In vivo real-time imaging of chemotherapy response on the liver metastatic tumor microenvironment using multiphoton microscopy

Tanaka,Koji; Okigami,Masato; Toiyama,Yuji; Morimoto,Yuki; Matsushita,Kohei; Kawamura,Mikio; Hashimoto,Kiyoshi; Saigusa,Susumu; Okugawa,Yoshinaga; Inoue,Yasuhiro; Uchida,Keiichi; Araki,Toshimitsu; Mohri,Yasuhiko; Mizoguchi,Akira; Kusunoki,Masato

doi:10.3892/or.2012.1983

November 2012 Volume 28 Issue 5

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November 2012 Volume 28 Issue 5

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Article

In vivo real-time imaging of chemotherapy response on the liver metastatic tumor microenvironment using multiphoton microscopy

Authors:
- Koji Tanaka
- Masato Okigami
- Yuji Toiyama
- Yuki Morimoto
- Kohei Matsushita
- Mikio Kawamura
- Kiyoshi Hashimoto
- Susumu Saigusa
- Yoshinaga Okugawa
- Yasuhiro Inoue
- Keiichi Uchida
- Toshimitsu Araki
- Yasuhiko Mohri
- Akira Mizoguchi
- Masato Kusunoki
View Affiliations / Copyright

Affiliations: Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan, Department of Neural Regeneration and Cell Communication, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
Pages: 1822-1830
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Published online on: August 23, 2012

https://doi.org/10.3892/or.2012.1983
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Abstract

In vivo real-time visualization of chemotherapy response at the cellular level provides us with direct evidence of what happens on the tumor microenvironment of metastatic organs. We imaged the response of metastatic tumor cells and host stromal cells to chemotherapeutics on liver metastatic xenografts in living mice using intravital two-photon laser scanning microscopy (TPLSM). Red fluorescent protein-expressing human colorectal cancer cells (HT29) was inoculated to the spleen of green fluorescent protein-expressing nude mice. 5-Fluorouracil or irinotecan was intraperitoneally administered after the formation of macroscopic liver metastases. Intravital TPLSM was performed at multiple time-points for time-series imaging of liver metastatic xenografts in the same mice. Under the 1st TPLSM, HT29 cells were visualized in hepatic sinusoids at the single cell level. Liver metastatic nodules consisting of viable cancer cells and surrounding stroma with tumor vessels were visualized under the 2nd TPLSM. After chemotherapy, tumor cell fragmentation, condensation, swelling and intracellular vacuoles were observed under the 3rd TPLSM. There was no obvious morphological difference in tumor response between these chemotherapeutics. Time-series intravital TPLSM imaging on the metastatic tumor xenografts may be useful for screening and evaluating new chemotherapeutics with less interindividual variability.

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1	Gallagher DJ and Kemeny N: Metastatic colorectal cancer: from improved survival to potential cure. Oncology. 78:237–248. 2010. View Article : Google Scholar : PubMed/NCBI
2	Cunningham D, Atkin W, Lenz HJ, et al: Colorectal cancer. Lancet. 375:1030–1047. 2010. View Article : Google Scholar
3	Folprecht G, Gruenberger T, Bechstein WO, et al: Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 11:38–47. 2010. View Article : Google Scholar
4	Brouquet A, Abdalla EK, Kopetz S, et al: High survival rate after two-stage resection of advanced colorectal liver metastases: response-based selection and complete resection define outcome. J Clin Oncol. 29:1083–1090. 2011. View Article : Google Scholar
5	Tanaka K, Inoue Y and Kusunoki M: The role of cytoreduction as a multidisciplinary treatment modality for metastatic colorectal cancer. Colorectal Cancer: Risk, Diagnosis and Treatments. Jenkins JE: Nova Science Publishers; New York, NY: pp. 161–176. 2010
6	Longley DB, Harkin DP and Johnston PG: 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 3:330–338. 2003. View Article : Google Scholar : PubMed/NCBI
7	Xu Y and Villalona-Calero MA: Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol. 13:1841–1851. 2002. View Article : Google Scholar : PubMed/NCBI
8	Raymond E, Faivre S, Chaney S, Woynarowski J and Cvitkovic E: Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther. 1:227–235. 2002.
9	Le Dévédec SE, van Roosmalen W, Pont C, et al: Two-photon intravital multicolour imaging to study metastatic behaviour of cancer cells in vivo. Methods Mol Biol. 769:331–349. 2011.PubMed/NCBI
10	Beerling E, Ritsma L, Vrisekoop N, Derksen PW and van Rheenen J: Intravital microscopy: new insights into metastasis of tumors. J Cell Sci. 124:299–310. 2011. View Article : Google Scholar : PubMed/NCBI
11	Ustione A and Piston DW: A simple introduction to multiphoton microscopy. J Microsc. 243:221–226. 2011. View Article : Google Scholar : PubMed/NCBI
12	Wang BG, König K and Halbhuber KJ: Two-photon microscopy of deep intravital tissues and its merits in clinical research. J Microsc. 238:1–20. 2010. View Article : Google Scholar : PubMed/NCBI
13	Toiyama Y, Mizoguchi A, Okugawa Y, et al: Intravital imaging of DSS-induced cecal mucosal damage in GFP-transgenic mice using two-photon microscopy. J Gastroenterol. 45:544–553. 2010. View Article : Google Scholar : PubMed/NCBI
14	Koike Y, Tanaka K, Okugawa Y, et al: In vivo real-time two-photon microscopic imaging of platelet aggregation induced by selective laser irradiation to the endothelium created in the beta-actin-green fluorescent protein transgenic mice. J Thromb Thrombolysis. 32:138–145. 2011. View Article : Google Scholar
15	Morimoto Y, Tanaka K, Toiyama Y, et al: Intravital three-dimensional dynamic pathology of experimental colitis in living mice using two-photon laser scanning microscopy. J Gastrointest Surg. 15:1842–1850. 2011. View Article : Google Scholar
16	Tanaka K, Morimoto Y, Toiyama Y, et al: Intravital dual-colored visualization of colorectal liver metastasis in living mice using two photon laser scanning microscopy. Microsc Res Tech. 75:307–315. 2012. View Article : Google Scholar : PubMed/NCBI
17	Tanaka K, Morimoto Y, Toiyama Y, et al: In vivo time-course imaging of tumor angiogenesis in colorectal liver metastases in the same living mice using two-photon laser scanning microscopy. J Oncol. 2012:2654872012. View Article : Google Scholar : PubMed/NCBI
18	Kawano H, Kogure T, Abe Y, Mizuno H and Miyawaki A: Two-photon dual-color imaging using fluorescent proteins. Nat Methods. 5:373–374. 2008. View Article : Google Scholar : PubMed/NCBI
19	Okabe M, Ikawa M, Kominami K, Nakanishi T and Nishimune Y: ‘Green mice’ as a source of ubiquitous green cells. FEBS Lett. 407:313–319. 1997.
20	Small RM, Lubezky N, Shmueli E, et al: Response to chemotherapy predicts survival following resection of hepatic colo-rectal metastases in patients treated with neoadjuvant therapy. J Surg Oncol. 99:93–98. 2009. View Article : Google Scholar : PubMed/NCBI
21	Mandard AM, Dalibard F, Mandard JC, et al: Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations Cancer. 73:2680–2686. 1994.PubMed/NCBI
22	Dworak O, Keilholz L and Hoffmann A: Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis. 12:19–23. 1997. View Article : Google Scholar : PubMed/NCBI
23	Becker K, Mueller JD, Schulmacher C, et al: Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer. 98:1521–1530. 2003. View Article : Google Scholar : PubMed/NCBI
24	Furie B and Furie BC: Mechanisms of thrombus formation. N Engl J Med. 359:938–949. 2008. View Article : Google Scholar : PubMed/NCBI
25	Ruggeri ZM: Platelet adhesion under flow. Microcirculation. 16:58–83. 2009. View Article : Google Scholar
26	Pasquier E, Kavallaris M and André N: Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol. 7:455–465. 2010. View Article : Google Scholar : PubMed/NCBI
27	Kerbel RS and Kamen BA: The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 4:423–436. 2004. View Article : Google Scholar : PubMed/NCBI
28	Talmadge JE, Singh RK, Fidler IJ and Raz A: Murine models to evaluate novel and conventional therapeutic strategies for cancer. Am J Pathol. 170:793–804. 2007. View Article : Google Scholar : PubMed/NCBI
29	Wilmanns C, Fan D, Obrian C, et al: Modulation of doxorubicin sensitivity and level of P-glycoprotein expression in human colon-carcinoma cells by ectopic and orthotopic environments in nude-mice. Int J Oncol. 3:413–422. 1993.PubMed/NCBI
30	Wilmanns C, Fan D, O’Brian CA, Bucana CD and Fidler IJ: Orthotopic and ectopic organ environments differentially influence the sensitivity of murine colon carcinoma cells to doxorubicin and 5-fluorouracil. Int J Cancer. 52:98–104. 1992. View Article : Google Scholar

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

In vivo real-time imaging of chemotherapy response on the liver metastatic tumor microenvironment using multiphoton microscopy

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