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Publicly Available Published by De Gruyter April 12, 2016

Animal models of colorectal peritoneal metastasis

Félix Gremonprez, Wouter Willaert and Wim Ceelen
From the journal Pleura and Peritoneum

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.

AuthorYearResearch questionCell line/tissueAnimalIP doseInterval before endpointsQuantification of PC
Patient derived xenografts
Navarro-Alvarez [20]2010Isolation of a CRC CD133− cancer stem cell line (NANK)Tissue from CRC primary and ovarian metastasisNOD-SCID2 mm3 fragments6–8 wCell isolation
Flatmark [19]2010IHC study of human PMP and related animal modelsTissue from mucinous CRCBALB/c nude3×3×3 m fragments1–3 mIHC markers of differentiation, proliferation, and metastasis
Kotanagi [18]1998Characterization of patient derived metastatic cell linesCRC patient derived cell lineSCID1×10740 dNumber and weight of nodules, histology
Human cell lines, transgene mice
Abdul-Wahid [21]2012Antitumor activity of CEA immunizationMC38.CEACEA.Tg2×10535 dNumber, volume
Human cell lines, SCID mice
Mikula-Pietrasik [32]2015Role of senescent Mesothelium in CRC metastasisSW480-lucSCID2×10618 dBioluminiscence (IVIS)
Inoue [33]2011Antitumor activity of a multifunctional Treg cell lineWiDr-EGFP-9NOD-SCID1×1075 wFluorescence stereomicroscopy; survival
Navarro-Alvarez [20]2010Isolation of a CRC CD133− cancer stem cell line (NANK)CD133− NANKNOD-SCID1×104–1×1058–12 wimmunostaining
Lubbe [34]2009Role of receptor guanylyl cyclase C (GCC) in cancer cell MMP-9T84 (wt or transduced with MMP-9)Cr:NIH-bg-nu-Xid1×1072 wPeritoneal biopsies for quantification of metastatic tumor burden by RT-PCR
Harada [35]2001Antitumor activity of antisense CD44sCD44 transfected LS174TSCID2 or 4×1064 wAscites volume, tumor weight
Sakamoto [36]2001Involvement of c-Src in carcinoma cell motility and metastasisHCT15SCID2×1063 wNumber of nodules, histology
Watson [37]1996Antitumor activity of the MMP inhibitor batimastatC170HM2SCID5×10628 dAscites volume and cell density, tumor weight
Yasui [38]1997Tumor metastasis of human CRC cell lines in SCID mice10 colorectal cell linesSCID5×1063 wNumber of nodules
Human cell lines, Immunodeficient mice
Gremonprez [30]2015Effect of pretreatment with VEG(R) inhibitors on IFP, Pt penetration, and tumor growth of isolated peritoneal tumorsHT29Athymic nude1.5×106 subperitoneal injection15 dIFP, tissue oxygenation, Pt distribution, tumor growth
Wang [39]2015Role of Cullin1 in inasive properties of CRCHCT116 and SW480BALB/c nude1×10622 dNumber, size nodules
Takemoto [40]2015Cytotoxic effects of lavage with hypotonic fluid in CRCDLD1, HT29, and CACO2BALB/c nude1×1064 weeksNumber, size, weight nodules
Shen [41]2015Interplay between SOX9 and S100P in metastasis and invasion of CRCTransfected HCT116Nude mice1×1071 monthIn-Vivo F Imaging System (Kodak)
Liu [42]2015Role of microRNA-409-3p in invasiveness and metastsasisTransfected SW480 and SW1116BALB/c nude2×1068 weeksNumber of nodules
Lee [43]2015Development of novel biodegradable hydrogel for delivery of bevacizumabHCT116BALB/c nude4×10662 dNone (survival)
Amini [44]2015Effect of mucin depletion with bromelain and N-acetylcysteine on metastatic potentialLS174TBALB/c nude1×10617 dNumber, weight
Tang [45]2014Efficacy of 5-FU loaded nanoparticle for IP deliveryHCT116BALB/c nude5×10528Number, volume
Tanaka [46]2014Effect of the TrkB inhibitor K252a on PMDLD1BALB/c nude5×1074 wSize, number
Rijpkema [47]2014Role of nuclear and fluorecent imaging guided surgery using a CEA targeting antibodyLS174TBALB/c nude1×1062 wSPECT-CT using 111In-DTPA-MN-14-IRDye 800CW
Li [48]2014Extent of hypoxia and 18F-FDG uptake in PCHT29Athymic nude5×1064–7 wascites pO2 (OxyLite); 18F-FDG uptake
Kondo [49]2014photodynamic diagnosis using 5-aminolevulinic acid to detect PMeGFP Transfected HT29BALB/c nude1×1062 weGFP fluorescence imaging
Al-kasspooles [50]2013Antitumor activity of a nanoparticulate formulation of SN38, a metabolite of irinotecanHT-29 and HCT116Athymic nude5×10645 dsurvival
Derbal-Wolfrom [51]2013Effect of increased oxygen load by treatment with myo-inositol trispyrophosphate on PCHT29Athymic nude1×107NASurvival
Shen [52]2012Antitumor activity of the NF-kappaB inhibitor BAY 11–7085HT29-lucAthymic nude1×1068–9 dNumber; Xenogen bioluminescent imaging system
Nayak [53]2012MR and PET imaging of HER overexpressign PM using 89Zr-Labeled PanitumumabLS174TAthymic nude1×1085–7 dBiodistribution and immunotargeting of tracer in PM
Ziauddin [54]2010Antitumor activity of vvTRAIL-mediated oncolytic gene therapyHCT116Athymic nude1×107NAsurvival
Straza [55]2010Antitumor activity of 4-methylthio-2-oxobutyric acid (MTOB)HCT116p53-/-Athymic nude3×106NASurvival, ascites volume, tumor weight
Li [56]2010Relation of 18F-FDG uptake with hypoxia in peritoneal tumorsHT29 and HCT-8Athymic nude5–10×1063–7 w18F-FDG distribution, IHC (pimonidazole and Hoechst 33342, BdU)
Lan [57]2010Antitumor activity of a cationic liposome coupled with the murine endostatin geneHCT116BALB/c nude3×1064 wAscites volume; human and mouse VEGF in serum and ascites
Hackl [58]2010Role of Activating transcription factor-3 (ATF3) in CRC metastasisATF3-shRNA or luc-shRNA Transfected HCT116Athymic nude3×10628 dPresence of ascites; number of nodules
Wagner [59]2009Antitumor activity of rapamycinSW620Athymic nude5×105NAAscites volume; tumor weight
Kishimoto [60]2009In vivo tumor illumination by IP adenoviral GFPHCT-116 and HCT-116-RFPAthymic nude3×10617dFluorescence Optical Imaging; histology
Li [61]2007Evaluation of hypoxia in PMHT29 and HCT-8Athymic nude5–10×1063–7 wIHC and in vitro fluorescence imaging
Kinuya [62]2007Antitumor activity of RIT with a 131I labelled IP A7 antibodyLS180BALB/c nude1×107variableSurvival
Jie [63]2007Antitumor activity of recombinant adenovirus, rvAdCMV/NK4LS174TBALB/c nude1×10715 dNumber, site, and weight of nodules
Sasaki [64]2006Antitumor activity of IP linoleic acid (LA)Colo320BALB/c nude1×10712 wNumber of metastatic foci
Kuniyasu [65]2006Antitumor activity of IP conjugated linoleic acid (CLA) on PMColo320BALB/c nude1×1074–16 wMumber of metastatic foci, survival
Koppe [66]2006Antitumor activity of radioimmunotherapy combined with gemcitabineLS174TBALB/c nude1×106NASurvival, tumor weight, IHC
Koppe [67]2006Antitumor activity of radioimmunotherapy combined with parecoxibLS174TBALB/c nude1×106NASurvival, mPCI, tumor weight, tracer biodistribution
Pourgholami [68]2005Antitumor activity of IP albendazoleHT29BALB/c nude1×1066 wNumber of nodules
Kinuya [69]2005Locoregional 186Re-RIT versus 131I-RIT for experimental PCLS180BALB/c nude1×107variableTissue radioactivity, number and weight of nodules, survival
Zeamari [70]2004Identifation of growth factors during peritoneal wounding in relation to tumor cell seedingHT29BALB/c nude1×10628 dTumor load (a. u.), PCR of granulation tissue
Koppe [71]2004Antitumor activity of 125/131I-, 186Re-, 88/90Y-, or 177Lu-Labeled Monoclonal Antibody MN-14 to CEALS174TBALB/c nude1×106NASurvival, tumor weight, tracer biodistribution
Favoulet [72]2004Antitumor activity of IP pirarubicinLS174TAthymic nude1×10721 dAscites volume, tumor size
Koppe [73]2003Antitumor activity of IP radioimmunotherapy using 131I-labeled MN-14LS174TBALB/c nude1×106variableBiodistribution, IHC
Kinuya [74]2003Antitumor activity of IP versus IV radioimmunotherapy with 131I-A7LS180BALB/c nude1×107variableSurvival, biodistribution
Stoeltzing [75]2002Effect of angiopoietin-1 on PMtumour growth and angiogenesisAng-1- or pcDNA transfected KM12L4Athymic nude1×106variableAscites volume, diameter of largest PM, number of nodules, IHC
Fan [76]2002Effect of the angiogenesis inhibitor TNP-470 on peritoneal disseminationLoVoBALB/c nude5×10710 d or 30 dSurvival, number and size of nodules
Hubbard [77]2002Antitumor activity of hyaluronan-based membraneKM12-L4BALB/c nudevariable28 dTumor weight, presence of ascites, histology
Shaheen [78]2001Antitumor activity of IP anti-VEGFR and anti-EGFR antibidiesKM12L4Athymic nude1×106NATumor size, ascites (semiquantitatively), IHC
Goto [79]2001Antitumor activity of gene therapy using the Cre/loxP systemLoVoAthymic nude1×10635 dTumor weight, histology
Kondo [80]2000Role of VEGF in peritoneal cancer growthVEGF transfected LoVoBALB/c nude2×106variableMetastatic pattern, number and size of nodules, ascites volume
Crosasso [81]1997Antitumor activity of IP 5-FU prodrug formulated in liposomes or immunoliposomesHT-29Athymic nude1.5×107variableHistology, Residual tumor mass (RTM, % of tumor mass in treated over that in control mice)
Asao [82]1995Role of Fucosyltransferases in cancer cell adhesionKM12C and KM12SMBALB/c nude1×1064 wTumor weight
Quadri [83]1995Biodistribution of IP In-111-labeled IgMSW620Athymic nude6×106VariableBiodistribution, whol body autoradiography
Human cell lines, Immunodeficient rats
Harlaar [84]2010Validation of bioluminiscence in PC animal modelsHT-29-luc-D6Athymic nude2×1068 wBioluminiscence, PCI
Mahteme [85]2005Effect of vasoconstriction on IP 5FU tumor uptakeLS 174TAthymic nude1×107variableWhole body autoradiography for biodistribution
Syngeneic cell lines, Immunocompetent mice
Carpinteri [86]2015Effect of laparoscopy with humidified-warm CO2 on peritoneal inflammation and metastasis(MSCV)-mCherry-CT26BALB/c1×10610 dNumber; Cherry-Red fluorescence (Maestro)
Zhang [87]2015Antitumor activity of IP curcumin in a thermosensitive hydrogelCT26BALB/c2×10522 dNumber of nodules, tumor weight, survival, IHC
Ryan [88]2015Antitumor activity of nuclear factor (NF)-κB inhibitionCT26/EV and CT26/IκB-α SRBALB/cvariablevariableTumor weight, histology, survival
Zhang [89]2014Antitumor effects of placenta-derived mesenchymal stem cells expressing endostatin EndostatinCT26BALB/c3×105variableNumber, size of nodules
Fan [90]2014Evaluation of docetaxel loaded microspheres for IP deliveryCT26BALB/c2×10514 dNumber, size
Sedlacek [91]2013Effect of peritoneal immunization by IP injected irradiated cancer cellseGFP transfected MC38C57BL/61×1063 or 7 dGFP fluorescence of resected omenta
Liu [92]2013Evaluation of camptothecine loaded polymeric microsphere in thermosensitive hydrogel for IP deliveryCT26BALB/c2×10520 dNumber and weight
Li [93]2013Role of high-mobility group box 1 (HMGB1) in PMCT26BALB/c1×1052 wmodified sPCI
Yao [94]2013Antitumor activity of a water-soluble BSA-SN38 conjugateCT26BALB/c2×10518 dTumor weight
Yu [95]2013Peritoneal immune response after IP vaccination with irradiated CT26 cellsCT26BALB/c5×105variablePeritoneal immune response
Lee [96]2013Effect of surgery on matrix metalloproteinase-9 activityMC38C57bl/6J1×1052 wmodified sPCI
Wu [97]2012Antitumor efficacy of Adeno-associated virus mediated human pigment epithelium-derived factor (PEDF)CT26BALB/c5×10518 dNumber, weight
Lehmann [98]2012Synergism of HIPEC with the SOD inhibitor diethyldithiocarbamate (DDC)MC38C57Bl/62×1067 dTumor mass
Tsai [99]2011Antitumor efficacy of 188Re-labeled nanoliposomes (IV)CT26BALB/c2×1057–14 dAscites weight, tumor weight, PET-CT
Puskas [100]2011Antitumor efficacy of an attenuated interleukin-2 fusion proteinMC38C57BL/6J5×1057 dFlow cytometry and CFU on omental lysates
Nishizaki [101]2011Inhibition of surgical trauma-enhanced PM by human catalase derivativesCT26-LucBALB/c1×1053 dLuminometry on omental and GI tract lysates
Dai [102]2011Antitumor activity of camptothecin-loaded microspheresCT26BALB/c2×10514 dSize, number
Ziauddin [54]2010Antitumor activity of vvTRAIL-mediated oncolytic gene therapyMC38C57bl/6J2×105NAsurvival
Wang [103]2010Antitumor activity of 5-FU-loaded hydrogel systemCT26BALB/c2×10520 dSize, number
Tanaka [104]2010Antitumor activity of the Transforming growth factor ß signaling inhibitor, SB-431542CT26BALB/cNS14 dCytotoxic T cell (CTL) activity against CT26
Lan [57]2010Antitumor activity of a cationic liposome coupled with the murine endostatin geneCT26-lucBALB/c3×1053 wBioluminiscence; gene expression; survival; tumor weight
Keese [105]2010Fluorescence lifetime imaging of chemotherapy induced apoptosis by optically monitoring the caspase-3 sensor statetHcred-DEVD-EGFP transfected CT26BALB/c1×10610 dFluorescence lifetime imaging microscopy (FLIM)
Wagner [59]2009Antitumor activity of rapamycinCT26BALB/c5×105NAAscites volume; tumor weight
Kulu [106]2009Comparison of IV versus IP administration of oncolytic herpes simplex virus 1CT26BALB/c1×10520 dTumor weight
Keese [107]2009Antitumor activity of doxorubicin and mitoxantrone drug eluting beads for PCEGFP-C26BALB/c1×10615 dIn vivo fluorescence microscopy; mPCI, tumor volume, PCR for EGFP
Lan [108]2007Antitumor activity of liposome coupled BikDD on PMCT-26-LucBALB/c1×105–1×10621 dBioluminiscence; tumor weight
Hyoudou [109]2007Antitumor activity of cationized catalase-loaded hydrogelCT-26-LucBALB/c1×10521 dBioluminiscence; Luminometry on organ lysates
Dvir-Ginzberg [110]2007Antitumor activity of IP scaffolds containing retroviral vector producing cellsMC38C57bl/65×105NASurvival, extent of PC (not quantified)
Hyoudou [111]2006IP PEG-catalase to inhibit peritoneal disseminationCT-26-LucBALB/c1×105variableBioluminiscence, expression of adhesion molecules, MMP activity in ascites
Helguera [112]2006Antitumor activity of IL-12 and GM-CSF mono-AbFPs against HER2/neu expressing PCCT26-HER2/neuBALB/c1×106NASurvival
Yu [113]2005Antitumor activity of gene therapy using LK68 cDNACT26-LK68-7BALB/c5×10514 dSurvival, number of nodules, ascites volume
Yamaguchi [114]2001Effect of CO2 pneumoperitoneum on hyaluronic acid production and PMCT26BALB/c5×1047 dNumber and weight of port site metastasis, histology
Miyata [115]2001Antitumor activity of MIP-1 gene therapyCT26BALB/c1.5×106NASurvival, gene expression
Moreno [116]2000Effects of pneumoperitoneum on tumor cell biology51BliMBALB/c1×102 or 5×1036 wSurvival, ferquence of IP tumor growth
Maruyama [117]1999Intraperitoneal versus intravenous CPT-11 for peritoneal seedingCT26BALB/c1.5×10614 dNumber of nodules
Guichard [118]1998Efficacy and pharmacokinetics of IP versus IV CPT-11CT26BALB/c2×106NASurvival, pharmacokinetics
Kurihara [119]1997Antitumor activity of oral UFT plus IV cisplatin (UFTP regimen)Colon 26 PMF-15CDF11×104NASurvival
Gutman [120]1996Antitumor activity of PO thalidomideCT26BALB/c1×10521 dNumber of nodules
Mayhew [121]1990Antitumor activity of free versus liposomal IP doxorubicinCT26BALB/c2×105NASurvival, pharmacokinetics
Syngeneic cell lines, Immunocompetent rats
Imano [122]2013Establishment of a PC model of the peritoneal extension type (PET)RCN-9Fischer 3441×1061–21 dHistology (tumor and submesothelial thickness)
Eriksson [123]2012Antitumor efficacy of 177Lu-DOTA-BR96BN7005-H1D2Brown Norway (BN)3×105 (subperitoneal)Up to 119 dTumor volume
Moretto [124]2011Antitumor efficacy of new platinum(II) metallointercalatorPRObBD-IX2×10635 dSemi-quantitative score of PC (0 to 3) and hemorrhagic ascites
Klaver [125]2011Antitumor activity of hyperthermia and IPC in PCCC531WAG/RijNS126 dmPCI, survival
Serafino [126]2011Antitumor activity of new IP bioconjugate of hyaluronic acid (HA) with SN-38DHD/K12/PRObBD-IX1×10628 dAscites volume, tumor volume (water immersion), mPCI
Klaver [127]2010Antitumor activity of surgery and HIPEC versus surgery alone for PCCC531WAG/Rij2×106NASurvival; mPCI
van der Bij [128]2008Role of tumor infiltrating macrophages in colorectal PCCC531sWAG/Rij0.5×10614 dNumber, diameter, IHC for ED2+ resident macrophages
Taguchi [129]2008Antitumor activity of KRN951RCN-9Fisher 3441×10714–21 dAscites volume, number of nodules, mesenteric vascularization
Oosterling [130]2008Role of 1 integrin-dependent tumor adehsion in PMCC531s and DiI-CC531sWAG/Rij21 dTumor load (mm); fluorescence imaging
Aarts [131]2008Antitumor activity of whole-body hyperthermia or fibrinolytic therapy combined with RIT adjuvant to surgery in PCCC531WAG/Rij2×106NASurvival, mPCI
Otto [132]2007Antitumor activity of intraperitoneal application of phospholipidsDHD/K12/TRbBD-IX2×10630 dmPC, tumor volume (water immersion), surface of PC (digitized)
Hribaschek [133]2007IV versus IP Taxol™ in experimental PCCC531WAG/Rij5×10630 dTumor weight, number of nodes per zone (omentum and peritoneum), microscopic tumor growth
Bobrich [134]2007Effect of IP administration of taurolidine/heparin on expression of adhesion molecules and PC extentDHD/K12/TRbBD-IX1×1044 wTumor weight, IHC
Aarts [135]2007Effect of timing of RIT as adjuvant therapy after CSCC531WAG/Rij2×106NASurvival, mPCI
Aarts [136]2007Radioimmunotherapy versus HIPEC after CSCC531WAG/Rij2×106NASurvival, mPCI, ascites volume, microscopic tumor
Pelz [137]2006Antitumor activity of HIPEC after CSCC531WAG/Rij2.5×10620 dTumor weight, mPCI, histology
Oosterling [138]2006Role of omentum in prevention of tumor growth in MRDDiI-CC531sWAG/Rij2×105variableDose-tumor load study, tumor score, fluorescence imaging
Nestler [139]2006Antitumor activity of IP angiostatinCC531WAG5×10621 dTumor weight, number of nodules
Koppe [140]2006Radiommunotherapy as adjuvant therapy after CS for PCCC531WAG/Rij2–5×106Survival, mPCI, tumor weight, IHC
Hribaschek [141]2006IV versus IP CPT-11 for experimental PCCC531WAG/Rij5×10630 dTumor weight, number of nodes per zone (omentum and peritoneum), microscopic tumor growth, ascites volume
van den Tol [142]2005Adhesion-preventing properties of IP icodextrinCC531sWAG/Rij0.5×10621 dmPCI, tumor adhesion
Oosterling [143]2005Role of macrophages on tumor histology and outcomeCC531WAG/Rij2×106variableSurvival, Omental weight, IHC
Alkhamesi [144]2005role of ICAM-1 in mesothelial–tumour adhesion and effectiveness of therapeutic interventionCC513WAG/Rij1×10514 dmPCI, IHC
Alkhamesi [145]2005Effect of novel nebulization technique on post laparoscopy tumor disseminationCC513WAG/Rij1×10514 dNumber and size of lesions, histology
Mahteme [146]2004IV versus IP 5-FU administration with or without CScolonic adenocarcinoma of rat originWistar rat1×1073 wWhole body autoradiography for biodistribution
Favoulet [72]2004Antitumor activity of IP pirarubicinDHD/K12/PRObBD-IX1×10630 dAscites volume, tumor size
Zayyan [147]2003Effect of CO2 flow rate during laparoscopy on cancer cell dispersalRCC2Fisher 3447.5×1064 wHistology for presence of tumor
Opitz [148]2003Effect of adhesion prophylactic substances and taurolidine/heparin on local recurrence and intraperitoneal tumorDHD/K12/TRbBD-IX1×1044 wAdhesion score, number and weight of nodules, histology
Hribaschek [149]2002Antitumor activity of IP CPT-11 or oxaliplatinCC531WAG/Rij5×10615 d or 30 dTumor weight, number of nodes per zone (omentum and peritoneum),
Gahlen [150]2002Efficacy of 5-ALA-induced protoporphyrin IX accumulation and fluorescence in experimental PCCC531WAG/Rij5×10512 dFluorescence Laparoscopy, spectrometry, histology
van den Tol [151]2001Effect of glove starch-induced peritoneal trauma on adhesions and PMCC531sWAG/Rij0.5×10621 dmPCI
Tan [152]2001Effect of hyaluronate on tumor cell metastatic potentialDHD/K12BD-IX0.5×1064 wNodule count
Hoffstetter [153]2001Effect of topical povidone-iodine on port site metastasisDHD/K12BD-IX2×1053 wNumber of port site metastases
Miyoshi [154]2001Peritoneal angiogenesis and VEGF role in colorectal PCRCN-9Fisher 3441×107variableMesenteric angiogenesis (intravital microscopy), ascites VEGF concentration
Cardozo [14]2001Establishment of PC model based on the CC531 cell lineCC531sWAG/Rij2×106variableTumor distribution, IHC
McCourt [155]2000Antitumor activity of IP TaurolidineDHD/K12/TRbBD-IX0.25×10624 dNumber of nodules
Hofstetter [156]2000Effect of CO2 insufflation on hematogeneous cancer spreadDHD/K12BD-IX2×1053 wIncidence of PM
van Rossen [157]1999Effect of RBC derived factors on tumor cell adhesion and PCCC531WAG/Rij1×1063 wmPCI
Onier [158]1999Antitumor activity of OM 174DHD/K12/PRObBD-IX1×106variableSurvival, mPCI, ascites volume
Jacobi [159]1999Effect of different insufflation gases and of taurolidine, heparin, or povidone-iodine on PCDHD/K12/TRbBD-IX1×1044 wTumor weight, histology, incidence of port site metastasis
Jacobi [160]1999Effects of taurolidine, heparin, and povidone iodine on PCDHD/K12/TRbBD-IX1×1044 wTumor weight, incidence of port site metastasis
Gahlen [161]1999δ-aminolevulinic acid (ALA) based fluorescence imaging for PC diagnosis and stagingCC531WAG/Rij5×10512 dFluorescence imaging (ALA), nodule size, histology
Gahlen [162]1999δ-aminolevulinic acid (ALA) based fluorescence imaging for PC diagnosisCC531WAG/Rij1×10612 dFluorescence imaging (ALA), histology
Lundberg [163]1998Effect of CO2- and air-induced pneumoperitoneum on tumor growthColon adenoCA, NOSWistar Fu1×10512 dmPCI, histology
Veenhuizen [164]1997Efficacy of mTHPC-mediated photodynamic therapyCC531WAG/Rij1×10610–14 dDrug biodistribution
Jacobi [165]1997Effect of IP taurolidine and heparin on growth of colon adenocarcinomaDHD/K12/PRObBD-IX1×1044 wTumor weight, histology
Jacquet [166]1996Effect of IP doxorubicin and rT-PA postoperative tumor implantsDHD/K12/PRObBD-IX6×10520 dIncidence of tumor implantation, tumor volume
Bouvy [167]1996Effect of CO2 pneumoperitoneum, gasless laparoscopy, and laparotomy on PCCC531WAG/Rij350 mg fragment and 5×1054 or 6 wmPCI
Onier [168]1993Antitumor efficacy of IP immunomodulator, OM163DHD/K12/PRObBD-IX1×1066 wmPCI, ascites volume, survival
Human cell line, immunocompetent Hamster
Wu [169]1998Effects of pneumoperitoneum on tumor implantationGW-39Syrian gold hamster1.6 or 3.2×1068 wNumber of tumor nodules
Wu [170]1997Effect of pneumoperitoneum on the implantation of tumor at trocar sitesGW-39Syrian gold hamster0.8×1068 wFrequency of tumor implantation
Large immunocompetent animal models
Turner [25]1998Establishment of a large animal model to evaluate RITLS174TSheep (cyclosporin treated)1×107 (Matrigel injection in peritoneal wall)3–6 wHistology, tracer uptake
Hewett [26]1996Movement of cells throughout the peritoneal cavity during laparoscopyLim1215Pig10–15×106immediatePresence of tumor cells in filters

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

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