1. The Multistep Nature of Cancer
Karobi Moitra (Ph.D)
NCI Frederick , NIH
Chapter 11: Cancer Inflammation Program
Multi-Step Tumorigenesis
Human Genetics Section
Frederick MD.
Copyright © Garland Science 2007

4. Clonal Expansion in Cancer
Peter Nowell (1976) hypothesized the clonal evolution of tumors
where a tumor arises initially from 1 specific cell which then develops
a growth advantage over other cells.

6. Multistep Genetic damage leads to Cancer

7. Multistep Genetic damage leads to Cancer

8. Normal cells evolve into cells with increasingly
neoplastic phenotypes through a process called
Tumor Progression

9. Normal to Invasive
Excessive growth Loss of cellular structure Excessive growth Invades
& tissue arrangement in place
Normal Hyperplasia Mild Carcinoma in
dysplasia situ (severe
dysplasia) Cancer
(invasive)

10. Carcinoma-in -situ
PIN = prostate intraepithelial neoplasia
CIN = cervical intraepithelial neoplasia
Leukoplakia = white patches of keratin
(precancerous).
Figure 11.7 The Biology of Cancer (© Garland Science 2007)

11. Phenotype
(observable
characteristics)
of
Multistep nature
Of cancer
Villus
Crypt
Adenoma = tumor of glandular origin
Figure 11.6 The Biology of Cancer (© Garland Science 2007)

12. Genetic changes in Multistep Tumorigenesis
Adenomatous Polyposis Coli (Colon cancer)
Note: DNA hypomethylation means undermethylation, it’s role in cancer
is not clearly understood.
18q TSG = DCC- deleted in colorectal cancer
Figure 11.10 The Biology of Cancer (© Garland Science 2007)

13. Darwinian Evolution and clonal succession:
Natural selection
Growth advantage
Figure 11.12 The Biology of Cancer (© Garland Science 2007)

14. Experimental evidence to support
The Multistep Nature of Cancer

15. Oncogenes collaborate to cause cancer:
Experiment in rat embryo cells
Figure 11.23 The Biology of Cancer (© Garland Science 2007)

16. Table 11.1 The Biology of Cancer (© Garland Science 2007)

17. Oncogenic collaboration
in transgenic mice
Mice were created that either bore
the MMTV-ras(mouse mammary
tumor virus) or MMTV-myc
transgene.Mice were crossbred
to create double transgenic mice
(with both transgenes) and their
tumor free survival followed over
many months.
Figure 11.24a The Biology of Cancer (© Garland Science 2007)

18. Mice carrying both
myc + ras have
less days of tumor-free
survival
T50 = no. of days required for
half of the mice to develop
detectable mammary carcinoma
Figure 11.24b The Biology of Cancer (© Garland Science 2007)

19. The intracellular signaling circuitry and collaboration between cancer-
associated genes
Figure 11.44 The Biology of Cancer (© Garland Science 2007)

20. The process of tumor formation is complex and involves
multiple steps
The complexity of this process is reflected in the long
time periods required for most human cancers to develop
These changes involve both the activation of oncogenes
and the inactivation of tumor suppressor genes