Animal Models of Colorectal Cancer in Chemoprevention and Therapeutics Development

Suman, Shubhankar; Fornace, Albert J.; Datta, Kamal

doi:10.5772/28497

Cited by 9 publications

(8 citation statements)

References 140 publications

(83 reference statements)

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“…3) and propagated the corresponding relative errors to generate RBE-based and RER-based risk estimates and confidence limits for the 28 Si ions. (17)(18)(19) and, in this case, both the order of tumorigenic effectiveness per unit dose as well as the dose-response shapes were similar for the mutant mouse intestinal vs. colon tumors (7).…”

mentioning

confidence: 84%

Harderian Gland Tumorigenesis: Low-Dose and LET Response

et al. 2016

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confidence: 84%

Harderian Gland Tumorigenesis: Low-Dose and LET Response

et al. 2016

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“…However, the status of the APC-independent proteasomal targeting of the β-catenin in heavy ion radiation-induced intestinal tumors has not been explored. In this study, using the APC Min/+ intestinal tumor mouse model ( 14 ), we demonstrated downregulation of RXRα expression, which may complement the disabled APC-dependent proteasomal degradation pathway to increase β-catenin accumulation in 56 Fe-induced tumors. Downregulation of RXRα observed in this study could potentially play a crucial role in heavy ion radiation-induced increased risk of intestinal tumorigenesis and would warrant further investigation.…”

Section: Introductionmentioning

confidence: 67%

Decreased RXRα is Associated with Increased β-Catenin/TCF4 in 56Fe-Induced Intestinal Tumors

et al. 2015

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Although it is known that accumulation of oncogenic β-catenin is critical for intestinal tumorigenesis, the underlying mechanisms have not yet been fully explored. Post-translational β-catenin level is regulated via the adenomatous polyposis coli (APC)-dependent as well as the APC-independent ubiquitin–proteasome pathway (UPP). Employing an APC-mutant mouse model (APCMin/+) the present study aimed to investigate the status of RXRα, an APC-independent factor involved in targeting β-catenin to UPP for degradation, in tumor-bearing and tumor-free areas of intestine after exposure to energetic 56Fe ions. APCMin/+ mice were exposed to energetic 56Fe ions (4 or 1.6 Gy) and intestinal tumor samples and tumor-free normal intestinal samples were collected 100–110 days after exposure. The status of TCF4, β-catenin, cyclin D1, and RXRα was examined using immunohistochemistry and immunoblots. We observed increased accumulation of the transcription factor TCF4 and its co-activator β-catenin as well as their downstream oncogenic target protein cyclin-D1 in 56Fe ion-induced intestinal tumors. Further, decreased expression of RXRα in tumors as well as in adjacent normal epithelium was indicative of perturbations in β-catenin proteasomal-targeting machinery. This indicates that decreased UPP targeting of β-catenin due to downregulation of RXRα can contribute to further accumulation of β-catenin and to 56Fe-induced tumorigenesis.

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“…Spontaneously metastatic tumors are rare in mice [35], limiting animal studies to orthotopic or ectopic models of metastasis. Xenogeneic systems are not feasible for these studies, because intact immunity is required to produce immunological responses following RT-IT.…”

Section: Discussionmentioning

confidence: 99%

Tumor Radiation Therapy Creates Therapeutic Vaccine Responses to the Colorectal Cancer Antigen GUCY2C

Witek

Blomain

Magee

et al. 2014

International Journal of Radiation Oncology*Biology*Physics

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PURPOSE Radiotherapy is thought to produce clinical responses in cancer patients, through not only direct toxicity to cancer cells and supporting tumor stroma cells, but also through activation of immunological effectors. More recently, radiotherapy (RT) has potentiated local and systemic effects of cancer immunotherapy (IT). However, combination regimens that maximize immunologic and clinical efficacy remain undefined. METHODS and MATERIALS We evaluated the impact of local RT on adenoviral-mediated vaccination against the colorectal cancer antigen GUCY2C (Ad5-GUCY2C) in a murine subcutaneous tumor model using mouse CT26 colon cancer cells (CT26-GUCY2C). Immune responses were assessed by ELISpot and clinical responses were assessed by tumor size and incidence. RESULTS The specific sequence of tumor-directed RT preceding Ad5-GUCY2C IT transformed inactive therapeutic Ad5-GUCY2C vaccination into a curative vaccine. GUCY2C-specific T cell responses were amplified (p<0.05), tumor eradication maximized (p<0.01), and tumor volumes minimized (p<0.001) in mice whose tumors were irradiated prior to, compared to following, Ad5-GUCY2C vaccination. The immunologic and antitumor efficacy of Ad5-GUCY2C was amplified comparably by unfractionated (8 Gy × 1), or biologically equivalent doses of fractionated (3.5 Gy × 3), RT. Antitumor effects of sequential RT and IT (RT-IT) depended on expression of GUCY2C by tumor cells and the adenoviral vaccine vector, and tumor volumes were inversely related to the magnitude of GUCY2C-specific T cell responses. Moreover, mice cured of CT26-GUCY2C tumors by RT-IT exhibited long-lasting antigen-dependent protection, resisting tumors formed by GUCY2C-expressing 4T1 breast cancer cells inoculated 50 days after CT26 cells. CONCLUSIONS Optimal sequencing of RT and IT amplifies antigen-specific local and systemic immune responses, revealing novel acute and long-term therapeutic antitumor protection. These observations underscore the importance of modality sequence optimization prior to initiating clinical trials of RT and IT to maximize immune and antitumor responses.

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Animal Models of Colorectal Cancer in Chemoprevention and Therapeutics Development

Cited by 9 publications

References 140 publications

Harderian Gland Tumorigenesis: Low-Dose and LET Response

Harderian Gland Tumorigenesis: Low-Dose and LET Response

Decreased RXRα is Associated with Increased β-Catenin/TCF4 in 56Fe-Induced Intestinal Tumors

Tumor Radiation Therapy Creates Therapeutic Vaccine Responses to the Colorectal Cancer Antigen GUCY2C

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