A Dominant Negative Type I Insulin-like Growth Factor Receptor Inhibits Metastasis of Human Cancer Cells

Sachdev, Deepali; Hartell, Julie S.; Lee, Adrian V.; Zhang, Xihong; Yee, Douglas

doi:10.1074/jbc.m305403200

Cited by 147 publications

(113 citation statements)

References 49 publications

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“…These observations have also been confirmed in vivo by studies showing that IRS-2 null animals had significantly decreased incidence of metastasis compared with wild-type mice when mated with transgenic mice that express the polyoma virus middle T antigen in the mammary gland (39). Several studies have reported that inhibition of IGF-IR inhibits metastasis of various cancer cells (40 -42 (42). However, only mice harboring parent LCC6 cells with wild-type IGF-IR formed lung metastases.…”

Section: Igf-ir and Metastasissupporting

confidence: 65%

“…The mere presence and activation of IGF-IR may not be sufficient to indicate potential response. For example, we have shown that inhibition of IGF-IR function in the LCC6 cell line does not affect tumor growth; rather, metastatic function is blocked (42). Because phase II clinical trials only detect tumor growth inhibition, regulation of this phenotype by IGF-IR blockade would not be observed.…”

Section: Conduct Of Clinical Trials With Anti^igf-ir Reagentsmentioning

confidence: 99%

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Disrupting insulin-like growth factor signaling as a potential cancer therapy

Sachdev

Yee

2007

Molecular Cancer Therapeutics

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327

182

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Section: Igf-ir and Metastasissupporting

confidence: 65%

Section: Conduct Of Clinical Trials With Anti^igf-ir Reagentsmentioning

confidence: 99%

Disrupting insulin-like growth factor signaling as a potential cancer therapy

Sachdev

Yee

2007

Molecular Cancer Therapeutics

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327

182

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“…Indeed, IGF-IR inhibition, using either dominant negative or pharmacological approaches, has been shown to inhibit breast tumour growth and metastasis both in vitro and in vivo Burtrum et al, 2003;Sachdev et al, 2003;Sachdev et al, 2004). Given these findings, multiple agents targeting IGF-IR have been developed, with several agents currently in early clinical trials (Garber, 2005).…”

mentioning

confidence: 99%

Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells

et al. 2006

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Activation of the type I insulin-like growth factor receptor (IGF-IR) regulates several aspects of the malignant phenotype, including cancer cell proliferation and metastasis. Phosphorylation of adaptor proteins downstream of IGF-IR may couple IGF action to specific cancer phenotypes. In this study, we sought to determine if insulin receptor substrate-1 and -2 (IRS-1 and -2) mediate distinct biological effects in breast cancer cells. Insulin receptor substrate-1 and IRS-2 were expressed in T47D-YA breast cancer cells, which lack IRS-1 and -2 expression, yet retain functional IGF-IR. In the absence of IRS-1 and -2 expression, IGF-IR activation was unable to stimulate proliferation or motility in T47D-YA cells. Expression of IRS-1 resulted in IGF-I-stimulated proliferation, but did not affect motility. In contrast, expression of IRS-2 enhanced IGF-I-stimulated motility, but did not stimulate proliferation. The aIR-3, an inhibitor of the IGF-IR, was unable to affect these IGF-stimulated phenotypes unless IRS-1 or -2 was expressed. Thus, IGF-IR alone is unable to regulate important breast cancer cell phenotypes. In these cells, IRS proteins are required for and mediate distinct aspects of IGF-IRstimulated behaviour. As multiple agents targeting the IGF-IR are currently in early clinical trials, IRS expression should be considered as a potential biomarker for IGF-IR responsiveness.

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“…65 IGF1R did not enhance motility in LCC6-DN cells (a breast cancer cell line with dominant negative IGF1R), in contrast to increased motility in wild-type LCC6 cells, suggesting that metastasis is inhibited by truncated IGF1R. 66 The injection of mice with LCC6, but not LCC6-DN, cells resulted in the formation of lung metastases, indicating that IGF1R regulates metastasis independently from tumour growth. 66 Using a similar approach, human KM12L4 colon cancer xenograft tumours induced in nude mice were significantly smaller when the KM12L4 cells were transfected with a truncated dominantnegative form of IGF1R than when using wild-type cells.…”

Section: Igf-ir Signalling In Malignancymentioning

confidence: 99%

“…66 The injection of mice with LCC6, but not LCC6-DN, cells resulted in the formation of lung metastases, indicating that IGF1R regulates metastasis independently from tumour growth. 66 Using a similar approach, human KM12L4 colon cancer xenograft tumours induced in nude mice were significantly smaller when the KM12L4 cells were transfected with a truncated dominantnegative form of IGF1R than when using wild-type cells. 67 In addition, the colon cancer cells with dominant negative IGF1R failed to produce liver metastases after splenic injection.…”

Section: Igf-ir Signalling In Malignancymentioning

confidence: 99%

The type 1 insulin-like growth factor receptor signalling system and targeted tyrosine kinase inhibition in cancer

Haisa

2013

J Int Med Res

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Type 1 insulin-like growth factor receptor (IGF1R) signalling plays a critical role in normal cell growth, and in cancer development and progression. IGF1R and the insulin-like growth factors 1 and 2 (IGF1 and IGF2) are involved in various aspects of the malignant phenotype, suggesting that IGF1R is a potential target for cancer therapy. IGF1R is particularly important in the establishment and maintenance of the transformed phenotype, in mediating proliferation, and for the survival of tumour cells with anchorage-independent growth. IGF1R also exerts antiapoptotic activity and has a substantial influence on the control of the cell and body size. This property enables transformed cells to form macroscopic tumours and to survive the process of detachment required for metastasis. Pharmaceutical companies are investigating molecules that target IGF1R, including specific low molecular weight tyrosine kinase inhibitors and monoclonal antibodies, both of which possess various advantages and display different activity profiles. This review article focuses on the preclinical and clinical development of low molecular weight IGF1R tyrosine kinase inhibitors. It is critical to pursue a thorough molecular analysis of the metabolic activity of IGF1R to avoid possible side-effects of its inhibition.

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A Dominant Negative Type I Insulin-like Growth Factor Receptor Inhibits Metastasis of Human Cancer Cells

Cited by 147 publications

References 49 publications

Disrupting insulin-like growth factor signaling as a potential cancer therapy

Disrupting insulin-like growth factor signaling as a potential cancer therapy

Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells

The type 1 insulin-like growth factor receptor signalling system and targeted tyrosine kinase inhibition in cancer

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