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Anticancer Res. 2019 Aug;39(8):4065-4071. doi: 10.21873/anticanres.13563.

Tumor-sealing Surgical Orthotopic Implantation of Human Colon Cancer in Nude Mice Induces Clinically-relevant Metastases Without Early Peritoneal Carcinomatosis.

Yoon SN1,2,3, Park JH1,2,4, Lwin TM1,2, Miyake K1,2,5, Singh SR6, Hoffman RM7,2,8, Bouvet M9,8,10.

Author information

1
AntiCancer, Inc., San Diego, CA, U.S.A.
2
Department of Surgery, University of California, San Diego, CA, U.S.A.
3
Department of Surgery, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea.
4
Department of Surgery, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea.
5
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
6
Basic Research Laboratory, National Cancer Institute, Frederick, MD, U.S.A. mbouvet@ucsd.edu singhshr@mail.nih.gov all@anticancer.com.
7
AntiCancer, Inc., San Diego, CA, U.S.A. mbouvet@ucsd.edu singhshr@mail.nih.gov all@anticancer.com.
8
Veterans Affairs San Diego Healthcare System, San Diego, CA, U.S.A.
9
Department of Surgery, University of California, San Diego, CA, U.S.A. mbouvet@ucsd.edu singhshr@mail.nih.gov all@anticancer.com.
10
Moores Cancer Center, University of California San Diego, San Diego, CA, U.S.A.

Abstract

BACKGROUND:

Surgical orthotopic implantation of human colon cancer tissue to the ceca of mice has been used to mimic behavior of cancer in human patients for the development of precision cancer medicine. However, with the current method of serosal surface implantation (SSI) of pieces of human colon cancer tissue, cancer cells are exposed to the peritoneum, which can artificially increase the rate of peritoneal carcinomatosis (PC) during the disease course. The objective of the present study was to introduce a tumor-sealing method (TSM) and compare it with SSI for the ability to produce clinically-relevant metastases without artificial PC.

MATERIALS AND METHODS:

HCT116 colon cancer cells transfected with green fluorescence protein (GFP) were cultured and then injected into the subcutaneous layer of athymic nude mice. Subcutaneous tumors were allowed to grow sufficiently to supply adequate tumor for orthotopic implantation. For SSI, a 1 mm3-sized tumor fragment was sutured to partially torn serosa of the cecum. For TSM, the blind end of the cecum was folded over the tumor fragment and sealed with sutures. At 20 days after implantation, all mice were opened to visualize PC by intravital fluorescence imaging. At necropsy, distant metastasis was investigated using frozen section of whole blocks of organs.

RESULTS:

At 20 days after implantation, PC rates in the SSI group and the TSM group were 80% (12/15) and 20% (3/15), respectively (p<0.001). The liver metastasis rate was 41.7% (5/12) in the SSI group and 50% (5/10) in the TSM group (p=0.696). The lung metastasis rate was 0% (0/12) in the SSI group and 10% (1/10) in the TSM group (p=0.201). The mean survival of mice without PC on the 20th day was significantly longer than that of mice with PC on the 20th day (69.1±14.7 vs. 44.5±12.4 days, p=0.001).

CONCLUSION:

These results suggest that TSM might be a more patient-like and useful method as a model of metastatic colon cancer than SSI.

KEYWORDS:

HCT116; Orthotopic xenograft; cecum; colon cancer; metastasis; microsurgery; mouse model; peritoneal carcinomatosis; surgical orthotopic implantation; survival

PMID:
31366489
DOI:
10.21873/anticanres.13563
[Indexed for MEDLINE]

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