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