The Effects of Epidermal Growth Factor Receptor Activation and Attenuation of the TGFβ Pathway in an Orthotopic Model of Colon Cancer

Ongchin, Melanie; Sharratt, Elizabeth; Dominguez, Ivan; Simms, Neka; Wang, Jing; Cheney, Richard; LeVea, Charles; Brattain, Michael G.; Rajput, Ashwani

doi:10.1016/j.jss.2009.02.002

Cited by 13 publications

(19 citation statements)

References 27 publications

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“…Thus, orthotopic tumor models have an advantage for reflecting to microenvironment's effects on tumor growth characteristics and their response to drug treatment [62]. We have successfully developed an orthotopic animal model for colon cancer as demonstrated in our prior studies [30,43,44]. This in vivo pre-clinical model using small molecule inhibitor PQIP demonstrates the potential importance of targeting IGF1R in human colon cancer.…”

Section: Discussionmentioning

confidence: 92%

“…Recently, studies have suggested that animal models using orthotopically implanted tumors are more predictive of responses than ectopic tumors [39][40][41]. We have established an orthotopic model of colon cancer [30,[40][41][42][43][44]. Consequently, we interrogated GEO orthotopic implants for response to PQIP in vivo.…”

Section: In Vivo Characterization Of the Igf1r Inhibitor In An Orthotmentioning

confidence: 99%

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Anti-tumor Activity of IGF-1R Kinase Inhibitor PQIP in Colon Cancer

Chowdhury

Dominguez²,

Sharratt³

et al. 2011

Clinic Experiment Pharmacol

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Insulin-Like Growth Factors (IGFs) and their receptor, IGF-1R, are frequently expressed in human colon cancers and play important roles in promoting malignancy. We demonstrate that colon cancer cells show dependence upon an IGF2/IGF-1R autocrine loop and have characterized the effects of an IGF1R kinase inhibitor (designated PQIP in vitro and in vivo). PQIP abrogated IGF-1R mediated activation of IRS-1/Akt to inhibit survival signaling and induce apoptosis. Furthermore, PQIP inhibited mitogenesis and anchorage-independent growth in soft agarose at concentrations consistent with inhibition of IGF-1R phosphorylation. Thus, PQIP showed potent in vitro antitumor activity in colon cancer cells. The effects of PQIP on the growth of orthotopically implanted GEO colon cancer xenografts were determined following daily treatment with 75 mg/Kg of drug by oral gavage. Decreased tumor burden in BALB/c nude mice without significant weight loss and toxicity was observed. Fluorescence intensity of the GFP labeled tumors was 3-fold higher in control mice than in treated mice. MRI analysis showed a 5-fold decrease tumor volume in treated mice. TUNEL analysis of treated and sham treated tumors indicated an 8-fold higher rate of apoptosis in PQIP treated tumors. Western blot analysis of the treated tissue samples showed inhibition of IGF1R activation and Akt signaling relative to sham treated animals. Therefore, PQIP represents an attractive therapeutic candidate for targeting IGF1R-dependent colon cancer.

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Section: Discussionmentioning

confidence: 92%

Section: In Vivo Characterization Of the Igf1r Inhibitor In An Orthotmentioning

confidence: 99%

Anti-tumor Activity of IGF-1R Kinase Inhibitor PQIP in Colon Cancer

Chowdhury

Dominguez²,

Sharratt³

et al. 2011

Clinic Experiment Pharmacol

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“…The development of orthotopic xenograft transplants from human CRC cell lines in our laboratory that recapitulates the metastatic pattern of the disseminated disease in patients allow for the study of CRC metastasis in vivo (2, 8, 22, 23). The major goal of this study was to analyze the role of PTEN in the development of metastases in CRC in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…The colon, including any primary tumor, was harvested in addition to the liver and lungs. These organs were explanted, imaged, and immediately placed in 10% neutral buffered formalin fixative for 24 hours as described previously (22). The tissues were then processed and embedded in paraffin.…”

Section: Methodsmentioning

confidence: 99%

Restoration of PTEN activity decreases metastases in an orthotopic model of colon cancer

Chowdhury

Ongchin

Wan

et al. 2013

Journal of Surgical Research

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Background Mutational loss of tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) is associated with malignant progression in many cancers including colorectal cancer (CRC). PTEN is involved in negatively regulating the Phosphatidylinositol 3-kinase (PI3K)/AKT oncogenic signaling pathway and has been implicated in the metastatic colonization process. Few in vivo models are available to study CRC metastasis. The purpose of this study was to determine the effect of restoring PTEN activity on metastases in an orthotopic murine model. Methods GFP labeled TENN, a highly metastatic human colon cancer cell line with mutational loss of PTEN gene and TENN clones (with restoration of PTEN gene) tumors were orthotopically implanted onto the colons of BALB/c nude mice and allowed to develop primary and metastatic tumors. Seven weeks post-implantation, mice were euthanized and organs extracted for examination. Results Both TENN and TENN clone cell lines demonstrated 100% primary invasion. However, compared to the parental TENN cells, which demonstrated 62% metastases to both lungs and liver, TENN clone cells showed an approximately 50% reduction in metastasis, with only 31.6% liver metastasis and no metastasis to the lungs. Conclusion Our study shows that reactivation of PTEN tumor suppressor pathway leads to a 50% reduction in CRC metastasis without affecting primary tumor formation. Importantly, PTEN restoration also changed the organotropic homing from liver and lung metastasis to liver metastasis only. This in vivo study demonstrates that PTEN might act specifically as a metastasis suppressor and thus efforts to target the PI3K/PTEN pathway are legitimate.

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“…In general, common molecular regulators coordinate tumor cytoskeletal remodelling by transducing external signals into actin processes. In colon cancer cells, tyrosine kinase receptors (e.g., EGF receptor, Eph receptors, Met receptors), G protein-coupled receptors (e.g., cholecystokinin receptors) and cytokine receptors (e.g., chemokine receptors, TGFreceptor) have been established as important inducers of the metastatic cell morphology (Dienstmann & Tabernero 2010;Dong et al, 2009;Fulton, 2009;Kitamura et al, 2010;Larsen & Dashwood, 2010;Ongchin et al, 2009;Yuet al, 2006). They activate the intracellular signalling system controlling cytoskeletal actin (e.g., focal adhesion kinases, rho-GTPases, Arp2/3 complex), which assembles the membrane protrusive structures mediating invasion (Linder, 2007;Yamaguchi & Condeelis, 2007).…”

Section: Control Of Invasive Cell Shapementioning

confidence: 99%