mTOR pathway in renal cell carcinoma

Hanna, Sara C.; Heathcote, Samuel A; Kim, William Y.

doi:10.1586/14737140.8.2.283

Cited by 49 publications

(39 citation statements)

References 82 publications

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“…Selective inhibition of the mTOR pathway can be achieved using rapamycin or rapamycin analogs temsirolimus (CCI-779, Wyeth Pharmaceuticals) and everolimus (RAD001, Novartis), which are currently in use in numerous clinical trials for solid tumors, with promising results in patients with advanced renal cell carcinoma. 12,13 To further investigate the potential role of mTOR signaling and inhibition in UCC of the bladder, we used human cancer specimens, xenograft models, and in vitro analysis to determine the effects of mTOR on cellular proliferation, apoptosis, tumor growth, and clinical outcomes in this cancer population.…”

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Mammalian Target of Rapamycin (mTOR) Regulates Cellular Proliferation and Tumor Growth in Urothelial Carcinoma

Hansel

Platt

Orloff

et al. 2010

The American Journal of Pathology

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Mammalian target of rapamycin (mTOR) signaling has been associated with aggressive tumor growth in many cancer models, although its role in urothelial carcinoma (UCC) has not been extensively explored. Expression of phosphorylated mTOR (P-mTOR) and a downstream target, ribosomal S6 protein (P-S6), was identified in 74% (90/121) and 55% (66/121) of muscle-invasive UCCs, respectively. P-mTOR intensity and %positive cells were associated with reduced diseasespecific survival (P ‫؍‬ 0.04, P ‫؍‬ 0.08, respectively). Moreover, P-mTOR intensity corresponded to increased pathological stage (P < 0.01), and mTOR activity was associated with cell migration in vitro. In addition, mTOR inhibition via rapamycin administration reduced cell proliferation in UCC cell lines RT4, T24, J82, and UMUC3 in a dose-dependent manner to 6% of control levels and was significant at 1 nmol/L in J82, T24, and RT4 cells (P < 0.01, P < 0.01, P ‫؍‬ 0.03, respectively) and at 10 nmol/L in UMUC3 cells (P ‫؍‬ 0.03). Reduced proliferation corresponded with reduced P-S6 levels by Western blot, and effects were ablated by pretreatment of cells with mTOR-specific siRNA. No effects of rapamycin on apoptosis were identified by TUNEL labeling or PARP cleavage. Administration of rapamycin to T24-xenografted mice resulted in a 55% reduction in tumor volume (P ‫؍‬ 0.03) and a 40% reduction in proliferation (P < 0.01) compared with vehicle-injected mice. These findings indicate that mTOR pathway activation frequently occurs in UCC and that mTOR inhibition may be a potential means to reduce UCC growth. (Am J Pathol

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confidence: 99%

Mammalian Target of Rapamycin (mTOR) Regulates Cellular Proliferation and Tumor Growth in Urothelial Carcinoma

Hansel

Platt

Orloff

et al. 2010

The American Journal of Pathology

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“…5,7 Proteins activated by TORC1 target several processes involved in cancer such as cell growth and proliferation, angiogenesis, and energy metabolism. 10,11 Recent findings suggest that mTOR can also interact with rictor and SIN1 instead of raptor to form a second complex (TORC2).…”

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Molecular Characterization of Preneoplastic Lesions Provides Insight on the Development of Renal Tumors

Stemmer

Ellinger‐Ziegelbauer

Ahr

et al. 2009

The American Journal of Pathology

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Kidneys are the second most frequent site for chemically induced cancers in rats. However, there is still limited information on direct effects of carcinogens on pathways involved in the development of kidney tumors. Since transformed tumor cells have different characteristics than their cell of origin, it was hypothesized that healthy tissue and progressing stages of preneoplastic lesions are differentially influenced by chemical carcinogens. To elucidate this question, TSC2؊/؊ Eker rats were gavaged with genotoxic aristolochic acid or nongenotoxic ochratoxin A for 3 and 6 months, respectively. Histopathology and cell proliferation analysis demonstrated a compound-and sex-specific onset of preneoplastic lesions. In contrast, comparable gene expression profiles of lasermicrodissected preneoplastic lesions from carcinogen-treated and control rats, including reduced expression of genes involved in carcinogen uptake and metabolism, point to a compound-independent lesion progression. Gene expression profiles and additional immunostaining suggested that clonal expansion of renal lesions appears primarily driven by disturbed mammalian target of rapamycin complex 1 and mammalian target of rapamycin complex 2 pathway regulation. Finally, prolonged carcinogen exposure resulted in only marginal gene expression changes in tubules with normal morphology, indicating that some tubules may have adapted to the treatment. Taken together, these findings indicate that the final outcome of in vivo carcinogenicity studies is primarily determined by time-restricted initial events, while lesion progression may be a compound-independent process, involving deregulated mTOR signaling in the Eker rat model.

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“…This pathway is activated with the mediation of PI3K/Akt as a result of TK receptor phosphorylation (activation). mTOR is the most important kinase responsible for endothelial cell survival, proliferation and migration and regulated via Akt (Hanna et al, 2008). It exists in two different macromolecular complexes sensitive to rapamycine and named mTORC1 and mTORC2.…”

Section: Mtor (Mammalian Target Of Rapamycin) Pathway and Drugs Targementioning

confidence: 99%

Review on Targeted Treatment of Patients with Advanced-Stage Renal Cell Carcinoma: A Medical Oncologist's Perspective

Tanrıverdi

2013

Asian Pacific Journal of Cancer Prevention

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Renal cell carcinomas make up 3% of all cancers and one in four patients is metastatic at time of diagnosis. This cancer is one of the most resistant to cytotoxic chemotherapy. Studies have shown that the efficiency of interferon-alpha and/or interleukin-2 based immune therapies is limited in patients with metastatic renal cell carcinoma but latest advances in molecular biology and genetic science have resulted in better understanding of its biology. Tumor angiogenesis, tumor proliferation and metastasis develop by the activation of signal message pathways playing a role in the development of renal cell carcinomas. Better definition of these pathways has caused an increase in preclinic and clinical studies into target directed treatment of renal cell carcinoma. Many recent studies have shown that numerous anti-angiogenic agents have marked clinical activity. In this article, the focus is on general characteristics of molecular pathways playing a major role in renal cell carcinoma, reviewing clinical information onagents used in the target directed treatment of metastatic lesions.

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mTOR pathway in renal cell carcinoma

Cited by 49 publications

References 82 publications

Mammalian Target of Rapamycin (mTOR) Regulates Cellular Proliferation and Tumor Growth in Urothelial Carcinoma

Mammalian Target of Rapamycin (mTOR) Regulates Cellular Proliferation and Tumor Growth in Urothelial Carcinoma

Molecular Characterization of Preneoplastic Lesions Provides Insight on the Development of Renal Tumors

Review on Targeted Treatment of Patients with Advanced-Stage Renal Cell Carcinoma: A Medical Oncologist's Perspective

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