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SPECT/CT of lung nodules using 111In-DOTA-c(RGDfK) in a mouse lung carcinogenesis model

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Abstract

Objective

Lung cancer is one of the leading causes of cancer-related deaths worldwide, including Japan. Although computed tomography (CT) can detect small lung lesions such as those appearing as ground glass opacity, it cannot differentiate between malignant and non-malignant lesions. Previously, we have shown that single photon emission computed tomography (SPECT) imaging using 111In-1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid-cyclo-(Arg-Gly-Asp-d-Phe-Lys) (DOTA-c(RGDfK)), an imaging probe of αvβ3 integrin, is useful for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. In this study, we aimed to assess the usefulness of SPECT/CT with 111In-DOTA-c(RGDfK) for the evaluation of the malignancy of lung cancer.

Methods

Lung tumors were induced by a single intraperitoneal injection (250 mg/kg) of urethane in male A/J mice. Twenty-six weeks after the urethane treatment, SPECT was performed an hour after injection of 111In-DOTA-c(RGDfK). Following this, the radioactivity ratios of tumor to normal lung tissue were measured by autoradiography (ARG) in the excised lung samples. We also examined the expression of αvβ3 integrin in mouse and human lung samples.

Results

Urethane treatment induced 5 hyperplasias, 41 adenomas and 12 adenocarcinomas in the lungs of 8 A/J mice. SPECT with 111In-DOTA-c(RGDfK) could clearly visualize lung nodules, though we failed to detect small lung nodules like adenoma and hyperplasias (adenocarcinoma: 66.7 %, adenoma: 33.6 %, hyperplasia: 0.0 %). ARG analysis revealed significant uptake of 111In-DOTA-c(RGDfK) in all the lesions. Moreover, tumor to normal lung tissue ratios increased along with the progression of carcinogenesis. Histopathological examination using human lung tissue samples revealed clear up-regulation of αvβ3 integrin in well-differentiated adenocarcinoma (Noguchi type B and C) rather than atypical adenomatous hyperplasia.

Conclusion

Although there are some limitations in evaluating the malignancy of small lung tumors using 111In-DOTA-c(RGDfK), SPECT with 111In-DOTA-c(RGDfK) might be a useful non-invasive imaging approach for evaluating the characteristics of lung tumors in mice, thus showing potential for use in humans.

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References

  1. Jemal A, Thun MJ, Ries LA, Howe HL, Weir HK, Center MM, et al. Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst. 2008;100:1672–94.

    Article  PubMed  Google Scholar 

  2. Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395–409.

    Article  PubMed  Google Scholar 

  3. MacMahon H, Austin JH, Gamsu G, Herold CJ, Jett JR, Naidich DP, et al. Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology. 2005;237:395–400.

    Article  PubMed  Google Scholar 

  4. Hori Y, Takasuka N, Mutoh M, Kitahashi T, Kojima S, Imaida K, et al. Periodic analysis of urethane-induced pulmonary tumors in living A/J mice by respiration-gated X-ray microcomputed tomography. Cancer Sci. 2008;99:1774–7.

    Article  PubMed  CAS  Google Scholar 

  5. Brooks PC. Role of integrins in angiogenesis. Eur J Cancer. 1996;32A:2423–9.

    Article  PubMed  CAS  Google Scholar 

  6. Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin αvβ3 for angiogenesis. Science. 1994;264:569–71.

    Article  PubMed  CAS  Google Scholar 

  7. Mizejewski GJ. Role of integrins in cancer: survey of expression patterns. Proc Soc Exp Biol Med. 1999;222:124–38.

    Article  PubMed  CAS  Google Scholar 

  8. Albert JM, Cao C, Geng L, Leavitt L, Hallahan DE, Lu B. Integrin αvβ3 antagonist cilengitide enhances efficacy of radiotherapy in endothelial cell and non-small-cell lung cancer models. Int J Radiat Oncol Biol Phys. 2006;65:1536–43.

    Article  PubMed  CAS  Google Scholar 

  9. Beer AJ, Schwaiger M. Imaging of integrin αvβ3 expression. Cancer Metastasis Rev. 2008;27:631–44.

    Article  PubMed  CAS  Google Scholar 

  10. Haubner R, Weber WA, Beer AJ, Vabuliene E, Reim D, Sarbia M, et al. Noninvasive visualization of the activated αvβ3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD. PLoS Med. 2005;2:e70.

    Article  PubMed  Google Scholar 

  11. Haubner R, Wester HJ, Weber WA, Mang C, Ziegler SI, Goodman SL, et al. Noninvasive imaging of αvβ3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res. 2001;61:1781–5.

    PubMed  CAS  Google Scholar 

  12. Yoshimoto M, Ogawa K, Washiyama K, Shikano N, Mori H, Amano R, et al. αvβ3 Integrin-targeting radionuclide therapy and imaging with monomeric RGD peptide. Int J Cancer. 2008;123:709–15.

    Article  PubMed  CAS  Google Scholar 

  13. Yoshimoto M, Hayakawa T, Mutoh M, Imai T, Tsuda K, Kimura S, et al. In vivo SPECT Imaging with 111In-DOTA-c(RGDfK) to detect early pancreatic cancer in a hamster pancreatic carcinogenesis model. J Nucl Med. 2012;53:765–71.

    Article  PubMed  Google Scholar 

  14. Festing MF, Lin L, Devereux TR, Gao F, Yang A, Anna CH, et al. At least four loci and gender are associated with susceptibility to the chemical induction of lung adenomas in A/J × BALB/c mice. Genomics. 1998;53:129–36.

    Article  PubMed  CAS  Google Scholar 

  15. Gariboldi M, Manenti G, Canzian F, Falvella FS, Radice MT, Pierotti MA, et al. A major susceptibility locus to murine lung carcinogenesis maps on chromosome 6. Nat Genet. 1993;3:132–6.

    Article  PubMed  CAS  Google Scholar 

  16. Jin ZH, Furukawa T, Galibert M, Boturyn D, Coll JL, Fukumura T, et al. Noninvasive visualization and quantification of tumor αvβ3 integrin expression using a novel positron emission tomography probe, 64Cu-cyclam-RAFT-c(-RGDfK-)4. Nucl Med Biol. 2011;38:529–40.

    Article  PubMed  CAS  Google Scholar 

  17. Sloan EK, Pouliot N, Stanley KL, Chia J, Moseley JM, Hards DK, et al. Tumor-specific expression of αvβ3 integrin promotes spontaneous metastasis of breast cancer to bone. Breast Cancer Res. 2006;8:R20.

    Article  PubMed  Google Scholar 

  18. McCabe NP, De S, Vasanji A, Brainard J, Byzova TV. Prostate cancer specific integrin αvβ3 modulates bone metastatic growth and tissue remodeling. Oncogene. 2007;26:6238–43.

    Article  PubMed  CAS  Google Scholar 

  19. Hosotani R, Kawaguchi M, Masui T, Koshiba T, Ida J, Fujimoto K, et al. Expression of integrin αvβ3 in pancreatic carcinoma: relation to MMP-2 activation and lymph node metastasis. Pancreas. 2002;25:e30–5.

    Article  PubMed  Google Scholar 

  20. Ma Q, Ji B, Jia B, Gao S, Ji T, Wang X, et al. Differential diagnosis of solitary pulmonary nodules using 99mTc-3P4-RGD2 scintigraphy. Eur J Nucl Med Mol Imaging. 2011;38:2145–52.

    Article  PubMed  Google Scholar 

  21. Zhu Z, Miao W, Li Q, Dai H, Ma Q, Wang F, et al. 99mTc-3PRGD2 for integrin receptor imaging of lung cancer: a multicenter study. J Nucl Med. 2012;53:716–22.

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Exploratory Research and a Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science, and Technology as well as Grants-in-Aid for Cancer Research and for the Third-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan. The authors would like to thank Enago (http://www.enago.jp) for the English language review.

Conflict of interest

The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Division of Cancer Prevention Research, National Cancer Center Research Institute, 5-1-1 Chuo-ku, Tokyo, 104-0045, Japan

    Takuya Hayakawa & Michihiro Mutoh

  2. Central Animal Division, National Cancer Center Research Institute, 5-1-1 Chuo-ku, Tokyo, 104-0045, Japan

    Toshio Imai

  3. Division of Pathology and Clinical Laboratory, National Cancer Center Hospital, 5-1-1 Chuo-ku, Tokyo, 104-0045, Japan

    Koji Tsuta

  4. Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan

    Takuya Hayakawa & Akinori Yanaka

  5. Functional Imaging Division, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan

    Hirofumi Fujii & Mitsuyoshi Yoshimoto

  6. Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Mitsuyoshi Yoshimoto

Authors
  1. Takuya Hayakawa
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  2. Michihiro Mutoh
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  3. Toshio Imai
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  4. Koji Tsuta
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  5. Akinori Yanaka
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  6. Hirofumi Fujii
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  7. Mitsuyoshi Yoshimoto
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Corresponding author

Correspondence to Mitsuyoshi Yoshimoto.

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Hayakawa, T., Mutoh, M., Imai, T. et al. SPECT/CT of lung nodules using 111In-DOTA-c(RGDfK) in a mouse lung carcinogenesis model. Ann Nucl Med 27, 640–647 (2013). https://doi.org/10.1007/s12149-013-0729-1

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  • DOI: https://doi.org/10.1007/s12149-013-0729-1

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