2. Introduction Cancer has been part of human existence for eons
By 300 B.C., Hippocrates coined the term “cancer” to describe the crablike shape of a tumor invading normal tissue
Cancer has or will affect one in three of us
Diagnosis and treatment are becoming increasingly individualized

3. Introduction Cancer is genetic, but is not usually inherited
Carcinogens are substances that cause cancer
- Most are mutagens (damage DNA)
Cancer is a group of diseases caused by loss of cell cycle control
- If a cell escapes normal control over its division rate, it forms a growth called a tumor 3

4. Figure 18.1 4

5. Introduction
A tumor is benign if it does not spread or “invade” surrounding tissue
A tumor is cancerous or malignant if it infiltrates nearby tissues
Metastasis
- The tumor spreads to other parts of the body via the blood or lymph vessels 5

6. Cancer-Causing Genes Oncogenes - More than 100
- Cause cancer if inappropriately activated
Tumor suppressor genes
- More than 30
- Deletion or inactivation causes cancer
- Cell cycle control/checkpoints
In addition, changes in gene expression accompany cancer 6

7. Cell Cycle Control
Timing, rate, and number of cell divisions depend on:
- Protein growth factors
- Signaling molecules from outside the cell
- Transcription factors within
Checkpoints control the cell cycle
- Ensure that mitotic events occur in the correct sequence 7

8. Cell Cycle Control
Figure 18.2 8

9. Loss of Cell Cycle Control
Many types of cancer result from faulty check points
Cancer sends a cell down a pathway of unrestricted cell division
Cancer cells either lose specializations or never specialize 9

10. Figure 18.3 10

11. Telomeres and Telomerase
Loss of control of telomere length may also contribute to cancer
Telomerase is the enzyme (complex of RNA and protein) that adds telomere sequences to the ends of chromosomes
Normal, specialized cells have telomerase turned off, limits cell division
Cancer cells have to express telomerase to be able to divide indefinitely 11

12. Inherited vs. Sporadic Cancer
Somatic mutations
- Occur sporadically in nonsex cells
- Result from a single dominant mutation or two recessive mutations in the same gene
- Cancer susceptibility not passed on to offspring
Germline mutations
- Cancer susceptibility passed on to offspring
- Usually requires second somatic mutation
- Rarer but strike earlier than sporadic cancers 12

13. Inherited vs. Sporadic Cancer
Figure 18.4 13

14. Origin of Cancer Cancer begins at the genetic and cellular levels
If not halted, cancer spreads through tissues to take over organs and organ systems
The origin and spread of cancer are summarized next 14

15. Figure 18.5 15

16. Characteristics of Cancer Cells
Divide continually (given space and nutrients), and quicker than normal cells
Contain heritable mutations
Transplantable
Dedifferentiated: lose their specialized identity
Have a different appearance
Cell surface has different types and/or number of antigen 16

17. Characteristics of Cancer Cells
Lack contact inhibition
Induce angiogenesis: formation of local blood vessels
Invasive: squeeze into any space available
Metastasize: move to new location in body 17

18. Figure 18.6 18

19. Angiogenesis Nurtures a Tumor
Figure 18.7 19

20. 20

21. Table 18.2

22. Origins of Cancer Cells
Cancer can begin at the cellular level in at least four ways:
- Activation of stem cells that produce cancer cells
- Dedifferentiation
- Increase in proportion of a tissue that consists of stem cells or progenitor cells
- Faulty tissue repair 22

23. Figure 18.8 23

24. Cancer By Loss of Specialization
Specialized cells lose some of their distinguishing features as mutations occur when they divide
Result is dedifferentiation
A biochemical “reversine” may stimulate differentiated cells to divide and produce progenitor cells in mice 24

25. Dedifferentiation Reverses Specialization
Figure 18.9 25

26. Cancers from Shifting Balance of Cell Types in a Tissue
Figure 18.10 26

27. Uncontrolled Tissue Repair May Cause Cancer
Figure 18.11 27

28. Oncogenes
Proto-oncogenes are normal versions of genes that promote cell division
Expression at the wrong time or in the wrong cell type leads to cell division and cancer
Proto-oncogenes are called oncogenes in their mutated form
One copy of an oncogenic mutation is sufficient to promote cell division 28

29. Oncogenes: Overexpression of a Normal Function
Viruses integrated next to a proto-oncogene can cause transcription when the virus is transcribed
Moving a proto-oncogene next to a highly transcribed gene can lead to overexpression of the proto-oncogene
Example: Burkitt lymphoma
- A translocation places a proto-oncogene next to an antibody gene 29

30. Oncogenes: Overexpression of a Normal Function
Chromosome 14
Chromosome 8
Figure 18.12 30

31. Fusion Proteins
Oncogenes are activated when a proto-oncogene moves next to another gene
The gene pair is transcribed together
The double gene product is a fusion protein
- It activates or lifts control of cell division 31

32. Acute Promyelocytic Leukemia
Translocation between chromosomes 15 and 17
Combination of retinoic acid cell surface receptor and an oncogene, myl
Fusion protein functions as a transcription factor
- When overexpressed causes cancer
Some patients respond to retinoid drugs 32

33. Chronic Myelogenous Leukemia (CML)
Most patients have a translocated Philadelphia chromosome (tip of 9 on 22)
Abl (chromosome 9) and bcr (chromosome 22) genes produce a fusion protein
BCR-ABL oncoprotein is a tyrosine kinase that excessively stimulates cell division
Understanding cellular changes allowed development of new drug, Gleevec, for treatment 33

34. Reading 18.1, Figure 2

35. Her-2/neu Product of an oncogene
Excessive levels in approximately 25% of breast cancer patients
Too many receptors
Too many signals to divide
Monoclonal antibody drug, Herceptin, binds to receptors, blocking signal to divide 35

36. Tumor Suppressor Genes
Cancer can be caused by loss of genes that inhibit cell division
Tumor suppressor genes normally stop a cell from dividing
Mutations of both copies of a tumor suppressor gene is usually required to allow cell division
Genes can also be lost by deletion or silenced by promoter hypermethylation 36

37. Retinoblastoma (RB) A rare childhood cancer
The RB gene is on chromosome 13
The RB protein binds transcription factors so that they cannot activate genes that carry out mitosis
- Normally halts the cell cycle at G1
Study of RB was the origin of the “two-hit” hypothesis of cancer causation 37

38. Two-Hit Hypothesis Two mutations or deletions are required
- One in each copy of the RB gene
For sporadic cases (non-inherited)
- Retinoblastoma is a result of two somatic mutations
For familial cases (inherited)
- Individuals harbor one germline mutant allele for the RB gene in each of their cells
- This is followed by a somatic mutation in the normal allele 38

39. p53 The p53 gene is the “guardian of the genome”
Determines if a cell has repaired DNA damage
If damage cannot be repaired, p53 can induce apoptosis
More than 50% of human cancers involve an abnormal p53 gene
Rare inherited mutations in the p53 gene cause a disease called Li-Fraumeni syndrome
- Family members have many different types of cancer at early ages 39

40. Figure 18.13

41. Tumor Suppressor Animation
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42. Breast Cancer Two main forms
- Familial form: A germline mutation is inherited and then a somatic mutation occurs in a breast cell
- Sporadic form: Two somatic mutations affect the same cell
Mutations in many genes can cause cancer 42

43. BRCA
The two major breast-cancer susceptibility genes are BRCA1 and BRCA2
- Encode proteins that join two others to form a complex that allows repair of double-stranded DNA breaks
Mutations in these genes have different incidences in different populations
Inheriting BRCA mutations increases the risk of other types of cancer 43

44. Other Genes
Genes whose protein products affect those of BRCA1, BRCA2, and p53 can cause breast cancer
Example: The ATM gene product adds a phosphate to the CHEK2 gene product, which then adds a phosphate to the BRCA1 protein
- Mutations in ATM and CHEK2 can cause breast cancer 44

45. MicroRNAs Revisited
MicroRNAs normally control the expression of proto-oncogenes and tumor suppressor genes
- Thus, when they are mutated or differentially expressed, cancer can result
Patterns of microRNA expression change as a cancer progresses
- This is being used to develop new, more sensitive ways to diagnose and treat cancer 45

46. Types of Genes Gatekeeper genes
- Directly control mitosis and apoptosis
Caretaker genes
- Control mutation rates and may have an overall effect, when mutant, in destabilizing the genome
Most cancers are the culmination of a series of mutations in several genes 46

47. Familial Adenomatous Polyposis (FAP)
5% of colon cancer cases are inherited
1 in 5000 in U.S. has FAP
Causes multiple polyps at an early age
Several mutations contribute
- APC genes mutate
- Activation of oncogenes (E.g. K-Ras)
- Mutations in TGF, p53, and other genes
- PRL-3 triggers metastasis
- Caretaker genes cause genomic instability 47

48. Figure 18.14 48

49. The Cancer Genome
Several large-scale projects are analyzing genomes of cancer cells
- These allow construction of descriptive “atlases” containing different types of information
Many mutations accompany cancer, but they interact in only a few pathways
- Once a pathway is implicated, scientists can look for or develop drugs to target it 49

50. Table 18.3 50

51. Environmental Causes of Cancer
Environmental factors contribute to cancer by mutating or altering the expression of genes that control the cell cycle, apoptosis, and DNA repair
Inheriting a susceptibility gene places a person farther along the road to cancer
- However, cancer can happen in somatic cells in anyone

52. Environmental Causes of Cancer
Individuals can lower the chance of developing cancer by:
- Avoiding high-risk environmental factors, such as smoking and excess sun exposure
- Taking “chemopreventative” nutrients such as folic acid and vitamin D

53. Cruciferous Vegetables Can Lower Cancer Risk
Figure 18.15

54. Methods to Study Cancer-Environment Links
Population Study: Compares incidence of a type of cancer among different groups of people
Case Control: Identify differences between patients with a type of cancer and healthy individuals matched for multiple characteristics
Prospective Studies: Two or more groups of individuals follow a specific regimen ( e.g., diet or activity plan) and are checked regularly for cancer

55. Figure 18.16

56. Cancer Diagnosis and Treatment
Most often, discovery of cancer follows a screening test
Oldest treatment is surgery, which removes the tumor
Radiation and chemotherapy non-selectively destroy rapidly dividing cells
Other drugs help patients tolerate the side effects 56

57. Cancer Diagnosis and Treatment
New types of cancer drugs:
- Stimulate cells to regain specialized characteristics
- Inhibit telomerase
- Induce apoptosis
- Inhibit angiogenesis
Genomics information is increasingly used
- Enables physicians to better match patient to treatment 57

58. Table 18.6