Reversibility and recurrence of IGF-IR-induced mammary tumors

Jones, Robert A.; Campbell, Craig I.; Wood, Geoffrey A.; Petrik, Jim; Moorehead, Roger A.

doi:10.1038/onc.2009.79

Cited by 48 publications

(71 citation statements)

References 49 publications

(58 reference statements)

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“…Therefore, the functions of IGF1R in CSCs have been the focus of recent investigations in several cancers, including breast cancer and hepatocellular carcinoma. 50,51 In this study, we showed that activation of IGF1R signaling is important for the maintenance of lung CSCs. More importantly, our data support a role for FBLN3 as an inhibitor of IGF1R signaling, and the results of the xenograft model support the potential application of FBLN3 to lung CSC therapy.…”

Section: Discussionmentioning

confidence: 92%

Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling

Kim

Choi

et al. 2013

Oncogene

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Fibulins (FBLNs), a family of extracellular matrix proteins, have recently been shown to act as tumor suppressors or activators in different cancers, and the underlying molecular mechanisms of their action in cancer remain unclear. We have previously shown that the expression of FBLN3 is suppressed by promoter hypermethylation and is associated with invasiveness in aggressive non-small cell lung cancer. In this study, we evaluated the roles and signaling mechanism of FBLN3 in lung cancer stem cells (CSCs). Forced expression of FBLN3 suppressed invasion and migration of lung adenocarcinoma cells and decreased the expression of epithelial-to-mesenchymal transition (EMT) activators, including N-cadherin and Snail. Stemness activities of lung adenocarcinoma cells were also suppressed by FBLN3 as indicated by a decrease in spheroid formation and the levels of stemness markers such as Sox2 and β-catenin. These effects of FBLN3 were mediated by the glycogen synthase kinase-3β, GSK3β/β-catenin pathway, and the upstream regulators of GSK3β, including phosphoinositide 3-kinase (PI3K)/AKT and insulin-like growth factor-1 receptor (IGF1R), were inactivated by FBLN3. Moreover, IGF1R was shown to be a direct target of FBLN3, which competitively inhibited insulin-like growth factor (IGF) action. To confirm the effect of FBLN3 on lung CSCs, aldehyde dehydrogenase-positive (ALDH+) A549 lung CSCs were sorted and treated with recombinant FBLN3 protein. FBLN3 clearly suppressed EMT, stemness activity and the over-activated IGF1R/PI3K/AKT/GSK3β pathway of the ALDH+ CSC subpopulation. In addition, injection of recombinant FBLN3 protein around subcutaneous xenografts established with ALDH+ CSCs in athymic nude mice significantly suppressed tumor growth and progression. Overall, our results show that FBLN3 suppresses both EMT and self-renewal of the lung CSCs by modulating the IGF1R/PI3K/AKT/GSK3β pathway and that FBLN3 would be useful as an alternative CSC therapy.

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Section: Discussionmentioning

confidence: 92%

Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling

Kim

Choi

et al. 2013

Oncogene

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“…Altered levels of IGF-1 and IGFBPs in patients with diabetes may play an important role in tumorigenesis and metastasis. In addition,Jones et al (2009) observed more rapid regression of small IGF-dependent tumors when compared to large tumors under IGF-1R suppression. Further analysis of the IGF pathway and its influence in various tumor stages is required in future studies.The presence of DM-related comorbidities has been shown to increase overall mortality in patients with cancer and influence clinical decision-making Van de Poll-Franse et al (2007).…”

mentioning

confidence: 89%

Diabetes mellitus negatively impacts survival of patients with colon cancer, particularly in stage II disease

Huang

Lin

Chen

et al. 2010

J Cancer Res Clin Oncol

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“…Overexpression of IGF1R activates the PI3-K and mitogen-activated protein kinases (MAPK) signal cascades, resulting in cell proliferation and resistance to chemotherapeutic agents, radiation, and targeted therapies using Tamoxifen and Herceptin [15][16][17]. Therapeutic agents targeting IGF1R are currently in clinical development [10][11][12][13][14][18][19][20][21][22][23], including those that inhibit the IGF1R tyrosine kinase using monoclonal antibodies and small molecules [24]. However, the clinical development of various IGF1R inhibitors has been put on hold due to lack of sufficient clinical efficacy.…”

Section: Introductionmentioning

confidence: 99%

Aberrant allele-switch imprinting of a novel IGF1R intragenic antisense non-coding RNA in breast cancers

Kang

Sun

Xue

et al. 2015

European Journal of Cancer

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Reversibility and recurrence of IGF-IR-induced mammary tumors

Cited by 48 publications

References 49 publications

Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling

Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling

Diabetes mellitus negatively impacts survival of patients with colon cancer, particularly in stage II disease

Aberrant allele-switch imprinting of a novel IGF1R intragenic antisense non-coding RNA in breast cancers

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