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Model Systems in Cancer Biology and Cancer Medicine Folder Title: Models Updated: February 7, 2013 Studying the Basic Biology of "Cancer" Generalizations About "Cancer" Model Systems and Research Objectives • Cell Biology and Cancer Genetic Structure Progression Biochemistry Cell Cycle Regulation • Growth Control, Immortalization, Apoptosis • Immunology and Cancer • Virology and Cancer • Cancer Chemotherapy Cancer Model Systems In Vitro (in Cell, Tissue, or Organ Culture) Normal Cells in Culture • Transformed Cells Chemically Virally By Irradiation Gene Transfection • Neoplastic Cells from Animal Tumors • Neoplastic Cells Cultured from Human Cancers Animal Tumor Models in Vivo Source of the Tumor Challenge Cells • Implanted Cultured Neoplastic Cells • Transplanted from Donor Animals Early vs Later Transplant Generations • Induced in the Tumor-bearing Host Animals Spontaneous (by Genetic Selection) Chemical, Viral, Radiation Induction • Excised from Veterinary Animals Tumor Models (Animal and Plant) in Vivo Host Species Mice (Inbred Strains) Rats, Hamsters, Guinea Pigs Rabbits Fish Cancers in Veterinary Animals Cancers in the Wild Animals Plants Animal Tumor Models in Vivo Routes of Challenge • • • • • • • IP (Intraperitoneal) SC (Sub-cutaneous) IM (Intra-Muscular) ID (Intra-dermal) IV (Intravenous) IT (Intra-thecal) PO (Orally) Animal Models in Cancer Chemotherapy Non-Mammalian Models Mammalian Models: • Mice and Rats • Hamsters • Guinea Pigs Strengths • Genetic and Physiological Relationship to Humans • Immune Response Similarities to Human Responses • Rapid Gestation • Small Body Size • Inbred Genetically Identical and Congenic Strains (congenic means engineered to be immunologically compatible) • Transgenic and Knockout Strains Problems: Ethical and Others (See Limitations in Mammalian Models, Slide 14 Later) Problems with Cultured and Transplanted Animal and Human Tumor Models Genetic drift between cell lines and original host animal; Viral or mycoplasm infection of lines; Line mix-ups; Genetic changes in later generation cell lines; Cell selection in conversion to continuous culture line Clinical Human Cancers as "Model" Systems Advantages: • The Closest "Model" to the Ultimate Goals ...The Best Model for Human Cancer • Patient Feed-back and Cooperation Limitations • Unmatched, genetically unique subjects • Powerful ethical limitations • Patient Independence and Failure to Comply • Prior or Concomitant Treatment Video on Clinical Trials in Patients Human Cancers in Animal Hosts Xenogeneic Tumor Models Immunologically Compromised Recipient Animals • Athymic (Nude) Mice (weak T-cell immune response) • NK Deficient (Beige Mice) • SCID Mice – Severe combined immuno-deficient mice • Immunosuppression by Irradiation or Drug Treatment Immunologically Privileged Sites • Hamster Cheek Pouch • Cornea of the Eye The previous slide shows human tumors growing in SCID Mice. How is it possible that these human tumors will grow in mice when humans and mice are clearly different species? 0 of 102 Comparisons of Two Primary Human Cancers vs these Cancers Propagated as Model Systems Primary excised surgical tumor pieces Cancer Comparisons Surgical specimens after 3 to 6 months growth sub-cutaneously in SCID Mice Prostate and colon cancer cell lines propagated in vitro and implanted into SCID mice Figure 13.8 The Biology of Cancer (© Garland Science 2007) p. 539 On the previous slide showing stained sections from primary excised tumors, tumors carried in SCID Mice, and tumors grown in mice from cell culture transplants What is the message from these comparisons? What is this slide telling us? Use one word or a very concise two or three words. What is the point in one to three words?) 0 of 102 Limitations for Mammalian Models in Cancer Chemotherapy Economic • Acquisition Costs • Cage Charges (Maintenance and Disposal) Technical • Handling (Drug Administration) • Addition and Removal of Therapeutic Agents • Numbers that can be Used • Significant Body Size (20 g for mice) Ethical/Political • Relationship to Humans • Animal Welfare and Animal Rights Concerns Fish Models in Cancer Chemotherapy and In Ultra-sonic Therapy in Cancers In Live Animal Models: Potential Advantages Economic • Very rapid, high volume breeding • Maintenance and Disposal Costs very Low Technical • Drug Administration via Water - Fish Exchange • Ultra-sonic Transmission via Water in an Immersed Target • Sequential Addition of Multiple Agents • Ability to Remove Drug Source • Body Size (0.5 to 2 g) • Digital Photographic Monitoring of External Tumor • Genetics and Inbred Strains well-established • Zebra Danio Genetic Sequence Done Ethical/Political • More readily acceptable Normal Speckled White Xiphophorus Hybrid SpeckledXiHi Dark Pigmentation, No External Tumor Xiphophorus Hybrid DarkXiHi External Malignant Melanoma on Xiphophorus Hybrid XiHiTumor Melanoma in Hybrid Tropical Fish (from Cancer Research, January 1, 1995) NodMel Human Patients as Cancer Models: Glioblastoma Multiforme Duke University Dr. Henry Friedman, 2010 YouTubeFriedman2010.doc http://www.youtube.com/watch?v=n1Z8yMxSf5E Henry Friedman and Glioblastoma Multiforme Video News Item MSNBC, February 9 and 10, 2010: Keith Olbermann on Kyler Van Nocker, Neuroblastoma, and Coverage for Experimental Therapy in Cancer. Played from Flash Drive (45 Megs) Children, Cancer Therapy, and Beads, Syracuse NY, 2011 http://centralny.ynn.com/content/top_stories/537100/a-creative-way-to-cope-with-cancer/ Beads4Cx18Mar11.doc Obesity in the United States and the Future of Disease Incidence, Including Cancer Obesity and Medical Costs, ABSNEWS, Feb. 16, 2011 ObesityABC16Feb11.doc http://abcnews.go.com/WNT/video/obesity-crisis-threatens-health-care-systemamericans-exercise-food-advice-tips-health-12935370
