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Chapter 11:Multi-Step Tumorigenesis
Copyright © Garland Science 2007
The Multistep Nature of Cancer
Karobi Moitra (Ph.D)Karobi Moitra (Ph.D)NCI Frederick , NIHNCI Frederick , NIHCancer Inflammation ProgramCancer Inflammation ProgramHuman Genetics SectionHuman Genetics SectionFrederick MD.Frederick MD.
Clonal Expansion in Cancer
Peter Nowell (1976) hypothesized the clonal evolution of tumorswhere a tumor arises initially from 1 specific cell which then developsa growth advantage over other cells.
Multistep Genetic damage leads to Cancer
Multistep Genetic damage leads to Cancer
Normal cells evolve into cells with increasinglyneoplastic phenotypes through a process called
Tumor Progression
Normal to Invasive
Milddysplasia
Carcinoma insitu (severedysplasia) Cancer
(invasive)
Normal Hyperplasia
Excessive growth Loss of cellular structure& tissue arrangement
Excessive growth in place
Invades
Figure 11.7 The Biology of Cancer (© Garland Science 2007)
Carcinoma-in -situ
PIN = prostate intraepithelial neoplasiaCIN = cervical intraepithelial neoplasiaLeukoplakia = white patches of keratin(precancerous).
Figure 11.6 The Biology of Cancer (© Garland Science 2007)
Phenotype(observablecharacteristics) ofMultistep natureOf cancer
Crypt
Villus
Adenoma = tumor of glandular origin
Figure 11.10 The Biology of Cancer (© Garland Science 2007)
Genetic changes in Multistep TumorigenesisAdenomatous Polyposis Coli (Colon cancer)
Note: DNA hypomethylation means undermethylation, it’s role in canceris not clearly understood.
18q TSG = DCC- deleted in colorectal cancer
Figure 11.12 The Biology of Cancer (© Garland Science 2007)
Darwinian Evolution and clonal succession:Natural selection
Growth advantage
Experimental evidence to support The Multistep Nature of Cancer
Figure 11.23 The Biology of Cancer (© Garland Science 2007)
Oncogenes collaborate to cause cancer:Experiment in rat embryo cells
Table 11.1 The Biology of Cancer (© Garland Science 2007)
Figure 11.24a The Biology of Cancer (© Garland Science 2007)
Oncogenic collaborationin transgenic mice
Mice were created that either borethe MMTV-ras(mouse mammary
tumor virus) or MMTV-myctransgene.Mice were crossbredto create double transgenic mice(with both transgenes) and theirtumor free survival followed over
many months.
Figure 11.24b The Biology of Cancer (© Garland Science 2007)
Mice carrying bothmyc + ras have less days of tumor-freesurvival
T50 = no. of days required for half of the mice to developdetectable mammary carcinoma
Figure 11.44 The Biology of Cancer (© Garland Science 2007)
The intracellular signaling circuitry and collaboration between cancer-associated genes
The process of tumor formation is complex and involvesmultiple steps
The complexity of this process is reflected in the longtime periods required for most human cancers to develop
These changes involve both the activation of oncogenesand the inactivation of tumor suppressor genes