Involvement of IGF-II in human cancer

Toretsky, Jeffrey A.; Helman, Lee J.

doi:10.1677/joe.0.1490367

Cited by 137 publications

(106 citation statements)

References 52 publications

Supporting

Mentioning

102

Contrasting

Unclassified

Order By: Relevance

“…These results are consistent with earlier reports involving IGF-IR-targeting therapy (24,42) and suggest that IGFs act mainly as antiapoptotic factors in the intestinal tumorigenesis process. Because IGF-neutralizing antibodies alone do not have a drastic effect on intestinal tumorigenesis, however, it may be necessary to combine them with chemotherapy or radiation therapy similar to IGF-IR-targeting therapy (43,44) or to limit the applications to highly IGF-dependent tumors (45). The combination therapy of IGF-neutralizing antibodies with an MMP inhibitor (36) or cyclooxygenase-2 inhibitor (46), both of which have inhibitory effects on intestinal polyp formation, is also attractive.…”

Section: Discussionmentioning

confidence: 99%

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Matsunaka

Miyamoto

Shitara

et al. 2010

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Insulin-like growth factors (IGF-I and IGF-II) play important roles in intestinal tumorigenesis. To investigate the effectiveness of IGF-targeting strategies, we conducted an in vivo study using anti-mouse neutralizing antibodies IGF-I (KM3168) and IGF-II (KM1468). Six-and 10-week-old Apc +/− mice were given KM3168 and/or KM1468 i.p. at two doses (0.01 or 0.1 μg/g weight) once or twice weekly for 4 weeks. To clarify the source of IGFs in vivo, we evaluated the expression levels of IGFs in the liver, normal small intestine, and polyps of the small intestine of Apc +/− mice. The phosphorylation status of IGF signalrelated molecules was examined using immunostaining to understand the mechanism underlying the effects of IGF-neutralizing antibody. The plasma half-life was 168 for KM3168 and 85 hours for KM1468. In two lineages of Apc +/− mice (Apc 1309 and Apc Min/+ ), a low dose (0.01 μg/g weight) of KM3168 and KM1468 significantly reduced the number of polyps when given once and twice weekly, respectively. Combined administration of the effective dose of each antibody had an additive effect. The liver was the main source of IGF-I, whereas the polyps of the small intestine and normal small intestine were the main source of IGF-II. IGF-neutralizing antibodies decreased the phosphorylation of IGF type 1 receptor and inhibited the signal transduction of the Akt pathway. These results suggest that IGF-I and IGF-II play important roles in polyp formation in Apc +/− mice and that specific antibodies to IGF-I and IGF-II may be promising antitumor agents. Mol Cancer Ther; 9(2); 419-28. ©2010 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Matsunaka

Miyamoto

Shitara

et al. 2010

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Excess IGF2 has detrimental systemic and local effects in vivo, promoting somatic overgrowth and an increased frequency of tumors. 23,24 Overexpression of IGF2 has been found in human colorectal and many other cancers. [24][25][26][27][28] However, studies on the transgenic mice in which IGF2 was overexpressed in salivary glands, mammary glands, lung, uterus and spleen, also under the control of MMTV promoter, show no pleomorphic adenomas or any other salivary gland tumors.…”

Section: Discussionmentioning

confidence: 99%

“…23,24 Overexpression of IGF2 has been found in human colorectal and many other cancers. [24][25][26][27][28] However, studies on the transgenic mice in which IGF2 was overexpressed in salivary glands, mammary glands, lung, uterus and spleen, also under the control of MMTV promoter, show no pleomorphic adenomas or any other salivary gland tumors. 29,30 It strongly suggests that overexpression of IGF2 alone might not be enough for initiation of tumorigenesis in the salivary glands.…”

Section: Discussionmentioning

confidence: 99%

Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice

Zhao¹,

Ren²,

Yang³

et al. 2005

Intl Journal of Cancer

View full text Add to dashboard Cite

Pleomorphic adenoma gene 1 (PLAG1) was found frequently rearranged and activated in human salivary gland pleomorphic adenomas. It encodes a developmentally regulated transcription factor. Ectopic overexpression of PLAG1 has been proposed to play a crucial role in tumorigenesis of salivary gland pleomorphic adenomas. It was reported that PLAG1 can activate the transcription of insulin-like growth factor 2 (IGF2), functioning as a protooncogene. In this report, we show that the salivary gland tumors developed in PLAG1 transgenic mice share major histopathologic features with human pleomorphic adenomas. It was found that b-catenin, the key component of Wnt signaling pathway, was upregulated at transcriptional level in tumors developed in 3 independent transgenic mouse lines. Immunohistochemical staining revealed that expression of b-catenin as well as c-myc, downstream of b-catenin in Wnt signaling pathway, was highly upregulated with overexpression of PLAG1 transgene in tumor and normal transgenic salivary gland tissues. Moreover, we found that PLAG1 can activate the transcription of mouse but not human b-catenin in the 3T3 cells cotransfected with reporter constructs. Sequence analysis shows there are 4 PLAG1 consensus binding sites in mouse b-catenin promoter region but not in human. Our findings provide the first in vivo evidence for the oncogenic activity of PLAG1 in pleomorphic adenoma tumorigenesis, reveal a valued animal model for human salivary gland tumors and suggest that Wnt signaling pathway may also contribute to the development of pleomorphic adenomas in transgenic mice. ' 2005 Wiley-Liss, Inc.Key words: pleomorphic adenoma gene 1; transgenic mice; b-catenin; pleomorphic adenomas The pleomorphic adenoma is the most common type of salivary gland tumor, which accounts for more than 50% of all salivary gland neoplasms. It usually behaves as the benign slow-growing tumor morphologically characterized by a biphasic pattern containing both epithelial and mesenchymal areas. 1 In recent years, a series of studies on tumorigenesis of salivary gland tumors has revealed that oncogenic activation of pleomorphic adenoma gene 1 (PLAG1) on 8q12 plays a crucial role in the development of pleomorphic adenomas originating from salivary glands. The major form of PLAG1 activation is reciprocal chromosomal translocations that lead to promoter swapping between PLAG1 gene, which is not expressed or weakly expressed in adult salivary glands, and the genes ubiquitously expressed in adult tissues, such as the b-catenin gene on 3p21, 2 the leukemia-inhibitory factor receptor (LIFR) gene on 5p13 and the transcription elongation factor SII gene on 3p21. 3-22. 3,4 The breakpoints of both fusion partner genes invariably occur in the 5 0 noncoding regions and consequently lead to ectopic expression of PLAG1 gene in salivary glands. In fact, the chromosomal translocations involving 8q12 only account for 39% of tumors. Other chromosomal abnormalities were also found to be associated with the formation of pleomorphic adenomas, such ...

show abstract

“…For example, a high level of expression of IGF-2 was associated with poor patient survival (p Ͻ 0.002 by Cox regression assay). Overexpression of IGF-2 has been implicated in progression and metastasis of many types of cancers, including colon cancer, breast cancer, Wilm's tumor, and neuroblastoma (Toretsky and Helman, 1996). The potential involvement of IGF-2 in the progression of gastric cancer clearly warrants further investigation.…”

Section: Expression Patterns Significantly Correlated With Patient Sumentioning

confidence: 99%

Variation in Gene Expression Patterns in Human Gastric Cancers

Chen

Leung

Yuen

et al. 2003

MBoC

286

239

View full text Add to dashboard Cite

Gastric cancer is the world's second most common cause of cancer death. We analyzed gene expression patterns in 90 primary gastric cancers, 14 metastatic gastric cancers, and 22 nonneoplastic gastric tissues, using cDNA microarrays representing ∼30,300 genes. Gastric cancers were distinguished from nonneoplastic gastric tissues by characteristic differences in their gene expression patterns. We found a diversity of gene expression patterns in gastric cancer, reflecting variation in intrinsic properties of tumor and normal cells and variation in the cellular composition of these complex tissues. We identified several genes whose expression levels were significantly correlated with patient survival. The variations in gene expression patterns among cancers in different patients suggest differences in pathogenetic pathways and potential therapeutic strategies

show abstract

Involvement of IGF-II in human cancer

Cited by 137 publications

References 52 publications

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice

Variation in Gene Expression Patterns in Human Gastric Cancers

Contact Info

Product

Resources

About