Félix Gremonprez, Wouter Willaert and Wim Ceelen

Animal models of colorectal peritoneal metastasis

Accessible
De Gruyter | Published online: April 12, 2016

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.

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.

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) HCT116p53-/- 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:

  1. Mechanisms and prevention of port site metastasis after laparoscopy

  2. Activity of IP chemotherapy, heparin, anti-adhesive products, gene therapy, photodynamic therapy, immunotherapy, or radioimmunotherapy

  3. Evaluation of novel pharmaceutical formulations and carriers for IP delivery

  4. 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.

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).

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

©2016 by De Gruyter Mouton