Stepwise transformation of primary thyroid epithelial cells by a mutant Ha‐<i>ras</i> oncogene: An in vitro model of tumor progression

Burns, Jorge S.; Blaydes, Jeremy P.; Wright, Pat A.; Lemoine, Louise; Bond, Jane A.; Williams, E. D.; Wynford-Thomas, David

doi:10.1002/mc.2940060208

Cited by 42 publications

(25 citation statements)

References 42 publications

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“…The rest of the nodules that yield RAS mutations are benign follicular adenomas. However, some evidence exists that these benign nodules are prone to malignant transformation (34)(35)(36)(37), and therefore patients with RAS-mutated nodules, even when caught at a premalignant stage, are likely to benefit from surgical excision to prevent the possible progression.…”

Section: On the Horizonmentioning

confidence: 99%

New Strategies in Diagnosing Cancer in Thyroid Nodules: Impact of Molecular Markers

Nikiforov

Yip

2013

Clinical Cancer Research

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Thyroid cancer is the most common type of endocrine malignancy, with approximately 55,000 new cases diagnosed in the United States in 2012. However, thyroid nodules are much more prevalent, particularly with increased age, and only a small fraction of those are malignant. Therefore, the major clinical challenge is to reliably differentiate those nodules that are malignant and need to be treated surgically from the majority of nodules that are benign and do not require surgery. The traditional diagnostic approach to this clinical situation is ultrasound-guided fine-needle aspiration (FNA) of the thyroid nodule followed by cytologic examination, which together reliably establish the diagnosis in 70% to 80% of cases. However, in the rest of nodules the presence of cancer cannot be ruled out by FNA cytology, hampering appropriate surgical management and frequently resulting in unnecessary surgical interventions. New approaches to diagnosis of cancer in thyroid nodules are based on mutational and other molecular markers, which can be reliably detected in cells aspirated during the FNA procedure. These markers offer significant improvement in the diagnostic accuracy of FNA cytology and are poised to make a profound effect on the management of patients with thyroid nodules. In addition to the molecular markers that have recently become available for clinical use, rapid development of new sequencing techniques is expected to further improve the accuracy of cancer diagnosis in thyroid nodules and allow for a fully individualized approach to the management of patients with thyroid nodules.

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Section: On the Horizonmentioning

confidence: 99%

New Strategies in Diagnosing Cancer in Thyroid Nodules: Impact of Molecular Markers

Nikiforov

Yip

2013

Clinical Cancer Research

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“…In our laboratory we have established an in vitro model of multi-step epithelial tumorigenesis initiated by infection of primary rat thyroid epithelial cells with a retroviral vector encoding mutant ras (Burns et al, 1992a;Blaydes et al, 1995). Following a period of rapid cell proliferation the majority of ras infected colonies cease to divide.…”

Section: Introductionmentioning

confidence: 99%

“…However a small proportion undergo a second, spontaneous immortalisation event which is invariably associated with a dramatic increase in the levels of p53 protein expression. We have established a panel of cell lines from these cells and have shown, by sequencing the entire p53 coding region, that the p53 protein is not mutated (Burns et al, 1992a;Blaydes et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Tolerance of high levels of wild-type p53 in transformed epithelial cells dependent on auto-regulation by mdm-2

et al. 1997

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“…In PC12 cells, Ras and cAMP induce neurite extension (13, 54) and promote cell survival (64). Ras and cAMP stimulate proliferation in thyroid cells (7,36,39), and Ras activity is required for the mitogenic effects of thyrotropin (TSH) (32). Despite the requirement for Ras, TSH downregulates signaling through Raf and the MAPK cascade (1), suggesting that Ras mediates its effects through alternate effectors in these cells.…”

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confidence: 99%

Differential Effects of Protein Kinase A on Ras Effector Pathways

Miller

Rioux

Prendergast

et al. 1998

Molecular and Cellular Biology

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Ras mutants with the ability to interact with different effectors have played a critical role in the identification of Ras-dependent signaling pathways. We used two mutants, Ras S35 and Ras G37 , which differ in their ability to bind Raf-1, to examine Ras-dependent signaling in thyroid epithelial cells. abolished TSH-stimulated changes in cell morphology and thyroglobulin expression, while Ras G37 had no effect on these activities. Together, the data indicate that cross talk between Ras and PKA discriminates between distinct Ras effector pathways.Ras proteins are important signaling intermediates that convey signals initiated at the cell surface to effector pathways in the cytoplasm. Ras exerts effects on cell transformation and proliferation, the actin cytoskeleton, differentiation, and apoptosis. It is likely that these effects are mediated by multiple effectors, including Raf-1, RalGDS (2), phosphatidylinositol 3-kinase (PI3K) (48), and other Ras-binding proteins (reviewed in reference 38), as well as members of the Rho family (26,44,45).The elucidation of multiple Ras effector pathways was greatly facilitated by the isolation of Ras mutants which interact with single downstream effectors (60). Ras S35 binds preferentially to Raf, while Ras G37 binds to RalGDS (49,53,60 While the differential effects of Ras S35 and Ras G37 on Raf and MAPK activity are consistently observed (23,25,27,46,49,60), other effects of these mutants vary. Both Ras S35 and Ras G37 transform some NIH 3T3 strains, inducing growth in medium with low serum levels, anchorage-independent proliferation, and tumor formation in nude mice (27). The activity of Ras G37 in these assays suggests that Ras stimulates some of the same biological effects through Raf-independent pathways and that the effector pathways used by Ras vary in different cell types. Consistently, Ras V12 stimulates transformation in most cells, while activated forms of Raf transform fibroblasts but not epithelial cells (41). If Ras signals through multiple effectors, the selection of a particular effector pathway should be regulated. One potential way to achieve such regulation is through cross talk between Ras and other signaling pathways.One of the best-studied examples of cross talk is that between Ras and protein kinase A (PKA). In many cells, cyclic AMP (cAMP) inhibits Ras signaling through Raf and the MAPK cascade (reviewed in reference 6). cAMP activates PKA, which phosphorylates Raf-1 at multiple serine residues. PKA-mediated phosphorylation reduces the affinity of Raf for Ras (17,63) and decreases Raf kinase activity (10,17,57), effects which may inhibit Ras-mediated proliferation. Ras and cAMP also collaborate to produce similar effects. In PC12 cells, Ras and cAMP induce neurite extension (13, 54) and promote cell survival (64). Ras and cAMP stimulate proliferation in thyroid cells (7,36,39), and Ras activity is required for the mitogenic effects of thyrotropin (TSH) (32). Despite the requirement for Ras, TSH downregulates signaling through Raf and the MAPK cascade...

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Stepwise transformation of primary thyroid epithelial cells by a mutant Ha‐ras oncogene: An in vitro model of tumor progression

Cited by 42 publications

References 42 publications

New Strategies in Diagnosing Cancer in Thyroid Nodules: Impact of Molecular Markers

New Strategies in Diagnosing Cancer in Thyroid Nodules: Impact of Molecular Markers

Tolerance of high levels of wild-type p53 in transformed epithelial cells dependent on auto-regulation by mdm-2

Differential Effects of Protein Kinase A on Ras Effector Pathways

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