Preclinical Mouse Models of Human Prostate Cancer and Their Utility in Drug Discovery

Serk In Park1, Sun Jin Kim2, Laurie K. McCauley3, Gary E. Gallick4

1 Department of Periodontics and Oral Medicine, The University of Michigan School of Dentistry, Ann Arbor, Michigan, 2 Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 3 Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, 4 Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 14.15
DOI:  10.1002/0471141755.ph1415s51
Online Posting Date:  December, 2010
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Abstract

In vivo animal studies are an essential component of prostate cancer research, and are particularly critical for studying interactions between tumor cells and their microenvironment. Numerous preclinical animal models of prostate cancer are available, including transgenic mouse models and human prostate cancer xenograft mouse models. In contrast to transgenic mouse models producing more heterogeneous cohorts of tumors, xenograft mouse models provide more controlled approaches. This unit describes procedures used to establish several distinct preclinical mouse models of human prostate cancer, including an orthotopic prostate xenograft model, an orthotopic bone metastasis model, an experimental metastasis model of intra‐cardiac injection, and a vossicle model of tumor‐bone interaction.Curr. Protoc. Pharmacol. 51:14.15.1‐14.15.27. © 2010 by John Wiley & Sons, Inc.

Keywords: prostate cancer; mouse models; orthotopic xenograft; metastasis; intra‐cardiac injection; vossicle; bone

     
 
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Table of Contents

  • Introduction
  • Basic Protocol 1: Orthotopic Prostate Cancer Mouse Model
  • Basic Protocol 2: Experimental Metastasis Model of Prostate Cancer by Intra‐Cardiac Tumor Cell Inoculation
  • Basic Protocol 3: Orthotopic Bone Tumor Model of Metastatic Prostate Cancer
  • Basic Protocol 4: Vossicle Model for the Study of Tumor‐Bone Interactions
  • Commentary
  • Literature Cited
  • Figures
  • Tables
     
 
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Materials

Basic Protocol 1: Orthotopic Prostate Cancer Mouse Model

  Materials
  • Male athymic mice, 6 to 12 weeks of age: these mice can be purchased from commercial vendors such as the National Cancer Institute‐Frederick Animal Production Area (NCr nu/nu) or Harlan Laboratories (Hsd athymic nude‐Foxn1nu)
  • Anesthetics: pentobarbital sodium (50 mg/ml; Nembutal from Abbott Laboratories) or ketamine/xylazine mixture [ketamine (100 mg/ml):xylazine (20 mg/ml):phosphate‐buffered saline = 3:2:5] or isoflurane gas anesthetics system (e.g., XGI‐8 Gas Anesthesia System from Caliper Life Sciences)
  • Ophthalmic ointment or sterile petroleum jelly
  • Prostate cancer cells in culture such as PC‐3 and LNCaP (ATCC) grown in complete culture medium (80% to 90% confluency in 150‐cm2 tissue culture flasks)
  • Complete cell culture medium (e.g., for LNCaP, PC‐3, and their derivatives): RPMI‐1640 (Gibco brand from Invitrogen) supplemented with 10% fetal bovine serum (HyClone brand from Thermo Scientific) and antibiotics (e.g., penicillin‐streptomycin from Invitrogen, cat. no.15070‐063)
  • Sterile phosphate‐buffered saline (PBS; Invitrogen, cat. no. 10010)
  • 0.25% Trypsin/EDTA (Invitrogen, cat. no. 25200)
  • 0.4% Trypan blue
  • Ca2+‐free and Mg2+‐free Hanks' balanced salt solution with phenol red indicator (HBSS; Invitrogen)
  • 70% ethanol gauze and/or 10% povidone‐iodine (Betadine)
  • Reference compounds (e.g., Dasatinib; Bristol‐Myers Squibb Oncology)
  • Sterilized cotton swabs (1/10 in. × 6 in. wood shaft cotton‐tipped applicators)
  • Hemacytometer
  • 50‐ml conical centrifuge tubes (e.g., Becton Dickinson, cat. no. 35‐2070)
  • Centrifuge
  • Surgical adhesive tape (e.g., 3M Micropore Surgical Tape)
  • Scissors (e.g., 41/2‐in. curved iris scissors) and forceps (e.g., 4 in. 1×2 teeth straight iris tissue forceps)
  • 1‐ml syringes and needles (27‐G × ½‐in. length; BD Medical)
  • Wound closing surgical metal clips, stapler, and remover (e.g., AutoClip applier, AutoClip remover, and 9‐mm EZ Clip; BD Medical)
  • Warming lamp or heating pad
  • Additional reagents and equipment for performing a viable cell count using a hemacytometer and trypan blue staining (Phelan, ) and euthanizing the animal (Donovan and Brown, )
NOTE: Intra‐prostatic injection is an open‐abdominal surgery. During the entire procedure, animals should be kept in specific pathogen‐free conditions (e.g., in a designated surgery room or laminar flow hood) and proper surgical aseptic technique should be applied to all surgical procedures.

Basic Protocol 2: Experimental Metastasis Model of Prostate Cancer by Intra‐Cardiac Tumor Cell Inoculation

  Materials
  • Male athymic mice, 6 to 12 weeks of age: National Cancer Institute‐Frederick Animal Production Area (NCr nu/nu) or Harlan Laboratories (Hsd athymic nude‐Foxn1nu)
  • Metastatic prostate cancer cells in culture, such as PC‐3 (ATCC) (expand the culture to produce at least 2‐ to 4‐fold more than the cell number considered necessary for the study)
  • Complete cell culture medium (e.g., for LNCaP, PC‐3 and their derivatives): RPMI‐1640 (Gibco brand from Invitrogen) supplemented with 10% fetal bovine serum (HyClone brand from Thermo Scientific) and antibiotics (Invitrogen)
  • Ca2+‐free and Mg2+‐free Hanks' Balanced Salt Solution with phenol red indicator (HBSS; Invitrogen)
  • Luciferin substrate (Caliper Life Sciences or Promega)
  • Phosphate‐buffered saline (PBS; Invitrogen, cat. no. 10010)
  • 10% buffered formaldehyde solution (Fisher brand 10% formalin from Fisher Scientific)
  • 10% EDTA solution [100 g EDTA tetrasodium salt (Sigma, cat. no. 03701) in 1 liter distilled H 2O; adjust the pH to 7.4]
  • Surgical adhesive tape (e.g., 3M Micropore Surgical Tape)
  • 70% ethanol gauze (BD Medical)
  • Fine‐point marker pen
  • 1‐ml syringes and needles (27‐G × 1/2 in. long; regular or short bevel; BD Medical)
  • Warming lamp or heating pad
  • In vivo bioluminescence imaging system (e.g., Xenogen IVIS‐200 from Caliper Life Sciences)
  • Isoflurane gas anesthetics system (e.g., XGI‐8 Gas Anesthesia System, Caliper Life Sciences)
  • Nose cone for isoflurane administration
  • Additional reagents and equipment for euthanizing the animals (Donovan and Brown, )
NOTE: Although an intra‐cardiac injection is minimally invasive, animals should be kept in a specific pathogen‐free environment during the entire procedure (e.g., in a designated surgery room or laminar flow hood).NOTE: It is strongly recommended that injection procedures be practiced before the actual experiment. For training purposes, any mouse strain may be used. Visualization of the ribs (by thoracic midline skin incisions) facilitates correct positioning of the injection needle. The needle passes through the third inter‐costal space (i.e., between the third and fourth ribs; note that the first rib is embedded under the clavicle and thus not visible). Instead of mock injection, draw blood and confirm that the blood is drawn from the left ventricle. Left ventricle blood is bright‐red oxygenated arterial blood, as opposed to the darker venous blood of the right ventricle.

Basic Protocol 3: Orthotopic Bone Tumor Model of Metastatic Prostate Cancer

  Materials
  • Male athymic mice, 6 to 12 weeks of age: National Cancer Institute‐Frederick Animal Production Area (NCr nu/nu) or Harlan Laboratories (Hsd athymic nude‐Foxn1nu)
  • Metastatic prostate cancer cells in culture such as PC‐3 (ATCC) (expand the culture to produce at least 2‐4 fold more cells than are necessary for the experiment)
  • Complete cell culture medium (e.g., for PC‐3, RPMI‐1640 medium, Gibco brand purchased from Invitrogen) supplemented with 10% fetal bovine serum and antibiotics (HyClone brand from Thermo Scientific)
  • Ca2+‐free and Mg2+‐free Hanks' balanced salt solution with phenol red indicator (HBSS; Invitrogen)
  • Reference compound (e.g., Imatinib, Novartis)
  • 10% buffered formaldehyde (Fisher brand 10% formalin from Fisher Scientific)
  • 10% EDTA solution [100 g EDTA tetrasodium salt (Sigma, cat. no. 03701) in 1 liter distilled H 2O; adjust the pH to 7.4]
  • Paraffin
  • 70% ethanol gauze (BD Medical)
  • 1‐ml syringes and needles (27‐G × 1/2‐in. long; BD Medical)
  • Small animal X‐ray imaging system (Faxitron)
  • Cotton swabs
  • Warming lamp or heating pad
  • Single‐edged prep razor blade (Fisher Scientific)
  • Additional reagents and equipment for euthanizing the animals (Donovan and Brown, )
NOTE: For more accurate volume injection, Hamilton syringes (e.g., microliter syringe model nos. 702, 705, or 725 with luer‐tip termination) with a regular hypodermic needle (27‐G × 1/2 in.) can be used. Priming the needle with a regular 1‐ml syringe before attaching to the Hamilton syringe will help remove trapped air bubbles.

Basic Protocol 4: Vossicle Model for the Study of Tumor‐Bone Interactions

  Materials
  • Post‐partum day‐4 neonatal transgenic or wild‐type mice
  • 100% ethanol spray
  • Phosphate‐buffered saline (PBS; Invitrogen, cat. no. 10010), strerile
  • Ca2+‐free and Mg2+‐free Hanks' balanced salt solution with phenol red indicator (HBSS; Invitrogen)
  • Host mice: Male athymic mice 6‐ to 12‐weeks‐old [National Cancer Institute‐Frederick Animal Production Area (NCr nu/nu), Harlan Laboratories, and Charles River Laboratories]
  • 10% buffered formaldehyde (Fisher brand 10% Formalin from Fisher Scientific)
  • 10% EDTA solution [100 g EDTA tetrasodium salt (Sigma, cat. no. 03701) in 1 liter distilled H 2O; adjust the pH to 7.4]
  • Surgical equipment including (all from Fisher Scientific):
    • Scissors (e.g., 4½ in. curved iris scissors)
    • Forceps (e.g., 4 in. 1×2 teeth straight iris tissue forceps)
    • Metzenbaum scissors (e.g., curved ¾ in.)
    • Scalpel holder
    • No. 15 surgical blades
  • 60‐mm dishes (BD Falcon), sterile
  • 70% ethanol gauze (BD Medical)
  • Hamilton syringes (e.g., Microliter models no. 75 or 701 with Luer‐tip termination; Hamilton) and regular hypodermic needles (27‐G × ½ in.; BD Medical)
  • Wound‐closing surgical metal clips, stapler, and remover (e.g., AutoClip applier, AutoClip remover, and 9‐mm EZ Clip; BD Medical)
  • In vivo bioluminescence imaging system (e.g., Xenogen IVIS‐200 from Caliper Life Sciences), optional
  • Small animal X‐ray imaging system (Faxitron)
  • Additional reagents and equipment for euthanizing the animals (Donovan and Brown, )
NOTE: Isolated vossicles must be implanted into the host immediately. Properly coordinate the number of donor and recipient animals before starting the experiment (e.g., one donor mouse can produce five to six vossicles, so five recipient mice should be anesthetized while isolating vossicles from a single donor mouse.
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Figures

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Literature Cited

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