Insulin-Like Growth Factor-II/Mannose 6-Phosphate Receptor Overexpression Reduces Growth of Choriocarcinoma Cells<i>in Vitro</i>and<i>in Vivo</i>

O’Gorman, David B.; Weiss, Jocelyn; Hettiaratchi, Anusha; Firth, Sue M.; Scott, Carolyn D.

doi:10.1210/en.2002-220548

Cited by 85 publications

(73 citation statements)

References 36 publications

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“…Overexpression of the receptor in human colorectal carcinoma cells has been reported to decrease cell growth and increase apoptosis in culture (Souza et al, 1999) and similar experiments with the human JEG-3 choriocarcinoma cell line (O'Gorman et al, 2002) and the MDA-MB 231 (Lee et al, 2003) breast tumor cell line have demonstrated decreased growth both in vitro and in vivo. Reduced expression of the receptor produced by various antisense strategies has the opposite effect of increasing cell proliferation and, in some case, reducing apoptosis.…”

Section: Introductionmentioning

confidence: 59%

Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor

Sahagian

2004

Oncogene

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The mannose 6-phosphate/IGF-2 receptor has been proposed to be a tumor suppressor gene on the basis of loss of heterozygosity and mutations in tumors from cancer patients. To test this hypothesis, the receptor was expressed in 66cl4, a mouse mammary tumor cell line deficient in the receptor. Expression of the receptor corrected the abnormal lysosomal trafficking phenotype displayed by these cells. Receptor expression had no apparent effect on growth or invasiveness of the cells in vitro but effectively inhibited formation of mammary tumors in BALB/c mice. Analysis of cell proliferation and apoptosis in tumors indicated that the primary effect of the receptor was to inhibit cell proliferation. Proliferation indices for receptor-deficient and receptor-expressing tumors, as determined by BrdU incorporation, were 24.6 and 7.6%, respectively. No significant effect of receptor expression on apoptosis was observed. Receptor expression similarly inhibited tumor growth in BALB/c scid mice indicating that cytotoxic T cells and other components of the immune system missing in scid mice are not involved in the receptor's tumor suppressing effect. These findings establish a role for the receptor as a bona fide tumor suppressor gene and together with previous studies, suggest an important role for the receptor in human and rodent cancers.

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Section: Introductionmentioning

confidence: 59%

Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor

Sahagian

2004

Oncogene

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“…24,44 Wise and Pravtcheva have demonstrated that the presence of an Igf2r transgene delays Igf2-induced mammary tumour formation in mice. 22 On the other hand, M6P/IGF2R downregulation has been shown to increase the growth rate and tumourigenicity of choriocarcinoma cells, 27 further highlighting the relevance of the M6P/IGF2R status for tumour progression. In vitro invasiveness of SCC-VII/IGF2R-1 and mock-transfected SCC-VII cells was assayed using either conditioned medium of fibroblasts (CMF) or purified growth factors (all used at a final concentration of 100 ng/ml) as chemoattractants.…”

Section: Discussionmentioning

confidence: 99%

“…26 For choriocarcinoma and breast tumour cells, the growth-suppressive capacity of M6P/ IGF2R has been also verified in vivo. [23][24][25] It is thought that the anti-proliferative activity of M6P/IGF2R in tumour cells is mainly due to its impact on IGF-II signalling. 24,44 Wise and Pravtcheva have demonstrated that the presence of an Igf2r transgene delays Igf2-induced mammary tumour formation in mice.…”

Section: Discussionmentioning

confidence: 99%

“…20,21 In support of the notion that M6P/IGF2R is a tumour suppressor, it has been reported that mammary tumour development is impaired in transgenic mice overexpressing the receptor. 22 Furthermore, M6P/IGF2R overexpression has been found to reduce the growth of cancer cells both in vitro and in vivo, [23][24][25] in some cases simultaneously promoting cell death. 26 Conversely, M6P/IGF2R downregulation by antisense or ribozyme approaches accelerates tumour cell proliferation and renders the cells more resistant to apoptotic stimuli.…”

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confidence: 99%

“…26 Conversely, M6P/IGF2R downregulation by antisense or ribozyme approaches accelerates tumour cell proliferation and renders the cells more resistant to apoptotic stimuli. 27,28 However, these studies were all performed using receptor-positive cancer cell lines, with only one of them displaying a reduced M6P/ IGF2R content. 25 Moreover, the impact of M6P/IGF2R on tumour invasion and metastasis is only poorly understood, with controversial results reported for breast cancer cells.…”

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confidence: 99%

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The mannose 6‐phosphate/insulin‐like growth factor II receptor restricts the tumourigenicity and invasiveness of squamous cell carcinoma cells

Probst¹,

Puxbaum²,

Svoboda³

et al. 2009

Intl Journal of Cancer

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The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) mediates biosynthetic sorting and endocytosis of various factors that impinge on the proliferation, migration and invasiveness of tumour cells. The gene encoding M6P/IGF2R is frequently lost or mutated in a wide range of malignant tumours including squamous cell carcinomas. We have previously shown that M6P/IGF2R-deficient SCC-VII murine squamous cell carcinoma cells secrete large amounts of pro-invasive lysosomal proteinases. Furthermore, the formation of mature lysosomes is impaired in SCC-VII cells. To assess the link between M6P/ IGF2R status and tumour invasion, we have now generated SCC-VII lines stably transfected with human M6P/IGF2R cDNA. Reconstitution of functional M6P/IGF2R expression in SCC-VII cells strongly improves the intracellular retention of lysosomal proteinases and restores the formation of mature lysosomes. In addition, the presence of heterologous M6P/IGF2R compromises the growth of SCC-VII cells both in vitro and in vivo. Remarkably, M6P/IGF2R expression also reduces the invasive capacity of SCC-VII cells in response to various chemoattractants. These results indicate that the M6P/IGF2R status influences the metastatic propensity of squamous cell carcinomas. ' 2008 Wiley-Liss, Inc.Key words: cathepsin; lysosome; proteolysis; squamous cell carcinoma; tumour invasion A key requirement for metastatic cancer cell invasion is the penetration of extracellular matrix (ECM) barriers. This process involves the degradation of different ECM proteins and proteoglycans. 1,2 Various proteinases have been implicated in ECM degradation associated with tumour invasion and metastasis, including urokinase-type plasminogen activator, matrix metalloproteinases and cathepsins. [3][4][5] The involvement of the latter enzymes in ECM proteolysis is perplexing, since cathepsins are normally localized in lysosomes. However, tumour cells often secrete significant amounts of these proteinases into the pericellular fluid, as first observed for cathepsin B. 6 As typical for lysosomal enzymes, the N-glycan moieties of cathepsins are modified during their biosynthesis with mannose 6-phosphate (M6P) residues which permit interaction with the main lysosomal sorting receptors, the 300-kDa mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) and the 46-kDa mannose 6-phosphate receptor (MPR46). 7 Evidence has been provided that excessive secretion of cathepsins by tumour cells may be due to transformation-induced changes to the M6P receptor pathway. [8][9][10] Lysosomal sorting via M6P/IGF2R is generally far more efficient than by MPR46, demonstrating that the former is the main lysosomal targeting receptor in mammalian cells. 11,12 However, M6P/IGF2R also binds a variety of other factors that impinge on the proliferation, migration and invasiveness of tumour cells, including insulin-like growth factor II (IGF-II), 13 transforming growth factor b, 14 urokinase-type plasminogen activator receptor 15 and plasminogen. 16 Hence, it is o...

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Protein Structure Similarity Clustering: Dynamic Treatment of PDB Structures Facilitates Clustering

et al. 2006

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Insulin-Like Growth Factor-II/Mannose 6-Phosphate Receptor Overexpression Reduces Growth of Choriocarcinoma Cellsin Vitroandin Vivo

Cited by 85 publications

References 36 publications

Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor

Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor

The mannose 6‐phosphate/insulin‐like growth factor II receptor restricts the tumourigenicity and invasiveness of squamous cell carcinoma cells

Protein Structure Similarity Clustering: Dynamic Treatment of PDB Structures Facilitates Clustering

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