Treatment of Transforming Growth Factor-Beta-Insensitive Mouse Renca Tumor by Transforming Growth Factor-Beta Elimination
Department of Preventive Medicine, Northwestern University, Evanston, Illinois, United States Urology
(Impact Factor: 2.19).
08/2008; 72(1):225-229. DOI: 10.1016/j.urology.2007.11.091
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.
Available from: Vidit Sharma
- "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. "
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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.
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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.
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ABSTRACT: The role of TGF-β in tumor development and progression is complex. Genetic mutations that disrupt the antiproliferative signaling effects of TGF-β play a key role in the process of malignant transformation for many types of tumors. Paradoxically, this loss of sensitivity to TGF-β's inhibitory actions often leads to TGF-β overexpression by the tumor cells or by normal cells that are recruited to the tumor microenvironment. Elevated concentrations of TGF-β in the tumor microenvironment have been shown to facilitate tumor growth and metastasis. Numerous published studies have provided evidence that inhibition of TGF-β using antibodies, soluble receptors and small molecule inhibitors of TGF-β signal transduction can have beneficial effects in murine models of cancer. Given the pleiotropic nature of TGF-β and its homeostatic role in numerous biological processes, serious concerns have been expressed regarding the safety of administering TGF-β antagonists to human patients. Interestingly, the results of numerous animal toxicology studies of TGF-β antibodies in normal rodents and primates have shown that administration of neutralizing anti-TGF-β antibodies is well tolerated and any adverse effects were reversible or self-limiting. Likewise, administration of a human anti-TGF-β antibody (fresolimumab) in three separate human phase 1 clinical trials has also been shown to be well tolerated.
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