Abstract: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 inhibit… Show more
“…24 In contrast, subnormal levels of ectopically expressed M6P/IGF2R did not affect the motility of receptor-deficient murine mammary tumour cells. 25 In the case of SCC-VII cells, the migratory response of M6P/IGF2R-positive cells was consistently lower than that of their parental counterparts, even though the former displayed near physiological M6P/IGF2R levels. These results indicate that the M6P/IGF2R status affects the ability of squamous cell carcinoma cells to penetrate ECM barriers.…”
Section: Discussionmentioning
confidence: 89%
“…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%
“…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. 24,25 We have previously shown that M6P/IGF2R-deficient SCC-VII murine squamous cell carcinoma cells secrete large amounts of matrix-degrading cathepsins.…”
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...
“…24 In contrast, subnormal levels of ectopically expressed M6P/IGF2R did not affect the motility of receptor-deficient murine mammary tumour cells. 25 In the case of SCC-VII cells, the migratory response of M6P/IGF2R-positive cells was consistently lower than that of their parental counterparts, even though the former displayed near physiological M6P/IGF2R levels. These results indicate that the M6P/IGF2R status affects the ability of squamous cell carcinoma cells to penetrate ECM barriers.…”
Section: Discussionmentioning
confidence: 89%
“…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%
“…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. 24,25 We have previously shown that M6P/IGF2R-deficient SCC-VII murine squamous cell carcinoma cells secrete large amounts of matrix-degrading cathepsins.…”
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...
“…To this end, we used the 4T1-Luc syngeneic metastatic mouse breast cancer model (24)(25)(26)(27). This model is based on the 4T1-Luc mouse mammary tumor cell line, which when injected intravenously disseminates to distant organs, homing to lungs, liver, bone, and brain over a short period of time.…”
Section: Archazolid Inhibits Metastasis In Vivomentioning
The abundance of the multimeric vacuolar ATP-dependent proton pump, V-ATPase, on the plasma membrane of tumor cells correlates with the invasiveness of the tumor cell, suggesting the involvement of V-ATPase in tumor metastasis. V-ATPase is hypothesized to create a proton efflux leading to an acidic pericellular microenvironment that promotes the activity of proinvasive proteases. An alternative, not yet explored possibility is that V-ATPase regulates the signaling machinery responsible for tumor cell migration. Here, we show that pharmacologic or genetic reduction of V-ATPase activity significantly reduces migration of invasive tumor cells in vitro. Importantly, the V-ATPase inhibitor archazolid abrogates tumor dissemination in a syngeneic mouse 4T1 breast tumor metastasis model. Pretreatment of cancer cells with archazolid impairs directional motility by preventing spatially restricted, leading edge localization of epidermal growth factor receptor (EGFR) as well as of phosphorylated Akt. Archazolid treatment or silencing of V-ATPase inhibited Rac1 activation, as well as Rac1-dependent dorsal and peripheral ruffles by inhibiting Rab5-mediated endocytotic/exocytotic trafficking of Rac1. The results indicate that archazolid effectively decreases metastatic dissemination of breast tumors by impairing the trafficking and spatially restricted activation of EGFR and Rho-GTPase Rac1, which are pivotal for directed movement of cells. Thus, our data reveals a novel mechanism underlying the role of V-ATPase in tumor dissemination. Cancer Res; 72(22); 5976-87. Ó2012 AACR.
“…We then tested whether the phenotypes observed are due to increased ligand supply by the introduction of a bovine keratin 10-driven transgene expressing a soluble full-length mouse Igf2r (K10DIgf2r), previously shown to act as a ligand trap and to limit IGF-II bioavailability (23,(34)(35)(36)(37).…”
The potent growth-promoting activity of insulin-like growth factor-II (IGF-II) is highly regulated during development but frequently up-regulated in tumors. Increased expression of the normally monoallelic (paternally expressed) mouse (Igf2) and human (IGF2) genes modify progression of intestinal adenoma in the Apc Min/+ mouse and correlate with a high relative risk of human colorectal cancer susceptibility, respectively. We examined the functional consequence of Igf2 allelic dosage (null, monoallelic, and biallelic) on intestinal adenoma development in the Apc Min/+ by breeding with mice with either disruption of Igf2 paternal allele or H19 maternal allele and used these models to evaluate an IGF-II-specific therapeutic intervention. Increased allelic Igf2 expression led to elongation of intestinal crypts, increased adenoma growth independent of systemic growth, and increased adenoma nuclear B-catenin staining. By introducing a transgene expressing a soluble form of the full-length IGF-II/mannose 6-phosphate receptor (sIGF2R) in the intestine, which acts as a specific inhibitor of IGF-II ligand bioavailability (ligand trap), we show rescue of the Igf2-dependent intestinal and adenoma phenotype. This evidence shows the functional potency of allelic dosage of an epigenetically regulated gene in cancer and supports the application of an IGF-II ligand-specific therapeutic intervention in colorectal cancer. (Cancer Res 2006; 66(4): 1940-8)
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