ObjectivesThe mouse renal cell carcinoma line, Renca, is insensitive to transforming growth factor-beta (TGF-β) in vitro. The present study was conducted to determine whether removal of TGF-β from these tumor cells would inhibit tumor progression in vivo.MethodsTGF-β elimination was accomplished either by administration of neutralizing TGF-β antibody into mice receiving intravenous injection of Renca tumor cells or infection of TGF-β antisense expression vector into these tumor cells before subcutaneous injection into recipient mice.ResultsAlthough a low dose of TGF-β antibody (5 mg/kg every 3 days) was without any effect, a high dose of TGF-β antibody (50 mg/kg every 3 days), administered to recipient mice, resulted in a significant reduction in lung metastasis and was accompanied by increased apoptosis in the tumor cells. When the tumor cells were transfected with a TGF-β1 antisense expressing vector, a significant reduction occurred in the tumor incidence, as well as the tumor burden. However, in nude mice, cells with reduced TGF-β1 production grew almost as well as did the unmodified Renca cells, suggesting that the host's immune system might play an antitumor role.ConclusionsThese results indicate that progression of Renca tumor can be inhibited by eliminating TGF-β from the tumor cells. Our results also suggest that, although insensitive to TGF-β under in vitro conditions, Renca tumors could be inhibited by TGF-β removal through the systemic host environment.
"The study was initiated using the subcutaneous (sc) injection of mouse prostate cancer TRAMP-C2 cells transfected with HSV1-tk-GFP-luciferase (SFG-nTGL) reporter gene expression vector ,  into the right flank region of 30 C57BL/6 mice as described earlier . Animals were randomly assigned to one of three groups following intraperitoneal injections with the specific anti-TGF-β neutralizing antibody 1D11 or control antibody 13C4 as described before , . All the mice were sacrificed after 15 injections of antibodies and group 3 were sacrificed on the same time interval. "
[Show abstract][Hide abstract] ABSTRACT: DNA methyltransferase (DNMT) is one of the major factors mediating the methylation of cancer related genes such as TGF-β receptors (TβRs). This in turn may result in a loss of sensitivity to physiologic levels of TGF-β in aggressive prostate cancer (CaP). The specific mechanisms of DNMT's role in CaP remain undetermined. In this study, we describe the mechanism of TGF-β-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy.
We used human CaP cell lines with varying degrees of invasive capability to describe how TGF-β mediates the expression of DNMT in CaP, and its effects on methylation status of TGF-β receptors and the invasive capability of CaP in vitro and in vivo. Furthermore, we determined the association between DNMT expression and clinical outcome after radical prostatectomy. We found that more aggressive CaP cells had significantly higher TGF-β levels, increased expression of DNMT, but reduced TβRs when compared to benign prostate cells and less aggressive prostate cancer cells. Blockade of TGF-β signaling or ERK activation (p-ERK) was associated with a dramatic decrease in the expression of DNMT, which results in a coincident increase in the expression of TβRs. Blockade of either TGF-β signaling or DNMT dramatically decreased the invasive capabilities of CaP. Inhibition of TGF-β in an TRAMP-C2 CaP model in C57BL/6 mice using 1D11 was associated with downregulation of DNMTs and p-ERK and impairment in tumor growth. Finally, independent of Gleason grade, increased DNMT1 expression was associated with biochemical recurrence following surgical treatment for prostate cancer.
Our findings demonstrate that CaP derived TGF-β may induce the expression of DNMTs in CaP which is associated with methylation of its receptors and the aggressive potential of CaP. In addition, DNMTs is an independent predictor for disease recurrence after prostatectomy, and may have clinical implications for CaP prognostication and therapy.
PLoS ONE 09/2011; 6(9):e25168. DOI:10.1371/journal.pone.0025168 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transforming growth factor-beta (TGF-beta) signals through receptor serine/threonine kinases and intracellular Smad effectors, regulating numerous epithelial cell processes. TGF-beta plays a crucial role in the cancer initiation and progression through tumor cell autonomous signaling and interactions with tumor microenvironment, but is featured with a butterfly effect upon the stages of tumorigenesis. TGF-beta signaling acts as a suppressor of epithelial cell tumorigenesis at early stages, but promotes tumor progression by enhancing migration, invasion, and survival of the tumor cells during the later stages. TGF-beta signaling also cross-talks with other cell survival signaling pathways. Tumor microenvironment contains many distinct cell types, which substantially influences the tumor cell growth and survival, and the invasion and metastasis. TGF-beta in the microenvironment, produced by cancer and/or stromal cells, is high and negatively correlates with disease progression and patient prognosis. Therefore, TGF-beta may affect tumor progression by multiple mechanisms in addition to its direct action on tumor cells, and the diversities of TGF-beta signaling in tumors imply a need for caution to TGF-beta-targeted strategies of tumor prevention and/or therapeutics.
Frontiers in Bioscience 01/2010; 15(1). DOI:10.2741/3614 · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Growth differentiation factor-9 (GDF9), a member of the bone morphogenetic protein (BMP) family and the transforming growth factor (TGF)-beta superfamily, has recently been implicated in the biological control of cancer cell behaviour. It has also been implicated in the development and spread of solid cancer. However, the role of GDF9 in kidney cancer remains to be investigated. In the present study, the expression of GDF9 in normal and malignant human kidney tissues and its molecular and cellular impact on human kidney cancer cells were investigated.
The expression of GDF9 in human kidney tissues and kidney cancer cell lines (UMRC-2 and CAKI-2) was assessed at both the mRNA and protein levels using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. GDF9 overexpression was induced by a mammalian GDF9 expression construct. The effect of GDF9 expression on cellular functions was examined in kidney cancer cells overexpressing GDF9 using a variety of in vitro assays.
In normal kidney tissues, stronger staining of GDF9 was seen in renal tubular epithelial cells, both in the cytoplasm and in the nucleus. In contrast, the staining of GDF9 was notably weak or absent in cells of tumour tissues. Human kidney cancer cell lines UMRC-2 and CAKI-2 had lost their GDG-9 expression. Overexpression of GDF9 reduced in vitro invasion and cellular growth and migration of kidney cell lines in vitro. Using the electric cell-substrate sensing (ECIS) method, it was further revealed that overexpression of GDF9 in these cells markedly reduced cellular migration and adhesion.
Human kidney tumours have a reduced or loss of expression of GDF9. In vitro, GDF9 overexpression suppresses the invasiveness, growth and migration of kidney cancer cells. This suggests that GDF9 is a potential tumour suppressor and may have prognostic and therapeutic implications in human kidney cancer.
Anticancer research 10/2012; 32(10):4375-83. · 1.83 Impact Factor
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