Animal models of colorectal peritoneal metastasis

Félix Gremonprez; Wouter Willaert; Wim Ceelen

doi:10.1515/pp-2016-0006

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Animal models of colorectal peritoneal metastasis

Félix Gremonprez , Wouter Willaert und Wim Ceelen

Veröffentlicht/Copyright: 12. April 2016

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Aus der Zeitschrift Pleura and Peritoneum Band 1 Heft 1

Abstract

Colorectal cancer remains an important cause of mortality worldwide. The presence of peritoneal carcinomatosis (PC) causes significant symptoms and is notoriously difficult to treat. Therefore, informative preclinical research into the mechanisms and possible novel treatment options of colorectal PC is essential in order to improve the prognostic outlook in these patients. Several syngeneic and xenograft animal models of colorectal PC were established, studying a wide range of experimental procedures and substances. Regrettably, more sophisticated models such as those giving rise to spontaneous PC or involving genetically engineered mice are lacking. Here, we provide an overview of all reported colorectal PC animal models and briefly discuss their use, strengths, and limitations.

Keywords: metastasis; mouse model; PDX model; peritoneal

Introduction

With an annual worldwide mortality rate of over half a million, colorectal cancer (CRC) remains a major cause of cancer related mortality [1]. Since malignant disease ultimately causes death by distant organ invasion, the unravelling of molecular mechanisms underlying hematogenous and lymphatic metastasis is a topic of intensive research activity [2]. In parallel, the introduction of targeted biological agents has met with considerable survival prolongation in patients with metastatic disease [3]. On the other hand, intraperitoneally located tumors may be at the origin of locoregional peritoneal spread. Although often coexisting with systemic disease, it is increasingly realised that colorectal tumor dissemination within the peritoneal cavity may represent a separate phenotypic and molecular entity. Established peritoneal carcinomatosis (PC) from CRC is much less responsive to systemic therapy and causes considerable morbidity in affected patients. Synchronous peritoneal metastases are found at the time of surgery with curative intent in about five to six percent of patients, and are more frequently observed in right sided cancers [4]. Peritoneal carcinomatosis is present in 25–30 % of patients with recurrent or metastatic colorectal cancer; in approximately 3 % isolated peritoneal disease without systemic spread is observed [5, 6]. Recognition of the causes and mechanisms of peritoneal metastasis may contribute to strategies to effectively prevent the development of PC in colorectal cancer. Moreover, in a small group of patients with low volume peritoneal disease, a locoregional treatment strategy combining surgery with intracavitary cytotoxic therapy has been shown to improve outcome [7]. The concept of intraperitoneal (IP) drug delivery in itself not entirely new. The earliest IP “drug therapy” was reported in 1744 by the English surgeon Christopher Warrick, who, apparently with great success, injected a mixture of ‘Bristol water’ and ‘claret’ (a Bordeaux wine) in the peritoneal cavity of a woman suffering from intractable ascites [8]. Intraperitoneal adjuvant chemotherapy has been extensively studied in stage III epithelial ovarian cancer, where it was found to be superior over intravenous (IV) chemotherapy alone in large randomized trials [9]. In patients with PC from appendiceal or colorectal origin, the combination of cytoreductive surgery (CRS) and intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC) has witnessed an impressive rise in clinical application over the past years [10]. In parallel, innovative pharmaceutical platforms such as targeted agents, nano-sized medicine and drug eluting beads have the potential to further increase the appeal of locoregional drug delivery.

Preclinical animal based research remains an essential tool in the unraveling of the pathophysiology of the metastatic cascade, and the therapeutic insights gained therefrom. Here, we provide a systematic overview of the animal models that have been used to study various aspects of peritoneal metastasis from colorectal origin.

Methods

A systematic search (completed 25/12/2015) was performed using Web of Science with the following keywords: [periton* and meta* and colo* and (animal or mice or mouse or rat or rodent or rabbit)]. Eligible studies reported on animal experiments involving, in part or exclusively, the establishment of colorectal peritoneal carcinomatosis by IP introduction of a colorectal cancer cell line or tissue fragment. Only papers published as full text were eligible. The resulting abstracts were scrutinized and those deemed to fit the criteria were retrieved as full text papers. Additional studies were searched for in the reference lists of these papers, and in the citing studies.

Results

The selection process (Figure 1) resulted in a total of 164 included papers, the details of which are summarized in Table 1. The large majority of studies used syngeneic rodent cell lines (usually CT26, MC38, or CC531) injected in the peritoneal cavity of immunocompetent mice or rats. Human colon cancer cells were xenogafted IP in athymic nude or BALB/c mice in 46 studies, and in athymic nude rats in two. Only a small minority of studies used SCID mice, patient derived xenografts, or tansgene animals.

Figure 1:

Literature search and selection process.

Table 1:

Overview of experimental animal models of colorectal peritoneal carcinomatosis.

Author	Year	Research question	Cell line/tissue	Animal	IP dose	Interval before endpoints	Quantification of PC
Patient derived xenografts
Navarro-Alvarez [20]	2010	Isolation of a CRC CD133− cancer stem cell line (NANK)	Tissue from CRC primary and ovarian metastasis	NOD-SCID	2 mm³ fragments	6–8 w	Cell isolation
Flatmark [19]	2010	IHC study of human PMP and related animal models	Tissue from mucinous CRC	BALB/c nude	3×3×3 m fragments	1–3 m	IHC markers of differentiation, proliferation, and metastasis
Kotanagi [18]	1998	Characterization of patient derived metastatic cell lines	CRC patient derived cell line	SCID	1×10⁷	40 d	Number and weight of nodules, histology
Human cell lines, transgene mice
Abdul-Wahid [21]	2012	Antitumor activity of CEA immunization	MC38.CEA	CEA.Tg	2×10⁵	35 d	Number, volume
Human cell lines, SCID mice
Mikula-Pietrasik [32]	2015	Role of senescent Mesothelium in CRC metastasis	SW480-luc	SCID	2×10⁶	18 d	Bioluminiscence (IVIS)
Inoue [33]	2011	Antitumor activity of a multifunctional Treg cell line	WiDr-EGFP-9	NOD-SCID	1×10⁷	5 w	Fluorescence stereomicroscopy; survival
Navarro-Alvarez [20]	2010	Isolation of a CRC CD133− cancer stem cell line (NANK)	CD133− NANK	NOD-SCID	1×10⁴–1×10⁵	8–12 w	immunostaining
Lubbe [34]	2009	Role of receptor guanylyl cyclase C (GCC) in cancer cell MMP-9	T84 (wt or transduced with MMP-9)	Cr:NIH-bg-nu-Xid	1×10⁷	2 w	Peritoneal biopsies for quantification of metastatic tumor burden by RT-PCR
Harada [35]	2001	Antitumor activity of antisense CD44s	CD44 transfected LS174T	SCID	2 or 4×10⁶	4 w	Ascites volume, tumor weight
Sakamoto [36]	2001	Involvement of c-Src in carcinoma cell motility and metastasis	HCT15	SCID	2×10⁶	3 w	Number of nodules, histology
Watson [37]	1996	Antitumor activity of the MMP inhibitor batimastat	C170HM₂	SCID	5×10⁶	28 d	Ascites volume and cell density, tumor weight
Yasui [38]	1997	Tumor metastasis of human CRC cell lines in SCID mice	10 colorectal cell lines	SCID	5×10⁶	3 w	Number of nodules
Human cell lines, Immunodeficient mice
Gremonprez [30]	2015	Effect of pretreatment with VEG(R) inhibitors on IFP, Pt penetration, and tumor growth of isolated peritoneal tumors	HT29	Athymic nude	1.5×10⁶ subperitoneal injection	15 d	IFP, tissue oxygenation, Pt distribution, tumor growth
Wang [39]	2015	Role of Cullin1 in inasive properties of CRC	HCT116 and SW480	BALB/c nude	1×10⁶	22 d	Number, size nodules
Takemoto [40]	2015	Cytotoxic effects of lavage with hypotonic fluid in CRC	DLD1, HT29, and CACO2	BALB/c nude	1×10⁶	4 weeks	Number, size, weight nodules
Shen [41]	2015	Interplay between SOX9 and S100P in metastasis and invasion of CRC	Transfected HCT116	Nude mice	1×10⁷	1 month	In-Vivo F Imaging System (Kodak)
Liu [42]	2015	Role of microRNA-409-3p in invasiveness and metastsasis	Transfected SW480 and SW1116	BALB/c nude	2×10⁶	8 weeks	Number of nodules
Lee [43]	2015	Development of novel biodegradable hydrogel for delivery of bevacizumab	HCT116	BALB/c nude	4×10⁶	62 d	None (survival)
Amini [44]	2015	Effect of mucin depletion with bromelain and N-acetylcysteine on metastatic potential	LS174T	BALB/c nude	1×10⁶	17 d	Number, weight
Tang [45]	2014	Efficacy of 5-FU loaded nanoparticle for IP delivery	HCT116	BALB/c nude	5×10⁵	28	Number, volume
Tanaka [46]	2014	Effect of the TrkB inhibitor K252a on PM	DLD1	BALB/c nude	5×10⁷	4 w	Size, number
Rijpkema [47]	2014	Role of nuclear and fluorecent imaging guided surgery using a CEA targeting antibody	LS174T	BALB/c nude	1×10⁶	2 w	SPECT-CT using ¹¹¹In-DTPA-MN-14-IRDye 800CW
Li [48]	2014	Extent of hypoxia and ¹⁸F-FDG uptake in PC	HT29	Athymic nude	5×10⁶	4–7 w	ascites pO₂ (OxyLite); ¹⁸F-FDG uptake
Kondo [49]	2014	photodynamic diagnosis using 5-aminolevulinic acid to detect PM	eGFP Transfected HT29	BALB/c nude	1×10⁶	2 w	eGFP fluorescence imaging
Al-kasspooles [50]	2013	Antitumor activity of a nanoparticulate formulation of SN38, a metabolite of irinotecan	HT-29 and HCT116	Athymic nude	5×10⁶	45 d	survival
Derbal-Wolfrom [51]	2013	Effect of increased oxygen load by treatment with myo-inositol trispyrophosphate on PC	HT29	Athymic nude	1×10⁷	NA	Survival
Shen [52]	2012	Antitumor activity of the NF-kappaB inhibitor BAY 11–7085	HT29-luc	Athymic nude	1×10⁶	8–9 d	Number; Xenogen bioluminescent imaging system
Nayak [53]	2012	MR and PET imaging of HER overexpressign PM using ⁸⁹Zr-Labeled Panitumumab	LS174T	Athymic nude	1×10⁸	5–7 d	Biodistribution and immunotargeting of tracer in PM
Ziauddin [54]	2010	Antitumor activity of vvTRAIL-mediated oncolytic gene therapy	HCT116	Athymic nude	1×10⁷	NA	survival
Straza [55]	2010	Antitumor activity of 4-methylthio-2-oxobutyric acid (MTOB)	HCT116^p53-/-	Athymic nude	3×10⁶	NA	Survival, ascites volume, tumor weight
Li [56]	2010	Relation of ¹⁸F-FDG uptake with hypoxia in peritoneal tumors	HT29 and HCT-8	Athymic nude	5–10×10⁶	3–7 w	¹⁸F-FDG distribution, IHC (pimonidazole and Hoechst 33342, BdU)
Lan [57]	2010	Antitumor activity of a cationic liposome coupled with the murine endostatin gene	HCT116	BALB/c nude	3×10⁶	4 w	Ascites volume; human and mouse VEGF in serum and ascites
Hackl [58]	2010	Role of Activating transcription factor-3 (ATF3) in CRC metastasis	ATF3-shRNA or luc-shRNA Transfected HCT116	Athymic nude	3×10⁶	28 d	Presence of ascites; number of nodules
Wagner [59]	2009	Antitumor activity of rapamycin	SW620	Athymic nude	5×10⁵	NA	Ascites volume; tumor weight
Kishimoto [60]	2009	In vivo tumor illumination by IP adenoviral GFP	HCT-116 and HCT-116-RFP	Athymic nude	3×10⁶	17d	Fluorescence Optical Imaging; histology
Li [61]	2007	Evaluation of hypoxia in PM	HT29 and HCT-8	Athymic nude	5–10×10⁶	3–7 w	IHC and in vitro fluorescence imaging
Kinuya [62]	2007	Antitumor activity of RIT with a ¹³¹I labelled IP A7 antibody	LS180	BALB/c nude	1×10⁷	variable	Survival
Jie [63]	2007	Antitumor activity of recombinant adenovirus, rvAdCMV/NK4	LS174T	BALB/c nude	1×10⁷	15 d	Number, site, and weight of nodules
Sasaki [64]	2006	Antitumor activity of IP linoleic acid (LA)	Colo320	BALB/c nude	1×10⁷	12 w	Number of metastatic foci
Kuniyasu [65]	2006	Antitumor activity of IP conjugated linoleic acid (CLA) on PM	Colo320	BALB/c nude	1×10⁷	4–16 w	Mumber of metastatic foci, survival
Koppe [66]	2006	Antitumor activity of radioimmunotherapy combined with gemcitabine	LS174T	BALB/c nude	1×10⁶	NA	Survival, tumor weight, IHC
Koppe [67]	2006	Antitumor activity of radioimmunotherapy combined with parecoxib	LS174T	BALB/c nude	1×10⁶	NA	Survival, mPCI, tumor weight, tracer biodistribution
Pourgholami [68]	2005	Antitumor activity of IP albendazole	HT29	BALB/c nude	1×10⁶	6 w	Number of nodules
Kinuya [69]	2005	Locoregional ¹⁸⁶Re-RIT versus ¹³¹I-RIT for experimental PC	LS180	BALB/c nude	1×10⁷	variable	Tissue radioactivity, number and weight of nodules, survival
Zeamari [70]	2004	Identifation of growth factors during peritoneal wounding in relation to tumor cell seeding	HT29	BALB/c nude	1×10⁶	28 d	Tumor load (a. u.), PCR of granulation tissue
Koppe [71]	2004	Antitumor activity of ^125/131I-, ¹⁸⁶Re-, ^88/90Y-, or ¹⁷⁷Lu-Labeled Monoclonal Antibody MN-14 to CEA	LS174T	BALB/c nude	1×10⁶	NA	Survival, tumor weight, tracer biodistribution
Favoulet [72]	2004	Antitumor activity of IP pirarubicin	LS174T	Athymic nude	1×10⁷	21 d	Ascites volume, tumor size
Koppe [73]	2003	Antitumor activity of IP radioimmunotherapy using ¹³¹I-labeled MN-14	LS174T	BALB/c nude	1×10⁶	variable	Biodistribution, IHC
Kinuya [74]	2003	Antitumor activity of IP versus IV radioimmunotherapy with ¹³¹I-A7	LS180	BALB/c nude	1×10⁷	variable	Survival, biodistribution
Stoeltzing [75]	2002	Effect of angiopoietin-1 on PMtumour growth and angiogenesis	Ang-1- or pcDNA transfected KM12L4	Athymic nude	1×10⁶	variable	Ascites volume, diameter of largest PM, number of nodules, IHC
Fan [76]	2002	Effect of the angiogenesis inhibitor TNP-470 on peritoneal dissemination	LoVo	BALB/c nude	5×10⁷	10 d or 30 d	Survival, number and size of nodules
Hubbard [77]	2002	Antitumor activity of hyaluronan-based membrane	KM12-L4	BALB/c nude	variable	28 d	Tumor weight, presence of ascites, histology
Shaheen [78]	2001	Antitumor activity of IP anti-VEGFR and anti-EGFR antibidies	KM12L4	Athymic nude	1×10⁶	NA	Tumor size, ascites (semiquantitatively), IHC
Goto [79]	2001	Antitumor activity of gene therapy using the Cre/loxP system	LoVo	Athymic nude	1×10⁶	35 d	Tumor weight, histology
Kondo [80]	2000	Role of VEGF in peritoneal cancer growth	VEGF transfected LoVo	BALB/c nude	2×10⁶	variable	Metastatic pattern, number and size of nodules, ascites volume
Crosasso [81]	1997	Antitumor activity of IP 5-FU prodrug formulated in liposomes or immunoliposomes	HT-29	Athymic nude	1.5×10⁷	variable	Histology, Residual tumor mass (RTM, % of tumor mass in treated over that in control mice)
Asao [82]	1995	Role of Fucosyltransferases in cancer cell adhesion	KM12C and KM12SM	BALB/c nude	1×10⁶	4 w	Tumor weight
Quadri [83]	1995	Biodistribution of IP In-111-labeled IgM	SW620	Athymic nude	6×10⁶	Variable	Biodistribution, whol body autoradiography
Human cell lines, Immunodeficient rats
Harlaar [84]	2010	Validation of bioluminiscence in PC animal models	HT-29-luc-D6	Athymic nude	2×10⁶	8 w	Bioluminiscence, PCI
Mahteme [85]	2005	Effect of vasoconstriction on IP 5FU tumor uptake	LS 174T	Athymic nude	1×10⁷	variable	Whole body autoradiography for biodistribution
Syngeneic cell lines, Immunocompetent mice
Carpinteri [86]	2015	Effect of laparoscopy with humidified-warm CO₂ on peritoneal inflammation and metastasis	(MSCV)-mCherry-CT26	BALB/c	1×10⁶	10 d	Number; Cherry-Red fluorescence (Maestro)
Zhang [87]	2015	Antitumor activity of IP curcumin in a thermosensitive hydrogel	CT26	BALB/c	2×10⁵	22 d	Number of nodules, tumor weight, survival, IHC
Ryan [88]	2015	Antitumor activity of nuclear factor (NF)-κB inhibition	CT26/EV and CT26/IκB-α SR	BALB/c	variable	variable	Tumor weight, histology, survival
Zhang [89]	2014	Antitumor effects of placenta-derived mesenchymal stem cells expressing endostatin Endostatin	CT26	BALB/c	3×10⁵	variable	Number, size of nodules
Fan [90]	2014	Evaluation of docetaxel loaded microspheres for IP delivery	CT26	BALB/c	2×10⁵	14 d	Number, size
Sedlacek [91]	2013	Effect of peritoneal immunization by IP injected irradiated cancer cells	eGFP transfected MC38	C57BL/6	1×10⁶	3 or 7 d	GFP fluorescence of resected omenta
Liu [92]	2013	Evaluation of camptothecine loaded polymeric microsphere in thermosensitive hydrogel for IP delivery	CT26	BALB/c	2×10⁵	20 d	Number and weight
Li [93]	2013	Role of high-mobility group box 1 (HMGB1) in PM	CT26	BALB/c	1×10⁵	2 w	modified sPCI
Yao [94]	2013	Antitumor activity of a water-soluble BSA-SN38 conjugate	CT26	BALB/c	2×10⁵	18 d	Tumor weight
Yu [95]	2013	Peritoneal immune response after IP vaccination with irradiated CT26 cells	CT26	BALB/c	5×10⁵	variable	Peritoneal immune response
Lee [96]	2013	Effect of surgery on matrix metalloproteinase-9 activity	MC38	C57bl/6J	1×10⁵	2 w	modified sPCI
Wu [97]	2012	Antitumor efficacy of Adeno-associated virus mediated human pigment epithelium-derived factor (PEDF)	CT26	BALB/c	5×10⁵	18 d	Number, weight
Lehmann [98]	2012	Synergism of HIPEC with the SOD inhibitor diethyldithiocarbamate (DDC)	MC38	C57Bl/6	2×10⁶	7 d	Tumor mass
Tsai [99]	2011	Antitumor efficacy of ¹⁸⁸Re-labeled nanoliposomes (IV)	CT26	BALB/c	2×10⁵	7–14 d	Ascites weight, tumor weight, PET-CT
Puskas [100]	2011	Antitumor efficacy of an attenuated interleukin-2 fusion protein	MC38	C57BL/6J	5×10⁵	7 d	Flow cytometry and CFU on omental lysates
Nishizaki [101]	2011	Inhibition of surgical trauma-enhanced PM by human catalase derivatives	CT26-Luc	BALB/c	1×10⁵	3 d	Luminometry on omental and GI tract lysates
Dai [102]	2011	Antitumor activity of camptothecin-loaded microspheres	CT26	BALB/c	2×10⁵	14 d	Size, number
Ziauddin [54]	2010	Antitumor activity of vvTRAIL-mediated oncolytic gene therapy	MC38	C57bl/6J	2×10⁵	NA	survival
Wang [103]	2010	Antitumor activity of 5-FU-loaded hydrogel system	CT26	BALB/c	2×10⁵	20 d	Size, number
Tanaka [104]	2010	Antitumor activity of the Transforming growth factor ß signaling inhibitor, SB-431542	CT26	BALB/c	NS	14 d	Cytotoxic T cell (CTL) activity against CT26
Lan [57]	2010	Antitumor activity of a cationic liposome coupled with the murine endostatin gene	CT26-luc	BALB/c	3×10⁵	3 w	Bioluminiscence; gene expression; survival; tumor weight
Keese [105]	2010	Fluorescence lifetime imaging of chemotherapy induced apoptosis by optically monitoring the caspase-3 sensor state	tHcred-DEVD-EGFP transfected CT26	BALB/c	1×10⁶	10 d	Fluorescence lifetime imaging microscopy (FLIM)
Wagner [59]	2009	Antitumor activity of rapamycin	CT26	BALB/c	5×10⁵	NA	Ascites volume; tumor weight
Kulu [106]	2009	Comparison of IV versus IP administration of oncolytic herpes simplex virus 1	CT26	BALB/c	1×10⁵	20 d	Tumor weight
Keese [107]	2009	Antitumor activity of doxorubicin and mitoxantrone drug eluting beads for PC	EGFP-C26	BALB/c	1×10⁶	15 d	In vivo fluorescence microscopy; mPCI, tumor volume, PCR for EGFP
Lan [108]	2007	Antitumor activity of liposome coupled BikDD on PM	CT-26-Luc	BALB/c	1×10⁵–1×10⁶	21 d	Bioluminiscence; tumor weight
Hyoudou [109]	2007	Antitumor activity of cationized catalase-loaded hydrogel	CT-26-Luc	BALB/c	1×10⁵	21 d	Bioluminiscence; Luminometry on organ lysates
Dvir-Ginzberg [110]	2007	Antitumor activity of IP scaffolds containing retroviral vector producing cells	MC38	C57bl/6	5×10⁵	NA	Survival, extent of PC (not quantified)
Hyoudou [111]	2006	IP PEG-catalase to inhibit peritoneal dissemination	CT-26-Luc	BALB/c	1×10⁵	variable	Bioluminiscence, expression of adhesion molecules, MMP activity in ascites
Helguera [112]	2006	Antitumor activity of IL-12 and GM-CSF mono-AbFPs against HER2/neu expressing PC	CT26-HER2/neu	BALB/c	1×10⁶	NA	Survival
Yu [113]	2005	Antitumor activity of gene therapy using LK68 cDNA	CT26-LK68-7	BALB/c	5×10⁵	14 d	Survival, number of nodules, ascites volume
Yamaguchi [114]	2001	Effect of CO₂ pneumoperitoneum on hyaluronic acid production and PM	CT26	BALB/c	5×10⁴	7 d	Number and weight of port site metastasis, histology
Miyata [115]	2001	Antitumor activity of MIP-1 gene therapy	CT26	BALB/c	1.5×10⁶	NA	Survival, gene expression
Moreno [116]	2000	Effects of pneumoperitoneum on tumor cell biology	51BliM	BALB/c	1×10² or 5×10³	6 w	Survival, ferquence of IP tumor growth
Maruyama [117]	1999	Intraperitoneal versus intravenous CPT-11 for peritoneal seeding	CT26	BALB/c	1.5×10⁶	14 d	Number of nodules
Guichard [118]	1998	Efficacy and pharmacokinetics of IP versus IV CPT-11	CT26	BALB/c	2×10⁶	NA	Survival, pharmacokinetics
Kurihara [119]	1997	Antitumor activity of oral UFT plus IV cisplatin (UFTP regimen)	Colon 26 PMF-15	CDF1	1×10⁴	NA	Survival
Gutman [120]	1996	Antitumor activity of PO thalidomide	CT26	BALB/c	1×10⁵	21 d	Number of nodules
Mayhew [121]	1990	Antitumor activity of free versus liposomal IP doxorubicin	CT26	BALB/c	2×10⁵	NA	Survival, pharmacokinetics
Syngeneic cell lines, Immunocompetent rats
Imano [122]	2013	Establishment of a PC model of the peritoneal extension type (PET)	RCN-9	Fischer 344	1×10⁶	1–21 d	Histology (tumor and submesothelial thickness)
Eriksson [123]	2012	Antitumor efficacy of ¹⁷⁷Lu-DOTA-BR96	BN7005-H1D2	Brown Norway (BN)	3×10⁵ (subperitoneal)	Up to 119 d	Tumor volume
Moretto [124]	2011	Antitumor efficacy of new platinum(II) metallointercalator	PROb	BD-IX	2×10⁶	35 d	Semi-quantitative score of PC (0 to 3) and hemorrhagic ascites
Klaver [125]	2011	Antitumor activity of hyperthermia and IPC in PC	CC531	WAG/Rij	NS	126 d	mPCI, survival
Serafino [126]	2011	Antitumor activity of new IP bioconjugate of hyaluronic acid (HA) with SN-38	DHD/K12/PROb	BD-IX	1×10⁶	28 d	Ascites volume, tumor volume (water immersion), mPCI
Klaver [127]	2010	Antitumor activity of surgery and HIPEC versus surgery alone for PC	CC531	WAG/Rij	2×10⁶	NA	Survival; mPCI
van der Bij [128]	2008	Role of tumor infiltrating macrophages in colorectal PC	CC531s	WAG/Rij	0.5×10⁶	14 d	Number, diameter, IHC for ED2+ resident macrophages
Taguchi [129]	2008	Antitumor activity of KRN951	RCN-9	Fisher 344	1×10⁷	14–21 d	Ascites volume, number of nodules, mesenteric vascularization
Oosterling [130]	2008	Role of 1 integrin-dependent tumor adehsion in PM	CC531s and DiI-CC531s	WAG/Rij		21 d	Tumor load (mm); fluorescence imaging
Aarts [131]	2008	Antitumor activity of whole-body hyperthermia or fibrinolytic therapy combined with RIT adjuvant to surgery in PC	CC531	WAG/Rij	2×10⁶	NA	Survival, mPCI
Otto [132]	2007	Antitumor activity of intraperitoneal application of phospholipids	DHD/K12/TRb	BD-IX	2×10⁶	30 d	mPC, tumor volume (water immersion), surface of PC (digitized)
Hribaschek [133]	2007	IV versus IP Taxol™ in experimental PC	CC531	WAG/Rij	5×10⁶	30 d	Tumor weight, number of nodes per zone (omentum and peritoneum), microscopic tumor growth
Bobrich [134]	2007	Effect of IP administration of taurolidine/heparin on expression of adhesion molecules and PC extent	DHD/K12/TRb	BD-IX	1×10⁴	4 w	Tumor weight, IHC
Aarts [135]	2007	Effect of timing of RIT as adjuvant therapy after CS	CC531	WAG/Rij	2×10⁶	NA	Survival, mPCI
Aarts [136]	2007	Radioimmunotherapy versus HIPEC after CS	CC531	WAG/Rij	2×10⁶	NA	Survival, mPCI, ascites volume, microscopic tumor
Pelz [137]	2006	Antitumor activity of HIPEC after CS	CC531	WAG/Rij	2.5×10⁶	20 d	Tumor weight, mPCI, histology
Oosterling [138]	2006	Role of omentum in prevention of tumor growth in MRD	DiI-CC531s	WAG/Rij	2×10⁵	variable	Dose-tumor load study, tumor score, fluorescence imaging
Nestler [139]	2006	Antitumor activity of IP angiostatin	CC531	WAG	5×10⁶	21 d	Tumor weight, number of nodules
Koppe [140]	2006	Radiommunotherapy as adjuvant therapy after CS for PC	CC531	WAG/Rij	2–5×10⁶		Survival, mPCI, tumor weight, IHC
Hribaschek [141]	2006	IV versus IP CPT-11 for experimental PC	CC531	WAG/Rij	5×10⁶	30 d	Tumor weight, number of nodes per zone (omentum and peritoneum), microscopic tumor growth, ascites volume
van den Tol [142]	2005	Adhesion-preventing properties of IP icodextrin	CC531s	WAG/Rij	0.5×10⁶	21 d	mPCI, tumor adhesion
Oosterling [143]	2005	Role of macrophages on tumor histology and outcome	CC531	WAG/Rij	2×10⁶	variable	Survival, Omental weight, IHC
Alkhamesi [144]	2005	role of ICAM-1 in mesothelial–tumour adhesion and effectiveness of therapeutic intervention	CC513	WAG/Rij	1×10⁵	14 d	mPCI, IHC
Alkhamesi [145]	2005	Effect of novel nebulization technique on post laparoscopy tumor dissemination	CC513	WAG/Rij	1×10⁵	14 d	Number and size of lesions, histology
Mahteme [146]	2004	IV versus IP 5-FU administration with or without CS	colonic adenocarcinoma of rat origin	Wistar rat	1×10⁷	3 w	Whole body autoradiography for biodistribution
Favoulet [72]	2004	Antitumor activity of IP pirarubicin	DHD/K12/PROb	BD-IX	1×10⁶	30 d	Ascites volume, tumor size
Zayyan [147]	2003	Effect of CO₂ flow rate during laparoscopy on cancer cell dispersal	RCC2	Fisher 344	7.5×10⁶	4 w	Histology for presence of tumor
Opitz [148]	2003	Effect of adhesion prophylactic substances and taurolidine/heparin on local recurrence and intraperitoneal tumor	DHD/K12/TRb	BD-IX	1×10⁴	4 w	Adhesion score, number and weight of nodules, histology
Hribaschek [149]	2002	Antitumor activity of IP CPT-11 or oxaliplatin	CC531	WAG/Rij	5×10⁶	15 d or 30 d	Tumor weight, number of nodes per zone (omentum and peritoneum),
Gahlen [150]	2002	Efficacy of 5-ALA-induced protoporphyrin IX accumulation and fluorescence in experimental PC	CC531	WAG/Rij	5×10⁵	12 d	Fluorescence Laparoscopy, spectrometry, histology
van den Tol [151]	2001	Effect of glove starch-induced peritoneal trauma on adhesions and PM	CC531s	WAG/Rij	0.5×10⁶	21 d	mPCI
Tan [152]	2001	Effect of hyaluronate on tumor cell metastatic potential	DHD/K12	BD-IX	0.5×10⁶	4 w	Nodule count
Hoffstetter [153]	2001	Effect of topical povidone-iodine on port site metastasis	DHD/K12	BD-IX	2×10⁵	3 w	Number of port site metastases
Miyoshi [154]	2001	Peritoneal angiogenesis and VEGF role in colorectal PC	RCN-9	Fisher 344	1×10⁷	variable	Mesenteric angiogenesis (intravital microscopy), ascites VEGF concentration
Cardozo [14]	2001	Establishment of PC model based on the CC531 cell line	CC531s	WAG/Rij	2×10⁶	variable	Tumor distribution, IHC
McCourt [155]	2000	Antitumor activity of IP Taurolidine	DHD/K12/TRb	BD-IX	0.25×10⁶	24 d	Number of nodules
Hofstetter [156]	2000	Effect of CO₂ insufflation on hematogeneous cancer spread	DHD/K12	BD-IX	2×10⁵	3 w	Incidence of PM
van Rossen [157]	1999	Effect of RBC derived factors on tumor cell adhesion and PC	CC531	WAG/Rij	1×10⁶	3 w	mPCI
Onier [158]	1999	Antitumor activity of OM 174	DHD/K12/PROb	BD-IX	1×10⁶	variable	Survival, mPCI, ascites volume
Jacobi [159]	1999	Effect of different insufflation gases and of taurolidine, heparin, or povidone-iodine on PC	DHD/K12/TRb	BD-IX	1×10⁴	4 w	Tumor weight, histology, incidence of port site metastasis
Jacobi [160]	1999	Effects of taurolidine, heparin, and povidone iodine on PC	DHD/K12/TRb	BD-IX	1×10⁴	4 w	Tumor weight, incidence of port site metastasis
Gahlen [161]	1999	δ-aminolevulinic acid (ALA) based fluorescence imaging for PC diagnosis and staging	CC531	WAG/Rij	5×10⁵	12 d	Fluorescence imaging (ALA), nodule size, histology
Gahlen [162]	1999	δ-aminolevulinic acid (ALA) based fluorescence imaging for PC diagnosis	CC531	WAG/Rij	1×10⁶	12 d	Fluorescence imaging (ALA), histology
Lundberg [163]	1998	Effect of CO₂- and air-induced pneumoperitoneum on tumor growth	Colon adenoCA, NOS	Wistar Fu	1×10⁵	12 d	mPCI, histology
Veenhuizen [164]	1997	Efficacy of mTHPC-mediated photodynamic therapy	CC531	WAG/Rij	1×10⁶	10–14 d	Drug biodistribution
Jacobi [165]	1997	Effect of IP taurolidine and heparin on growth of colon adenocarcinoma	DHD/K12/PROb	BD-IX	1×10⁴	4 w	Tumor weight, histology
Jacquet [166]	1996	Effect of IP doxorubicin and rT-PA postoperative tumor implants	DHD/K12/PROb	BD-IX	6×10⁵	20 d	Incidence of tumor implantation, tumor volume
Bouvy [167]	1996	Effect of CO₂ pneumoperitoneum, gasless laparoscopy, and laparotomy on PC	CC531	WAG/Rij	350 mg fragment and 5×10⁵	4 or 6 w	mPCI
Onier [168]	1993	Antitumor efficacy of IP immunomodulator, OM163	DHD/K12/PROb	BD-IX	1×10⁶	6 w	mPCI, ascites volume, survival
Human cell line, immunocompetent Hamster
Wu [169]	1998	Effects of pneumoperitoneum on tumor implantation	GW-39	Syrian gold hamster	1.6 or 3.2×10⁶	8 w	Number of tumor nodules
Wu [170]	1997	Effect of pneumoperitoneum on the implantation of tumor at trocar sites	GW-39	Syrian gold hamster	0.8×10⁶	8 w	Frequency of tumor implantation
Large immunocompetent animal models
Turner [25]	1998	Establishment of a large animal model to evaluate RIT	LS174T	Sheep (cyclosporin treated)	1×10⁷ (Matrigel injection in peritoneal wall)	3–6 w	Histology, tracer uptake
Hewett [26]	1996	Movement of cells throughout the peritoneal cavity during laparoscopy	Lim1215	Pig	10–15×10⁶	immediate	Presence of tumor cells in filters

^[1]

Research questions and topics

From the wide variety of reported research topics, only a small minority addressed fundamental mechanisms of the peritoneal metastatic cascade. Experimental designs and questions include:

Mechanisms and prevention of port site metastasis after laparoscopy
Activity of IP chemotherapy, heparin, anti-adhesive products, gene therapy, photodynamic therapy, immunotherapy, or radioimmunotherapy
Evaluation of novel pharmaceutical formulations and carriers for IP delivery
Evaluation of novel optical, fluorescence, or radioactivity based imaging techniques for diagnosis and staging of PC

Choice of cell line and animal model

Syngeneic models

Syngeneic or allograft models use cells or tissue derived from the same genetic background. The recipient animals have a normal immunity, and the resulting IP tumors therefore display a more representative microenvironment. On the other hand, these colon tumors are chemically induced and are not representative of the genetic and molecular heterogeneity of human cancers. Obviously, use of syngeneic models is the preferred approach for the study of cancer immunotherapy.

Figure 2:

Example of dynamic contrast enhanced MRI combined with two compartment pharmacokinetic modelling in a nude mouse carrying two isolated peritoneal HT29 tumors.

In immunocompetent mice, all published studies have used either the CT26 (colon tumor 26) or MC38 cell line, which are syngeneic to the BALB/c and C57BL/6 mouse, respectively. Both cell lines were developed in 1975 by exposing mice to repeated intrarectal applications of N-nitroso-N-methylurethane (NMU) or 1,2-dimethylhydrazine dihydrochloride (DMH) [11]. CT26 is a rapid-growing grade IV carcinoma that is easily implanted and readily metastasizes; it shares molecular features with aggressive, undifferentiated, refractory human colorectal carcinoma cells [12]. The MC-38 murine colon tumor is a grade III adenocarcinoma [11]. Both cell lines cause widespread PC two to three weeks after IP injection.

In immunocompetent rats, the most commonly cited model is the syngeneic CC531 cell line in the WAG (Wistar Albino Glaxo) or WAG/Rij rat. Tumor CC531 is a DMH-induced, transplantable adenocarcinoma exhibiting weak immunogenicity and which has been widely used in metastasis research [13]. Upon IP injection, the CC531 cell line causes widespread carcinomatosis and haemorrhagic ascites after three weeks [14]. In Fischer F344 rats, the spontaneously metastatic RCN-9 syngeneic cell line was established by subcutaneous administration of DMH [15]. Other syngeneic, chemically induced rat colon cancer models include the BN7005-H1D2 cell line in the Brown Norway rat, DHD/K12/TRb in the BD IX rat, and RCC2 in the Fischer F344 rat.

Xenograft models

Xenograft models involve the transplantation of human cancer cells or tissue to immunodeficient animals. Nude mice (athymic nude and BALB/c nude) and the athymic nude rat have a biallelic mutation of the FOXN1 gene (which in humans encodes the Forkhead box protein N1), leading to an athymic state and the hairless phenotype. These animals are unable to generate mature T lymphocytes and the related adaptive immune response. Severe combined immunodeficiency (SCID) mice carry a homozygous mutation of a gene coding for Prkdc, an enzyme involved in DNA repair, resulting in absent or atypical T and B lymphocytes. Non obese diabetic (NOD) SCID mice have, in addition, deficient natural killer (NK) cell function. The disadvantages of xenografted models are higher costs due to isolation requirements, the fact that the stromal component of the tumors is rodent, that the hosts are immunodeficient, and that most of the tumor lines were developed using early technology. Also, a striking feature of xenografted tumors is early and extensive necrosis, which may hamper efficacy and imaging studies. In addition, use of a “standard” cell line can result in a population that is not truly representative of the original tumor and may therefore respond differently to therapy compared to. In fact, the use xenograft models has been debated due to their low ability to predict clinical response [16]. The colon cancer cell lines that were used in xenografted PC models include HCT116, LS174T, and HT29.

Patient derived xenografts (PDX)

In order to overcome the most important drawback of xenograft models, i. e. the loss of genetic and morphological heterogeneity of the original tumor, patient derived xenografts (PDX) were developed [17]. These models consist of patient derived cancer cells or tissues transplanted in immunodeficient animals. PDX models have a long latency period and low engraftment rate, and are therefore very costly to maintain. They are ideally suited for testing novel and “personalized” cancer therapeutics. In the field of colorectal peritoneal metastasis, three studies reported the use of PDX. Kotanagi et al. obtained colorectal PM tissue fragments from a patient with stage IV right sided colon cancer [18]. Intraperitoneal injection of a single cell suspension resulted in poorly differentiated PC in four out of five SCID mice. Flatmark and coworkers implanted tumor fragments originating from mucinous colonic or appendiceal cancer in BALB/c nude mice [19]. Mice developed mucinous ascites and widespread mucinous implants; after several passages the ascites component became more prominent. The histological and molecular properties of the engrafted tumors closely resembled those of the originating clinical material. Tumor tissue fragments from an ovarian metastasis in a stage IV colon cancer patient was transplanted IP in NOD-SCID mice by Navarro-Alvarez et al. [20] The resulting xenografts were used to identify and characterize a novel tumor-initiating cell (NANK).

Genetically engineered mouse models

Genetically engineered mice (GEM) including transgenic, knock-out, knock-in, and their intercrosses have not been used in the study of colorectal peritoneal metastasis. Only one author describes the use of mice expressing human CEA as a transgene [21].

Large animal models

Larger animals are rarely used in PC research. Apart from the cost and handling issues, colorectal syngeneic or xenograft models are unavailable in large animals. In rabbits, a non-colorectal PC model based on the V×2 cell line is available. The V×2 cell line is derived from the Shope papilloma virus (family Papovaviridae), an oncogenic DNA virus, transmitted by biting arthropods and causing hyperkeratotic skin lesions resulting in malignant transformation in the rabbit [22]. A ‘gastric’ peritoneal carcinomatosis model based on the V×2 cell line was proposed by Tang et al. [23, 24] The authors simulated gastric cancer with early stage PC in New Zealand white rabbits (Oryctolagus cuniculus) by transmural injection of V×2 cells in the stomach. Turner and coworkers succeeded in engrafting human colon cancer cells (LS174T) in cyclosporine treated sheep by subperitoneal injection [25]. Tumors grew at all sites within three weeks, and were used to study the biodistribution of a radiolabelled antibody. The use of a pig model was reported by Hewett, who studied the pneumoperitoneum induced movement of colon cancer cells immediately after IP instillation [26].

Establishment of experimental PC

An orthotopic PC model is easily established by IP injection of cancer cells, which results in widespread and progressive carcinomatosis, leading to cachexia, hemorrhagic ascites, and death of the animal. The efficacy (engraftment or take rate) and speed of this process depend on the number of cells injected, virulence of the cell line used, and immunocompetence of the host. Although this model is orthotopic, the metastatic process and its underlying biology are different from spontaneous PC arising from a primary colon cancer. Cespedes and coworkers established a primary colon cancer model by submucosal injection of HCT116 cells in the colon of nude mice, and observed the development of PC in 100 % of the animals [27]. Using this model, the same group showed that use of a colon cancer cell line overexpressing Snail1, which decreases E-cadherin, completely blocked spontaneous PC [28]. Similarly, Puig et al. injected patient derived colon cancer cell lines into the cecal wall of NOD-SCID mice and observed spontaneous PC when cell lines were used originating from cancer with a mucinous differentiation [29]. The disadvantage of the IP injection and spontaneous PC models is that the resulting tumor load is difficult to quantify. Also, their very small size precludes detailed physiological or drug penetration study at the individual tumor level. We recently established a colorectal PC model consisting of two isolated peritoneal nodules, which develop upon subperitoneal injection of HT29 cells in Matrigel.™ [30] This model allowed assessment of tumor tissue interstitial fluid pressure, oxygenation, platinum penetration, and growth delay (Figure 2).

Experimental endpoints

Extent and distribution of PC

Most authors have quantified the extent of experimental PC by a scoring system based on the number and/or size of peritoneal implants, similar to the peritoneal cancer index (PCI) that is clinically used. Use of such a score is difficult when the tumor forms a confluent mass or film rather than isolated nodules. Others have used the total weight or volume (as determined by water displacement) of the tumor mass, ascites presence and volume, or the metastatic pattern as endpoints. Alternatively, the extent of microscopic disease has been studied on resected omental tissue, peritoneal biopsies, or omental lysates using (immune)histology or PCR. The above methods require invasive procedures. Several authors have quantified PC load at different time points using optical (fluorescence or bioluminescence) techniques based on cancer cell lines transfected with a green or red fluorophore, or with the firefly luciferase gene. Alternatively, cells may be labeled immediately before injection with quantum dots or other reporters [31]. These techniques are sensitive and fast, and allow reproducible quantification using a variety of image processing methods. Some authors have used bioluminescence of organ and tissue lysates in order to quantify tumor growth.

Survival

In studies investigating novel therapies of colorectal cancer, survival is an important endpoint. Since advanced PC causes considerable animal suffering, care should be taken to sacrifice the animals whenever a predefined humane endpoint is reached. Actuarial (rather than actual) survival is usually calculated, and comparisons made with the log rank test or the Cox model.

Other endpoints

Various other endpoints were reported. Some authors have analysed the pO₂, VEGF concentration, or immune response of tumor associated ascites. Others have imaged PC distribution using optical techniques (Figure 3), or have analysed the biodistribution of isotope labelled tracers in tissue or in the whole animal.

Figure 3:

Fluorescence imaging of red fluorescent HCT-116 colorectal peritoneal metastases using intraperitoneal injection of OBP-401, a telomerase-dependent, replication competent adenovirus expressing GFP (green fluorescent protein).

Conclusions and recommendations

Colorectal peritoneal metastasis remains little studied in preclinical models, when compared to ovarian cancer or liver metastasis research. Standardized, reproducible syngeneic and xenograft colorectal PC models are available in rodents. The choice of a specific model is dictated by the aim of the study. Technical models involving IP chemoperfusion or laparoscopy are easier in a rat model. Tumor physiology, pharmacokinetics, and growth delay are better studied in isolated peritoneal tumors established by peritoneal implantation of tissue fragments or subperitoneal injection. Very few genetically modified mouse models have been reported in PM research. With the advent of sophisticated genome editing tools such as CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats associated nuclease 9), the use of genetically engineered models is expected to gain in importance in the near future.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Received: 2016-2-25

Accepted: 2016-3-4

Published Online: 2016-4-12

Published in Print: 2016-3-1

Artikel in diesem Heft

https://doi.org/10.1515/pp-2016-0006

Schlagwörter für diesen Artikel

metastasis; mouse model; PDX model; peritoneal