| 61. |
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| 62. |
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| 63. |
- Mehrara, Esmaeil, 1971, et al.
(författare)
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Specific growth rate versus doubling time for quantitative characterization of tumor growth rate.
- 2007
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Ingår i: Cancer research. - 0008-5472. ; 67:8, s. 3970-5
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Tidskriftsartikel (refereegranskat)abstract
- Doubling time (DT) is widely used for quantification of tumor growth rate. DT is usually determined from two volume estimations with measurement time intervals comparable with or shorter than DT. Clinical data show that the frequency distribution of DT in patients is positively skewed, with some very long DT values compared with the average DT. Growth rate can also be quantified using specific growth rate (SGR; %/d), equal to ln2/DT. The aim of this work was to compare DT and SGR as growth rate variables. Growth rate calculations were computer simulated for a tumor with DT of 100 days, measurement time interval of 1 to 200 days, and volume estimation uncertainty of 5% to 20%. Growth rate variables were determined and compared for previously published clinical data. The study showed that DT is not a suitable variable for tumor growth rate because (a) for short measurement time intervals, or high volume uncertainties, mean DT can either overestimate or underestimate the average growth rate; (b) DT is not defined if the consecutively estimated volumes are equal; and (c) the asymmetrical frequency distribution of DT makes it unsuitable for common statistical testing. In contrast, mean SGR and its equivalent DT give the correct values for average growth rate, SGR is defined for all tumor volume changes, and it has a symmetrical frequency distribution. SGR is also more accurate to use when discussing, for example, growth fraction, cell loss rate, and growth rate heterogeneities within the tumor. SGR should thus be used, instead of DT, to quantify tumor growth rate.
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| 64. |
- Miller, Todd W, et al.
(författare)
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Loss of Phosphatase and Tensin Homologue Deleted on Chromosome 10 Engages ErbB3 and Insulin-Like Growth Factor-I Receptor Signaling to Promote Antiestrogen Resistance in Breast Cancer
- 2009
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Ingår i: CANCER RESEARCH. - 0008-5472. ; 69:10, s. 4192-4201
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Tidskriftsartikel (refereegranskat)abstract
- Knockdown of the tumor suppressor phosphatase Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) with shRNA in three estrogen receptor (ER)-positive breast cancer cell lines resulted in increased phosphatidylinositol-3 kinase (PI3K) and AKT activities, resistance to tamoxifen and fulvestrant, and hormone-independent growth. PTEN knockdown induced the up-regulation of ER transcriptional activity in MCF-7 cells but decreased ER protein levels and transcriptional activity in T47D and MDA-361 cells. Tamoxifen and fulvestrant treatment inhibited estradiol-induced Ell transcriptional activity in all shPTEN cell lines but did not abrogate the increased cell proliferation induced by PTEN knockdown. PTEN knockdown increased basal and ligand-induced activation of the insulin-like growth factor-I (IGF-I) and ErbB3 receptor tyrosine kinases, and prolonged the association of the p85 PI3K subunit with the IGF-I receptor (IGF-IR) effector insulin receptor substrate-1 and with ErbB3, implicating VITA in the modulation of Signaling upstream of PI3K. Consistent with these data, PTEN levels inversely correlated with levels of tyrosine-phosphorylated IGF-IR in tissue lysate arrays of primary breast cancers. Inhibition of IGF-IR and/or ErbB2-mediated activation of ErbB3 with tyrosine kinase inhibitors restored hormone dependence and the growth inhibitory effect of tamoxifen and fulvestrant. oil shPTEN cells, suggesting that cotargeting both Ell and receptor tyrosine kinase pathways holds promise for the treatment of patients with ER+, PTEN-deficient breast cancers.
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| 65. |
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| 66. |
- Nilsson, Ulrika W., et al.
(författare)
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Estradiol and tamoxifen regulate endostatin generation via matrix metalloproteinase activity in breast cancer in vivo
- 2006
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 66:9, s. 4789-4794
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Tidskriftsartikel (refereegranskat)abstract
- Matrix metalloproteinases (MMP) are important regulators of tumor progression and angiogenesis. MMPs generate both proangiogenic and antiangiogenic fragments, such as vascular endothelial growth factor and endostatin. The in vivo activation of MMPs and endostatin generation occur mainly in the extracellular environment by interactions of different cell types. Therefore, these processes are necessary to study in the extracellular space in vivo. Sex steroids play a dominant role in breast carcinogenesis, by largely unknown mechanisms. In the present study, we used in vivo microdialysis to directly quantify MMP-2 and MMP-9 activity and sample endostatin from both stroma (murine) and tumor (human) cells in vivo in solid MCF-7 tumors in nude mice. We found that tamoxifen in combination with estradiol increased tumor MMP-2/MMP-9 in vivo activity, endostatin levels, and decreased tumor vascularization compared with estradiol treatment only. The stroma-derived endostatin was three to five times higher than cancer cell–generated endostatin. After inhibition of MMP-2/MMP-9, endostatin levels decreased, providing evidence that these proteases are highly involved in the generation of endostatin. Our results support the previously reported concept that MMPs may serve as negative regulators of angiogenesis. The regulation of endostatin generation by modulation of MMP-2/MMP-9 activities suggests a previously unrecognized mechanism of estradiol and tamoxifen, which may have implications for the pathogenesis of breast cancer.
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| 67. |
- Nordén, Madeleine, 1979, et al.
(författare)
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Down-regulation of the sodium/iodide symporter explains 131I-induced thyroid stunning.
- 2007
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Ingår i: Cancer research. - 0008-5472. ; 67:15, s. 7512-7
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Tidskriftsartikel (refereegranskat)abstract
- (131)I radiation therapy of differentiated thyroid cancer may be compromised by thyroid stunning (i.e., a paradoxical inhibition of radioiodine uptake caused by radiation from a pretherapeutic diagnostic examination). The stunning mechanism is yet uncharacterized at the molecular level. We therefore investigated whether the expression of the sodium/iodide symporter (NIS) gene is changed by irradiation using (131)I. Confluent porcine thyroid cells on filter were stimulated with thyroid-stimulating hormone (TSH; 1 milliunit/mL) or insulin-like growth factor-I (IGF-I; 10 ng/mL) and simultaneously exposed to (131)I in the culture medium for 48 h, porcine NIS mRNA was quantified by real-time reverse transcription-PCR using 18S as reference, and transepithelial iodide transport was monitored using (125)I(-) as tracer. TSH increased the NIS expression >100-fold after 48 h and 5- to 20-fold after prolonged stimulation. IGF-I enhanced the NIS transcription at most 15-fold but not until 5 to 7 days. (131)I irradiation (7.5 Gy) decreased both TSH-stimulated and IGF-I-stimulated NIS transcription by 60% to 90% at all investigated time points. TSH and IGF-I stimulated NIS synergistically 15- to 60-fold after 5 days. NIS expression was reduced by (131)I also in costimulated cells, but the transcription level remained higher than in nonirradiated cells stimulated with TSH alone. Changes in NIS mRNA always correlated with altered (125)I(-) transport in cultures with corresponding treatments. It is concluded that down-regulation of NIS is the likely explanation of (131)I-induced thyroid stunning. Enhanced NIS expression by synergistically acting agents (TSH and IGF-I) partly prevents the loss of iodide transport expected from a given absorbed dose, suggesting that thyroid stunning might be pharmacologically treatable.
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| 68. |
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| 69. |
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| 70. |
- Olsson, Anna-Karin, et al.
(författare)
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The minimal active domain of endostatin is a heparin-binding motif that mediates inhibition of tumor vascularization
- 2004
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 64:24, s. 9012-9017
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Tidskriftsartikel (refereegranskat)abstract
- Endostatin constitutes the COOH-terminal 20,000 Da proteolytic fragment of collagen XVIII and has been shown to possess antiangiogenic and antitumorigenic properties. In the present study, we have investigated the role of the heparin-binding sites in the in vivo mechanism of action of endostatin. The majority of the heparin binding is mediated by arginines 155/158/184/270 in endostatin, but there is also a minor site constituted by arginines 193/194. Using endostatin mutants lacking either of these two sites, we show that inhibition of fibroblast growth factor-2-induced angiogenesis in the chicken chorioallantoic membrane requires both heparin-binding sites. In contrast, inhibition of vascular endothelial growth factor-A-induced chorioallantoic membrane angiogenesis by endostatin was only dependent on the minor heparin-binding site (R193/194). These arginines were also required for endostatin to inhibit fibroblast growth factor-2- and vascular endothelial growth factor-A-induced chemotaxis of primary endothelial cells. Moreover, we show that a synthetic peptide corresponding to amino acids 180-199 of human endostatin (which covers the minor heparin-binding site) inhibits endothelial cell chemotaxis and reduces tumor vascularization in vivo. Substitution of arginine residues 193/194 for alanine attenuates the antiangiogenic effects of the peptide. These data show an essential role for heparin binding in the antiangiogenic action of endostatin.
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