%0 Journal Article
%~ Pubmed
%A Amritraj, A
%A Hawkes, C
%A Phinney, A L
%A Mount, H T
%A Scott, C D
%A Westaway, D
%A Kar, S
%T Altered levels and distribution of IGF-II/M6P receptor and lysosomal enzymes in mutant APP and APP + PS1 transgenic mouse brains.
%B Neurobiology of aging
%D 2007
%V 30
%N 1
%P 54-70
%@ 1558-1497
%X The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor participates in the trafficking of lysosomal enzymes from the trans-Golgi network or the cell surface to lysosomes. In Alzheimer's disease (AD) brains, marked up-regulation of the lysosomal system in vulnerable neuronal populations has been correlated with altered metabolic functions. To establish whether IGF-II/M6P receptors and lysosomal enzymes are altered in the brain of transgenic mice harboring different familial AD mutations, we measured the levels and distribution of the receptor and lysosomal enzymes cathepsins B and D in select brain regions of transgenic mice overexpressing either mutant presenilin 1 (PS1; PS1(M146L+L286V)), amyloid precursor protein (APP; APP(KM670/671NL+V717F)) or APP+PS1 (APP(KM670/671NL+V717F)+PS1(M146L+L286V)) transgenes. Our results revealed that levels and expression of the IGF-II/M6P receptor and lysosomal enzymes are increased in the hippocampus and frontal cortex of APP and APP+PS1, but not in PS1, transgenic mouse brains compared with wild-type controls. The changes were more prominent in APP+PS1 than in APP single transgenic mice. Additionally, all beta-amyloid-containing neuritic plaques in the hippocampal and cortical regions of APP and APP+PS1 transgenic mice were immunopositive for both lysosomal enzymes, whereas only a subset of the plaques displayed IGF-II/M6P receptor immunoreactivity. These results suggest that up-regulation of the IGF-II/M6P receptor and lysosomal enzymes in neurons located in vulnerable regions reflects an altered functioning of the endosomal-lysosomal system which may be associated with the increased intracellular and/or extracellular A beta deposits observed in APP and APP+PS1 transgenic mouse brains.
%Z FOR Codes: 111603 110902



%0 Journal Article
%~ Pubmed
%A Heinzelmann-Schwarz, Viola A
%A Scolyer, Richard A
%A Scurry, James P
%A Smith, Alison N
%A Gardiner-Garden, Margaret
%A Biankin, Andrew V
%A Baron-Hay, Sally
%A Scott, Carolyn
%A Ward, Robyn
%A Fink, Daniel
%A Hacker, Neville F
%A Sutherland, Robert L
%A O'brien, Philippa M
%T Low meprin alpha expression differentiates primary ovarian mucinous carcinoma from gastrointestinal cancers that commonly metastasise to the ovaries.
%B Journal of Clinical Pathology
%D 2006
%V 60
%N 6
%P 622-6
%@ 0021-9746
%X Currently, no specific immunohistochemical markers are available to differentiate primary mucinous epithelial ovarian cancer (MOC) from adenocarcinomas originating at other sites that have metastasised to the ovary, which may have an impact on patient management and prognosis.



%0 Journal Article
%~ Pubmed
%A Heinzelmann-Schwarz, V A
%A Gardiner-Garden, M
%A Henshall, S M
%A Scurry, J P
%A Scolyer, R A
%A Smith, A N
%A Bali, A
%A Vanden Bergh, P
%A Baron-Hay, S
%A Scott, C
%A Fink, D
%A Hacker, N F
%A Sutherland, R L
%A O'Brien, P M
%T A distinct molecular profile associated with mucinous epithelial ovarian cancer.
%B British Journal of Cancer
%D 2006
%V 94
%N 6
%P 904-13
%@ 0007-0920
%X Mucinous epithelial ovarian cancers (MOC) are clinically and morphologically distinct from the other histological subtypes of ovarian cancer. To determine the genetic basis of MOC and to identify potential tumour markers, gene expression profiling of 49 primary ovarian cancers of different histological subtypes was performed using a customised oligonucleotide microarray containing >59 000 probesets. The results show that MOC express a genetic profile that both differs and overlaps with other subtypes of epithelial ovarian cancer. Concordant with its histological phenotype, MOC express genes characteristic of mucinous carcinomas of varying epithelial origin, including intestinal carcinomas. Differences in gene expression between MOC and other histological subtypes of ovarian cancer were confirmed by RT-PCR and/or immunohistochemistry. In particular, galectin 4 (LGALS4) was highly and specifically expressed in MOC, but expressed at lower levels in benign mucinous cysts and borderline (atypical proliferative) tumours, supporting a malignant progression model of MOC. Hence LGALS4 may have application as an early and differential diagnostic marker of MOC.



%0 Journal Article
%~ Isi
%A Petry, C. J.
%A Ong, K. K.
%A Wingate, D. L.
%A Brown, J.
%A Scott, C. D.
%A Jones, E. Y.
%A Pembrey, M. E.
%A Dunger, D. B.
%T Genetic variation in the type 2 insulin-like growth factor receptor gene and disparity in childhood height.
%B Growth Hormone & Igf Research
%D 2005
%C United Kingdom
%I Churchill Livingstone
%V 15
%N 6
%P 363-368
%@ 1096-6374
%X 
%Z FOR Codes: 110306



%0 Journal Article
%~ Pubmed
%A Baron-Hay, Sally
%A Boyle, Frances
%A Ferrier, Alan
%A Scott, Carolyn
%T Elevated serum insulin-like growth factor binding protein-2 as a prognostic marker in patients with ovarian cancer.
%B Clinical Cancer Research
%D 2004
%V 10
%N 5
%P 1796-806
%@ 1078-0432
%X PURPOSE: The purpose of this research was to examine the diagnostic and prognostic significance of elevated serum insulin-like growth factor binding protein (IGFBP)-2 levels in women with ovarian cancer from diagnosis through treatment to relapse or remission. EXPERIMENTAL DESIGN: Serum collected pre- and postoperatively in women newly diagnosed with ovarian cancer, during adjuvant chemotherapy cycles, at 6 months follow-up and at relapse was analyzed for IGFBP-2. Control serum was from women undergoing pelvic or abdominal surgery for benign ovarian disease or nonovarian pathology. RESULTS: IGFBP-2 at diagnosis was significantly elevated (P < 0.0001) in women with ovarian cancer (887 +/- 62 ng/ml) compared with benign controls (337 +/- 25 ng/ml), and women undergoing nonovarian surgery (439 +/- 49 ng/ml) and correlated positively with tumor stage and cellular differentiation but not with CA125. Unexpectedly, IGFBP-2 levels increased additionally 1-week postoperatively in ovarian cancer patients (1581 +/- 90 ng/ml; P = 0.0027) as well as controls (977 +/- 95 ng/ml; P < 0.0001) and was higher in women who had suboptimal debulking compared with optimal debulking of their tumor. IGFBP-2 levels returned to normal in women without evidence of progressive disease, but remained significantly elevated in women who later relapsed. Patients with IGFBP-2 levels in the highest tertile at diagnosis had a significantly shorter progression-free interval and overall survival. CONCLUSION: In ovarian cancer IGFBP-2 is elevated at diagnosis, and corresponds to stage and histology with patients in the highest tertile of IGFBP-2 more likely to relapse and have a poorer outlook. Identification of these patients at diagnosis may allow more individualized, aggressive adjuvant treatment and follow-up, and IGFBP-2 may therefore be an important additional prognostic marker in this disease.



%0 Journal Article
%~ Pubmed
%A Gicquel, C
%A Weiss, J
%A Amiel, J
%A Gaston, V
%A Le Bouc, Y
%A Scott, C D
%T Epigenetic abnormalities of the mannose-6-phosphate/IGF2 receptor gene are uncommon in human overgrowth syndromes.
%B Journal of Medical Genetics
%D 2004
%V 41
%N 1
%P e4
%@ 1468-6244
%X 



%0 Journal Article
%~ Pubmed
%A Scott, C D
%A Firth, S M
%T The role of the M6P/IGF-II receptor in cancer: tumor suppression or garbage disposal?
%B Hormone and metabolic research. Hormon- und Stoffwechselforschung. Hormones et metabolisme
%D 2004
%V 36
%N 5
%P 261-71
%@ 0018-5043
%X The mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR) is an intriguing protein with multiple ligands and multiple functions. Approximately 90 - 95 % of the receptor is located intracellularly, with 5 - 10 % being on the cell surface. It has long been known to play an essential intracellular role in the transport of newly-synthesized lysosomal enzymes from the trans-Golgi network (TGN) to the lysosomes. More recently, however, the loss of this receptor has been described in some tumour types, suggesting that it may play a role in tumour suppression. The focus has therefore shifted to elucidating the role played by the cell surface receptor and its interaction with its diverse ligands in tumour growth and progression. The list of ligands is continuously increasing and includes growth factors such as IGF-II and transforming growth factor beta (TGFbeta). This review will address the question of whether the M6P/IGF-IIR plays a direct role in tumour suppression or merely plays an indirect role as a transporter for ligands designated for degradation in the lysosomes.



%0 Journal Article
%~ Pubmed
%A Lee, Jason S
%A Weiss, Jocelyn
%A Martin, Janet L
%A Scott, Carolyn D
%T Increased expression of the mannose 6-phosphate/insulin-like growth factor-II receptor in breast cancer cells alters tumorigenic properties in vitro and in vivo.
%B International journal of cancer. Journal international du cancer
%D 2003
%V 107
%N 4
%P 564-70
%@ 0020-7136
%X The mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR) is thought to act as a suppressor of tumor growth by binding the mitogenic peptide IGF-II and modulating its extracellular levels via degradation. This receptor has been found to be absent or nonfunctional in a high proportion of breast tumors as a result of LOH and mutation of the gene. In our study, we have examined the effect of increasing expression of M6P/IGF-IIR on breast cancer cell tumorigenicity. MDA-MB-231 breast cancer cells stably transfected with M6P/IGF-IIR cDNA exhibited not only a greatly reduced ability to form tumors but also a markedly reduced growth rate in nude mice. In vitro, increased M6P/IGF-IIR expression resulted in 2-fold reduced uptake of IGF-II and was associated with reduced cellular invasiness and motility. Cells with increased M6P/IGF-IIR expression exhibited reduced phosphorylation of IGF-I receptor and p44/42 MAPK compared to vector transfectants, or wild-type MDA-MB-231 cells. These results therefore suggest that M6P/IGF-IIR levels can modulate breast cancer cell tumorigenicity by a mechanism that may involve altered IGF-I receptor signaling.



%0 Journal Article
%~ Pubmed
%A O'Gorman, David B
%A Weiss, Jocelyn
%A Hettiaratchi, Anusha
%A Firth, Sue M
%A Scott, Carolyn D
%T Insulin-like growth factor-II/mannose 6-phosphate receptor overexpression reduces growth of choriocarcinoma cells in vitro and in vivo.
%B Endocrinology
%D 2002
%V 143
%N 11
%P 4287-94
%@ 0013-7227
%X The IGF-II/mannose-6 phosphate receptor (IGF-II/M6PR) interacts with multiple tumor growth factors, including IGF-II and latent TGFbeta1. The IGF-II/M6PR has been proposed to be a tumor growth suppressor, a hypothesis supported by our previous finding that decreased IGF-II/M6PR expression enhances tumor growth. In this study, we further demonstrate that IGF-II/M6PR overexpression, resulting from cDNA transfection of JEG-3 choriocarcinoma cells, leads to a decreased cellular growth rate in vitro and decreased tumor growth in nude mice. Examination of several IGF-II/M6PR ligands in receptor-overexpressing cells showed no change in endogenous IGF-II or secretion of procathepsins D and L but an increase in latent TGFbeta1 secretion and activation. Cells transfected with cDNA for a truncated, soluble form of the receptor, previously shown to inhibit IGF-II-stimulated DNA synthesis, displayed a very slow growth rate in vitro and in nude mice but showed no alteration in TGFbeta1 levels. This suggests that, in IGFII/M6PR-transfected cells, increased levels of soluble IGF-II/M6PR may play a role in growth inhibition. Overall, the findings in this study are consistent with the hypothesis that the IGF-II/M6PR suppresses tumor growth.
%Z FOR Codes: 111299 110306



%0 Journal Article
%A Chenevix-Trench, G
%A Spurdle, AB
%A Gatei, M
%A Kelly, H
%A Marsh, A
%A Chen, X
%A Donn, K
%A Cummings, M
%A Nyholt, D
%A Jenkins, MA
%A Scott, C
%A Pupo, GM
%A D?rk, T
%A Bendix, R
%A Kirk, J
%A Tucker, K
%A McCredie, MRE
%A Hopper, JL
%A Sambrook, J
%A Mann, GJ
%A Khanna, KK
%T Dominant Negative ATM Mutations in Breast Cancer Families
%B Journal Of The National Cancer Institute
%D 2002
%C Journals Dept,2001 Evans Rd, Cary, Nc, 27513
%I Oxford Univ Press Inc
%V 94
%N 
%P 205-215
%@ 0027-8874
%X 



%0 Journal Article
%A Scott, CD
%A Cianfarani, S
%A Geremia, C
%A Germani, D
%T Growth, IGF System, and Cortisol in Children with Intrauterine Growth Retardation: Is Catch-up Growth Affected by Reprogramming of the Hypothalamic-Pituitary-Adrenal Axis?
%B Pediatric Research
%D 2002
%C Inc, 351 West Camden St, Baltimore, Md, 21201-2436
%I Int Pediatric Research Foundation
%V 51
%N 
%P 94-99
%@ 0031-3998
%X 



%0 Book Section
%A Cianfarani, S
%A Geremia, C
%A Scott, CD
%A Germani, D
%T Growth, IGF system, and cortisol in children with intrauterine growth retardation: is catch-up growth affected by reprogramming of the hypothalamic-pituitary-adrenal axis?
%B Pediatric Research
%D 2001
%C Melbourne, Australia
%I Melbourne University Press
%V 
%N 
%P 217-230
%@ 0 522 84924 5
%X 



%0 Journal Article
%~ Pubmed
%A Delhanty, P J
%A Scott, C D
%A Babu, S
%A Baxter, R C
%T Acid-labile subunit regulation during the early stages of liver regeneration: implications for glucoregulation.
%B American journal of physiology. Endocrinology and metabolism
%D 2001
%V 280
%N 2
%P E287-95
%@ 0193-1849
%X The initiation of liver regeneration is regulated by endogenously produced growth factors and cytokines and is accompanied by suppression of growth hormone (GH) binding to hepatocytes. We have demonstrated some of these factors, particularly GH, which modulate acid-labile subunit (ALS) expression in vitro. Consequently, we investigated ALS hepatic mRNA and serum levels in rats for 24 h after partial hepatectomy (PHx). There was a significant suppression of ALS gene expression (approximately 50%, P < 0.005) and serum levels (approximately 30%, P < 0.02) by 12 h in PHx rats relative to controls. Relative to intact animals, hepatic mRNA and serum levels of ALS were suppressed by approximately 60% at 24 h. Similarly, hepatic GH receptor mRNA levels were significantly reduced in PHx animals. Moreover, hepatocytes isolated from PHx animals were less responsive to GH than those from controls. Overall, our results demonstrate that suppression of ALS gene expression and serum levels during liver regeneration relates to lowered hepatic GH sensitivity. Suppressed circulating ALS may alter insulin-like growth factor bioavailability and constitute a mechanism to maintain relatively normal glucoregulation after loss of liver mass.



%0 Journal Article
%A Ong, K
%A Kratzsch, J
%A Kiess, W
%A Study Team, ALSPAC
%A Costello, M
%A Scott, CD
%A Dunger, D
%T Size at birth and cord blood levels of insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/mannose-6-phospate receptor in term human infants
%B Journal of Clinical Endocrinology and Metabolism
%D 2000
%C 
%I Endocrine Society
%V 85
%N 
%P 4266-4269
%@ 0021-972X
%X 



%0 Journal Article
%A Scott, CD
%A Weiss, J
%T Soluble insulin-like growth factor II/mannose 6-phosphate receptor inhibits DNA synthesis in insulin-like growth factor II sensitive cells
%B Journal of Cellular Physiology
%D 2000
%C 
%I Wiley-Liss Inc
%V 182
%N 
%P 62-68
%@ 0021-9541
%X