1. Cancer Biology Bob Duronio Gidi Shemer metastatic tumors
Figure Molecular Biology of the Cell (© Garland Science 2008)

2. Cells within a tissue are normally highly organized and tightly regulated.
Cells of a certain type are restricted to proper area
Cell proliferation is tightly controlled

3. Cancer
Cells lose all controls

4. We are Making Progress !

5. US Mortality, 2004 No. of deaths % of all deaths Rank Cause of Death
1. Heart Diseases 652,
2. Cancer ,
3. Cerebrovascular diseases 150,
4. Chronic lower respiratory diseases 121,
5. Accidents (Unintentional injuries) 112,
6. Diabetes mellitus 73,
7. Alzheimer disease ,
Influenza & pneumonia 59,
Nephritis ,
10. Septicemia ,
Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

6. 2007 Estimated US Cancer Deaths*
Men 289,550
Women 270,100
Lung & bronchus 31%
Prostate 9%
Colon & rectum 9%
Pancreas 6%
Leukemia 4%
Liver & intrahepatic 4% bile duct
Esophagus 4%
Urinary bladder 3%
Non-Hodgkin % lymphoma
Kidney 3%
All other sites %
26% Lung & bronchus
15% Breast
10% Colon & rectum
6% Pancreas
6% Ovary
4% Leukemia
3% Non-Hodgkin lymphoma
3% Uterine corpus
2% Brain/ONS
2% Liver & intrahepatic bile duct
23% All other sites
Lung cancer is, by far, the most common fatal cancer in men (31%), followed by prostate (9%), and colon & rectum (9%). In women, lung (26%), breast (15%), and colon & rectum (10%) are the leading sites of cancer death.
The most abundant cancer in male is prostate, the most abundant cancer in women is breast (both= ~33%)
ONS=Other nervous system.
Source: American Cancer Society, 2007.

7. This Lecture properties of cancer cells tumor progression
what causes cancer?
accumulation of mutations
oncogenes and tumor-suppressor genes

8. Cancer: an Aberration of Normal Development
Cancer cells exhibit behaviors found in normal cells during development & differentiation.
However, these behaviors are separated from developmental controls.

9. Most normal cells have a limited potential to divide.
Properties of Cancer Cells
Most normal cells have a limited potential to divide.
senescent cells

10. Normal Stem Cells can Divide Indefinitely, but Under Tight Control

11. Properties of Cancer Cells
Cancer cells are "immortalized”,
just like stem cells, but w/o control.
tumor

12. Normal cells stop proliferating under contact inhibition.
in vitro
in vivo
Figure Molecular Biology of the Cell (© Garland Science 2008)

13. Properties of Cancer Cells
Cancer cells are not under contact inhibition. 2
Figure Molecular Biology of the Cell (© Garland Science 2008)

14. Normal cells form differentiated tissues.

15. Properties of Cancer Cells
Cancer cells do not form differentiated tissues.
tumor

16. Properties of Cancer Cells
Normal cells may undergo apoptosis.
as part of a developmental program.
when cells become “dangerous” (e.g. DNA damage).

17. Properties of Cancer Cells
Cancer cells avoid apoptosis.
blue cells =
breast cancer cells
yellow cells = apoptotic cells
Dave McCarthy and Annie Cavanagh

18. Cancer cells are invasive.
Properties of Cancer Cells
Cancer cells are invasive.
normal tissue
invasive tumor
Figure Molecular Biology of the Cell (© Garland Science 2008)

19. Normal cells can be invasive at the right time and place.
Dave McClay
Seward Hung

20. Properties of Cancer Cells
Cancer cells are "immortalized”.
Cancer cells are not under contact inhibition.
Cancer cells do not form differentiated tissues.
Cancer cells avoid apoptosis.
Cancer cells are invasive.

21. Naming Cancers epithelial cells connective tissue muscle tissue
epithelial cells: carcinoma %
connective tissues: sarcoma 1%
blood and lymphatic systems: lymphoma, leukemia, etc.
neuroectodermal system: neuroblastoma, retinoblastoma, etc.

22. Naming Cancers Prefix Meaning adeno- gland chondro- cartilage
erythro- red blood cell
hemangio- blood vessels
hepato- liver
lipo- fat
lympho- lymphocyte
melano- pigment cell
myelo- bone marrow
myo- muscle
osteo- bone

23. Cancer develops through gradual changes
in cell morphology and properties.
benign tumor
malignant tumor

24. Figure 20-9 Molecular Biology of the Cell (© Garland Science 2008)

25. Tumor Progression tumor = abnormal growth of cells
benign- self contained
malignant- invasive

26. Cancer Cells Induce Angiogenesis
consequences
1. Nutrients and oxygen are supplied to the tumor.
2. New blood vessels provide as easy way out.

27. Metastasis

28. Figure 20-17 Molecular Biology of the Cell (© Garland Science 2008)

30. Cellular Changes Required for Metastasis
Figure Molecular Biology of the Cell (© Garland Science 2008)

31. Molecular Changes Required for Metastasis
Cells need to lose cell-cell adhesion contacts.
Cells need to penetrate through the matrix.

32. Molecular Changes Required for Metastasis
Loss of cadherins is detected in all tumors.
Metastatic cells produce high concentrations of MMPs (matrix-metalloproteinases).

33. Cancer : Accumulation of Mutations
What Causes Cancer?
Cancer : Accumulation of Mutations
random mutations (mistakes at the assembly line)
inherited mutations (pre-disposition)
viral infections
environmental factors (chemical;physical)

34. The first Association Between Occupation and Cancer
Percivall Pott found that chimney sweeps show substantially higher rates of skin cancer.

35. British chimney sweeps didn’t do anything about it.
Danish chimney sweeps : a daily bath after work.
A sad British chimney sweep
Result: significantly lower rates of skin cancer amongst Danish chimney sweeps, compared with British, even a century later.

36. A happy Danish Chimney Sweep
at work
with the family

37. Yamagiwa Took One Step Further
Coal tar condensates induced skin carcinoma in rabbits.
Chemicals can directly induce cancer.
Cancer can be studied in the lab.
Yamagiwa
Figure 2.21b The Biology of Cancer (© Garland Science 2007)

38. Carcinogens = Agents that Contribute to the Formation of a Tumor
Figure 20-20b Molecular Biology of the Cell (© Garland Science 2008)

39. + = Carcinogens are not always mutagens.
Specifically alarming: many of these carcinogens are found in cigarette smoke
In many cases Carcinogens are also mutagens, but there are also other cases. Carcinogens can “help” a cancerous cell without creating a mutation. For example, the risk of getting certain mouth and throat cancers is increase a 100 fold if a person is a serious smoker and consumes distilled alcohols. Ethanol is not a mutagen, but it has toxic effects on the epithelial cells lining the mouth and the throat. The reaction of the body: stimulating proliferation. The problem: if a cell is already mutant and over proliferative, it will be the first to react to this stimulus. As a result, there will be a clonal expansion of this cell and its descendants and more possibilities for one of them to acquire more mutations
Carcinogens are not always mutagens.
100 fold increased risk for head and neck cancers + =

40. A Process of Natural Selection
One Mutation is Not Enough !!
A Process of Natural Selection
Accumulation of mutations

41. Cancer Cells Accumulate Chromosomal Abnormalities
Figure Molecular Biology of the Cell (© Garland Science 2008)

42. The fact that cancer is a multi-step process is reflected in correlation between age and incidence of cancers.
Figure Molecular Biology of the Cell (© Garland Science 2008)

43. A Process of Natural Selection
One Mutation is Not Enough !!
A Process of Natural Selection

44. Cancer at the Molecular Level
Signal transduction moves information from the cell surface to the nucleus
& other cellular targets.

45. What Types of Genes are Mutated in Cancers?
Two Broad Categories
Oncogenes
mutational activation of proteins
Tumor suppressor genes
mutational inactivation of proteins

46. They are similar, but NOT identical.
Oncogenes
proto-oncogene
oncogene
They are similar, but NOT identical.
A proto-oncogene: a normal cellular gene that can become an oncogene, upon DNA damage.

47. An Oncogene Acts in a Dominant Fashion
If oncogenes are dominant,
what is the normal functions of the proto-oncogenes?

48. cellular signaling machinery stuck in the ON State
Oncogenes
cellular signaling machinery stuck in the ON State
one mutated copy = over active protein = over proliferation, over-survival, etc.

49. cell proliferation The c-myc Proto-oncogene is a Transcription Factor.
Normally, c-myc is stimulated by growth factors.
c-myc
c-myc
c-myc
c-myc
c-myc
cell proliferation
Acta Cytologica, 05
Gene amplification turns myc into an oncogene.

50. What Types of Genes are Mutated in Cancers? Two Broad Categories
Oncogenes
mutational activation of proteins
Tumor suppressor genes
mutational inactivation of proteins

51. The good guys become bad guys.
Oncogenes
The good guys become bad guys.
Tumor suppressor genes
We are losing the good guys.

52. dominant
recessive
Figure Molecular Biology of the Cell (© Garland Science 2008)

53. Mutations in p53 can be found in >50% of tumors.
Example
P53: the Master Guardian
Mutations in p53 can be found in >50% of tumors.
Figure 9.8 The Biology of Cancer (© Garland Science 2007)

54. no cell cycle arrest (over-proliferation) angiogenesis no apoptosis
Without 2 copies of P53:
no cell cycle arrest (over-proliferation)
angiogenesis
no apoptosis
no DNA repair (more mutations)

55. How to read a Paper Before We Summarize
for the paper, as well as for each figure
1) What is the question addressed here?
2) How did the researchers address this question?
3) what are the results?
4) what are the conclusions?

56. Summary
Cancer cells exhibit behaviors found in normal cells, but in cancer these behaviors are not under control.
tumor
Cancer develops through gradual changes in cell properties.
Various factors lead to accumulation of DNA damage- cancer.
Oncogenes and tumor-suppressor genes are the molecules behind cancer.