Transforming growth factor-beta type II receptor confers tumor suppressor activity in murine renal carcinoma (renca) cells

Engel, Jason D.; Kundu, Shilajit; Yang, Tony T.; Lang, Sharon; Goodwin, Shannon; Janulis, Lynn; Cho, Jin Seon; Chang, Jay; Kim, Seong‐Jin; Lee, Chung

doi:10.1016/s0090-4295(99)00093-x

Cited by 25 publications

(12 citation statements)

References 15 publications

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“…in vitro models. Other investigators have examined human RCC lines and identified alterations in the expression of TGFb signaling pathway intermediaries such as TBR2 and the Smads (Engel et al, 1999), but these observations have not been validated in the clinical biology of RCC. Ramp et al (1997b) found that TBR3 mRNA was expressed in only 1/13 RCC cell lines examined.…”

Section: Discussionmentioning

confidence: 99%

“…Alterations in TGFb signaling have also been implicated in RCC. Lee and colleagues demonstrated loss of TBR2 expression in an aggressive murine model of RCC and that re-expression of TBR2 abrogated the aggressive phenotype (Kundu et al, 1998;Engel et al, 1999). Others have demonstrated downregulation of TBRs in human RCC cell lines and resistance to TGFb, again implicating alterations in TGFb signaling, mediated through alterations in receptor expression, as important events in RCC biology (Ramp et al, 1997a).…”

Section: Discussionmentioning

confidence: 99%

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Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

et al. 2003

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Renal cell carcinoma (RCC) is a major health issue. Whereas localized disease can be cured surgically, there is no effective therapy for metastatic disease. The development of an effective therapy will require an understanding of the pathways that are important in RCC carcinogenesis and progression. Using genomic profiling of patientmatched tissue, we have identified aberrations in the transforming growth factor b (TGFb) signaling pathway in RCC. We observed loss of type III TGFb receptor (TBR3) expression in all RCC samples. This suggests that TBR3 loss is an early event in RCC carcinogenesis and plays a sentinel role in the acquisition of a tumorigenic phenotype. We also observed subsequent loss of type II TGFb receptor (TBR2) expression in metastatic RCCs. We propose that loss of TBR3 is necessary for RCC carcinogenesis, and that loss of TBR2 leads to acquisition of a metastatic phenotype. To this end, we have identified a human renal cell carcinoma line (UMRC6) that is representative of localized, nonmetastatic RCC, reflecting a loss of TBR3, but not TBR2 expression. Another cell line, UMRC3, is highly metastatic, having lost TBR3 and TBR2 expression. We demonstrate functional loss of TGFb responsiveness in these cell lines as observed through phenotypic and transcriptional responsiveness to exogenous TGFb. Restoring TBR2 and TBR3 expression in UMRC3 cells attenuates cell proliferation, completely restores TGFb-mediated transcriptional responses, and completely blocks anchorage independent-growth: while restoration of TBR2 partially restores TGFb-mediated signaling. Based on these data, we propose that dysregulation in TGFb signaling, through stepwise loss in receptor expression, plays a prominent role in RCC carcinogenesis and progression. In addition, these studies unequivocably demonstrate a link between loss of TBR3 and a human disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

et al. 2003

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“…Transforming growth factor (TGF)␤, TGF␤ receptor II (TGF␤RII) and its down-stream effector, tissue inhibitor of metalloproteinase 3 (TIMP3), were exclusively down-regulated in the poor outcome group. Loss of the TGF␤II signaling pathway previously was shown to be important for the development of aggressive cancers (29), and loss of TIMP3 expression by promoter methylation was shown to increase tumorigenicity because of unregulated matrix metalloproteinases (30). The identification of this pathway as down-regulated in aggressive ccRCC suggests numerous targets for intervention to supplement the still low response rate of current adjuvant therapies, such as IFN-␣ and IL-2 injection.…”

Section: Expression Signatures Of Rcc Specific To Particular Clinicalmentioning

confidence: 99%

Gene expression profiling of clear cell renal cell carcinoma: Gene identification and prognostic classification

Takahashi

Rhodes

Furge

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

353

240

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To better understand the molecular mechanisms that underlie the tumorigenesis and progression of clear cell renal cell carcinoma (ccRCC), we studied the gene expression profiles of 29 ccRCC tumors obtained from patients with diverse clinical outcomes by using 21,632 cDNA microarrays. We identified gene expression alterations that were both common to most of the ccRCC studied and unique to clinical subsets. There was a significant distinction in gene expression profile between patients with a relatively nonaggressive form of the disease [100% survival after 5 years with the majority (15͞17 or 88%) having no clinical evidence of metastasis] versus patients with a relatively aggressive form of the disease (average survival time 25.4 months with a 0% 5-year survival rate). Approximately 40 genes most accurately make this distinction, some of which have previously been implicated in tumorigenesis and metastasis. To test the robustness and potential clinical usefulness of this molecular distinction, we simulated its use as a prognostic tool in the clinical setting. In 96% of the ccRCC cases tested, the prediction was compatible with the clinical outcome, exceeding the accuracy of prediction by staging. These results suggest that two molecularly distinct forms of ccRCC exist and that the integration of expression profile data with clinical parameters could serve to enhance the diagnosis and prognosis of ccRCC. Moreover, the identified genes provide insight into the molecular mechanisms of aggressive ccRCC and suggest intervention strategies.

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“…Ос іль и іна тивацію си нально о шлях ТФР-β1 виявлено більшості п хлин людини, то прип с ається, що йо о інта тність є важливою переш одою на шлях розвит анцеро енез [4,22,34,50]. Найчастіше зміни си нальном шлях ТФР-β1 зачіпають рецептори тип ІІ цьо о цито іна [22,[51][52][53]. При ра товстої иш и та шл н ово-иш ово о тра т виявлено зміщення рам и зчит вання ена дано о рецептора, при ліомах мають місце йо о точ ові м тації, при ра підшл н ової залози, яєчни а, ший и мат и, шл н ово-иш ово о тра т та при лімфомах -делеції чи інсерції, при ра ле ені, простати, ротової порожнини, орла, щитоподібної залози, сечово о міх ра та при лімфомі Бер іта -втрата нормальної е спресії ена, а при різних формах ра молочної залози, ле ені і товстої иш и -ф н ціональна іна тивація ена рецептора тип ІІ ТФР-β1.…”

Section: р с стой аunclassified

Novel mechanisms for action of extremal agents: the role of transforming growth factor type beta

Stoika

2008

Biol. Stud.

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У статті наведено рез льтати, отримані протя ом останніх ро ів співробіт-ни ами відділ , еровано о автором, а та ож за альнено дані літерат ри щодо ролі трансформ ючо о фа тора рост бета-тип в механізмах дії на ор анізм тварин і людини е стремальних чинни ів різної природи -хімічних, фізичних, механічних, патобіоло ічних. По азано, що та і чинни и стим люють літини ссавців до прод ції цьо о цито іна, я ий сл є ін ібітором рост й інд тором апоптоз літин епітеліально о походження і більшості ім но омпетентних літин. Продемонстровано, я ий спосіб літини п хлин здатні наб вати резистентності до дії дано о цито іна, ни аючи йо о при ніч вально о вплив .Ключові слова: е стремальні чинни и, трансформ ючий фа тор рост бета-тип , п хлинні літини, ім но омпетентні літини, ме-ханізми, резистентність. NOVEL MECHANISMS FOR ACTION OF EXTREMAL AGENTS: THE ROLE OF TRANSFORMING GROWTH FACTOR TYPE BETA R. S. StoikaInstitute of Cell Biology, NAS of Ukraine 14-16, Drahomanov St., Lviv 79005, Ukraine e-mail: stoika@cellbiol.lviv.uaThe article summarizes the results obtained during the last years at the Department headed by the article author, as well as literature data, on the role of transforming growth factor type beta in the action towards animal and human organisms of extremal agents of different nature -chemical, physical, mechanical, pathobiological.

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Transforming growth factor-beta type II receptor confers tumor suppressor activity in murine renal carcinoma (renca) cells

Cited by 25 publications

References 15 publications

Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

Gene expression profiling of clear cell renal cell carcinoma: Gene identification and prognostic classification

Novel mechanisms for action of extremal agents: the role of transforming growth factor type beta

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