common histologically defined subtype of renal cell carcinoma (RCC). To define the molecular mechanism in the progression of ccRCC, we focused on LOX-like protein 2 (LOXL2), which is critical for the first step in collagen and elastin cross-linking. Using exon array analysis and quantitative validation, LOXL2 was shown to be significantly upregulated in clinical specimens of human ccRCC tumor tissues, compared with adjacent noncancerous renal tissues, and this elevated expression correlated with the pathologic stages of ccRCC. RNAi-mediated knockdown of LOXL2 resulted in marked suppression of stress-fiber and focal adhesion formation in ccRCC cells. Moreover, LOXL2 siRNA knockdown significantly inhibited cell growth, migration, and invasion. Mechanistically, LOXL2 regulated the degradation of both integrins a5 (ITGAV5) and b1 (ITGB1) via protease-and proteasome-dependent systems. In clinical ccRCC specimens, the expression levels of LOXL2 and integrin a5 correlated with the pathologic tumor grades. In conclusion, LOXL2 is a potent regulator of integrin a5 and integrin b1 protein levels and functions in a tumor-promoting capacity in ccRCC.Implications: This is the first report demonstrating that LOXL2 is highly expressed and involved in ccRCC progression by regulating the levels of integrins a5 and b1. Mol Cancer Res; 12(12); 1807-17. Ó2014 AACR. IntroductionRenal cell carcinoma (RCC) is the leading cause of death among urological malignancies, and clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of RCC. Early-stage ccRCC is usually curable by clinical surgery, but a large number of early-stage ccRCC cases are asymptomatic, with approximately one-third of all patients presenting with locally metastatic cancer at the time of diagnosis (1). Therefore, a better understanding of the molecular mechanisms of ccRCC progression is crucial for the discovery of novel prognostic markers and targeted therapies.A genetic hallmark of ccRCC is the inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. VHL functions as a part of an E3 ubiquitin ligase complex that

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Expression of transforming growth factor ? in renal cell carcinoma and matched non-involved renal tissue

Cited by 36 publications

References 26 publications

TGF-β Promotes the Establishment of Renal Cell Carcinoma Bone Metastasis

TGF-β Promotes the Establishment of Renal Cell Carcinoma Bone Metastasis

Transforming growth factor-β downregulates interleukin-2-induced phosphorylation of signal transducer and activator of transcription 5 in human renal cell carcinoma

LOXL2 Status Correlates with Tumor Stage and Regulates Integrin Levels to Promote Tumor Progression in ccRCC

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