1

Chapter 19

Cancer

RISK versus BENEFIT

2

OUTLINE• Introduction• Normal Cells• Regulation of Cell Division• Tumor Suppressor Genes and Apoptosis• Normal Cell Characteristics• Cancer Cell Characteristics• Angiogenesis• Metastasis• Causes of Cancer• Diagnosis and Treatment of Cancer

3

Introduction• The study of cancer is called?• Oncology.• The medical specialist for cancer?• Oncologist.• 1/3 Americans will deal with cancer in their

lifetime!• > 50% will survive their cancer.• The critical factor is early detection.• The earlier the cancer is detected, the more

likely it can be effectively treated.• With cancer, FEAR can kill you. . . . .

4

Normal Cells

• With few exceptions, cells within a tissue adhere to one another and are joined by various junctions.

• Chemical signals between cells tell them whether they should be dividing or not dividing.– Stimulatory growth factors.– Inhibitory growth factors.

5

Regulation of Cell Division• Two sets of genes control cell division.

– Proto-oncogenes. Code for transcription factors that control

gene expression. When mutated they become Oncogenes. “tumor genes”, “lump genes”.

– Tumor suppressor genes. Some are transcription factors that control

the expression of proto-oncogenes, while others prevent molecules in the stimulatory pathway from working.

6

Cell Cycle Regulation

7

From the following article:Cancer: Drivers and passengersDaniel A. Haber and Jeff SettlemanNature 446, 145-146(8 March 2007)

                                                                           

8

Tumor Suppressor Genes and Apoptosis

• Certain tumor suppressor genes (TSG) also control the occurrence of apoptosis.

• “Cell death”.– Enzymes that carry out apoptosis are

always present in a cell, but are held in check by inhibitors.

Gene p53 brings about apoptosis when DNA is damaged.

Apoptosis protects the body from cells with abnormal chromosomes or “run away” cell division.

9

Function of p53

10

Replicative Potential

• After cells become fully differentiated they can no longer divide.– Chromosomes in human cells end with

repetitive DNA sequences, telomeres.Telomeres get shorter after each cell

cycle.Cells can undergo 60 – 70 divisions.

11

Normal Cell Characteristics

• Genetically stable.• Differentiate and adhere to other cells.• Respond appropriately to growth signals.• Undergo apoptosis when DNA repair fails.• Undergo a limited number of cell cycles.

12

13

Cancer Cells

• Carcinogenesis - Development of cancer or “cancer beginnings”.

– Cancer is over 100 different diseases………– Cancer (“crab”) is a “genetic disease” requiring

a number of mutations (at least ten), each propelling cells toward tumor development benign, malignant.

Each tumor is composed of cells that are experiencing uncontrolled growth.

Cancer cells are non-specialized and do not contribute to body functioning.

14

Cancer Cell Characteristics

• Genetically unstable.• Not differentiated - Do not adhere to other

cells (no “contact inhibition”).• Insensitive to inhibitory growth signals.• No apoptosis when DNA repair fails.• Unlimited number of cell cycles (immortal).• Induce and sustain angiogenesis.• Invade and metastasize.

15

Cancer Cells

16

Carcinogenesis

• Takes many years because it requires many mutations that occur over time.

• 3 Phases (Steps):

• Initiation.

• Promotion.

• Progression.

17

18

Regulation of Cell Cycle• Approximately 100 oncogenes discovered that can

cause increased cell growth (by producing proteins) and lead to tumors, ie. “gas pedal”.

– Genes “turned on” which should be off / “gain-of-function” mutations.

– Form when mutations occur in proto-oncogenes.– Most frequent are in ras gene family –> ras protein

which causes cells to no longer respond to inhibitory growth factors and grow out of control.

• Tumor suppressor genes undergo mutations.– Approximately half-dozen identified.– Genes “turned off” which should be on / “loss-of-

function” mutations.– Most common in cancer development is p53.

19

Normal Cells

20

Cancer Cells

21

Unlimited Replicative Potential

• Cancer cells have unlimited replicative potential because all division restraints, including apoptosis and telomere shortening (telomerase), have been removed.

• In other words, they are essentially immortal.

22

Angiogenesis• Angiogenesis is the formation of new blood

vessels.– Cancer cells release signals, such as

vascular endothelial growth factor (VEGF), that bind to receptors on the epithelial cells of blood vessels.

New blood vessels branch and send capillaries into the center of a tumor.

Occurs when cell mass is ~1 million cells. Essential to provide oxygen/nutrients, to

remove carbon dioxide/wastes. . . . .

23

Metastasis

• A benign tumor is a disorganized, usually encapsulated, mass that does not invade adjacent tissue.– Malignancy (malignant tumor) is present

when metastasis establishes new tumors distant from the primary tumor.

Due to mutations, cancer cells tend to be motile because they have a disorganized internal cytoskeleton and lack intact actin filament bundles.

24

25

26

27

• Based on what we know about cancer and the processes surrounding it,

• cancer cells might be viewed as normal cells

• which have reverted to their “embryonic state”

• by activation of oncogenes and inactivation of tumor suppressor genes

• and, therefore, demonstrate characteristics normally seen in cells during the early stages of embryonic development which . . .

28

Types of Cancer by Origin:

• Carcinomas (Adenocarcinomas).

• Arise from epithelial cells (glandular epithelial cells).

• Sarcomas.

• Arise from connective / muscle tissue.

• Leukemia and lymphomas.

• Arise from bone marrow (blood cancer) and from lymphatic tissue.

29

The Top 4 Cancers in the United States Population (by death rate):

• #1 - Lung cancer

• #2 – Colon cancer

• #3 – Breast cancer

• #4 – Prostate cancer

30

Causes

and

Prevention of Cancer

31

32

Causes of Cancer• Heredity.

– Certain cancers, such as breast, lung, and colon cancers, run in families.

– Some childhood cancers are inherited as a dominant gene.

– Examples: BRCA1, BRCA2, RB. RET, WT1.• Environmental Carcinogens.

– “cancer generator”, an environmental agent that can trigger cancer, ie. radiation and organic chemicals.

– Mutagen increases chances of DNA mutation.– Carcinogens contribute to cancer development.

33

Causes of Cancer

Radiation. Skin cancers – U.V. radiation in

sunlight and tanning beds. Radon gas can lead to lung cancer. X rays and nuclear radiation.

34

Causes of Cancer

Organic chemicals. Tobacco smoke - contains carcinogens

that can lead to cancers of the lung, mouth, larynx, bladder, kidney, and pancreas.

Foods – rich in saturated fats and low in fiber are correlated with increased cancer rates for the colon, rectum, and prostate.

Pollutants – industrial chemicals, pesticides, and herbicides are mutagenic and can lead to cancer.

35

36

Causes of Cancer

Viruses. Have been linked to liver cancer,

cervical cancer, form of lymphoma, and nasopharyngeal cancer.

Only 6 viruses implicated in human cancer.

Examples: HBV (HCV), HPV, EBV, HIV, KSHV, HTLV.

37

HEALTH FOCUS “Prevention of Cancer”• Protective behaviors……..

• The right diet………

• What vitamins are associated with cancer prevention?

• A and C

38

Diagnosis of Cancer

• Warning Signs.– Change in bowel or bladder habits.– A sore that does not heal.– Unusual bleeding or discharge.– Thickening or lump (in breast/elsewhere).– Indigestion or difficulty swallowing.– Obvious change in wart or mole.– Nagging cough or hoarseness.

39

Routine Screening Tests• Cervical Cancer

– Pap smears– Used since 1938, one of most effective

screens.– New vaccine!?

• Breast Cancer.– Monthly self-exam.– Annual examination by physician.– Mammography.

• Melanoma……………

40

41

Health Focus

Shower Check for Cancer

42

43

44

45

46

Routine Screening Tests• Colon Cancer.

– Digital rectal examination.– Flexible sigmoidoscopy.– Stool occult blood test.– Colonoscopy.– (CEA blood test).

• See Table 19.1 in text, “Recommendations for the Early Detection of Cancer in Average-Risk Asymptomatic People”.

47

Routine Screening Tests

• Tumor Marker Tests.– Blood tests for tumor antigens/antibodies

produced against tumors.– Used to detect first-time cancers and

cancer relapses.– PSA (prostate specific antigen): prostate

cancer.– CEA: colon cancer relapse.– CA-125: ovarian cancer.– AFP: liver cancer.

48

Routine Screening Tests• Genetic Tests.

– Test for genetic mutations in proto-oncogenes and tumor suppressor genes by testing DNA.

– When an individual tests positive for the presence of marker genes. . . . .

– The individual should be vigilant for signs of cancer.

– Examples: ras gene for colon cancer, BRCA1 for breast cancer, RET – thryoid, p16 – melanoma, “microsatellites” – bladder, telomerase.

49

Routine Screening Tests

• Confirming Diagnosis.– Surgery.– Needle biopsies.– Imaging techniques such as CAT scans,

MRI, radioactive scans (using administered radioisotopes), ultrasound.

50

Prognosis

• The predicted outcome of a disease (cancer).

• Depends on:

• (1) Whether the tumor has spread to surrounding tissue.

• (2) Whether there is lymph node involvement.

• (3) Whether distant tumors have begun.

51

Treatment of Cancer

52

Treatment of Cancer• Traditional (Standard) Therapies.

– Surgery when “in situ” (localized).– Radiation (localized).

To kill cancer cells missed by surgery.Radiation should cause cancer cells to

mutate and undergo apoptosis.Cancers of the cervix, early prostate,

larynx, Hodgkin’s disease.– epithelial cells lining systems, hair cells. – Side effects depend on (1) part of body

and (2) amount of radiation.

53

Treatment of Cancer

– Chemotherapy (systemic).Used for “metastatic cancers”.Most chemotherapeutic drugs kill cells

by damaging their DNA or interfering with DNA synthesis.

However, these agents also impact normal, rapidly dividing cells . . . . . .

Epithelial cells lining systems, hair cells.Example: use of Taxol (bark of Pacific

yew tree) – “taxoids” to treat ovarian cancer, breast, head, neck.

Problem: resistance!

54

Treatment of Cancer

– Bone Marrow Transplants.Are used when the patient is to receive

high doses of chemotherapy and radiation in combination.

Is needed to replace the blood-forming tissues destroyed by the treatment.

Autotransplantation involves . . . . Can also be used treat leukemias.

55

Treatment of Cancer

• Future (Newer) Therapies.• Immunotherapy:

– Cancer vaccine therapy – Melacine. (“active”)– Monoclonal antibody therapy. (“passive”)

A type of Immunotherapy. Used to deliver radioactive isotopes or

chemotherapeutic drugs to cancer cells.– p53 gene therapy.

Retroviruses and adenoviruses are used to carry normal genes into cancerous tissues.

56

Treatment of Cancer

– Inhibitory drug therapy.Also called Chemoprevention.Drugs that deactivate the enzymes that

allow metastasis.“Turning off” angiogenesis using

antiangiogenic drugs (ie. angiostatin, endostatin).

Promoting differentiation (promyelocytic leukemia).

Preventing carcinogenesis (Tamoxifen prevents breast cancer).

57

Treatment of Cancer

– Complementary therapy.Due to the insistence of patients, some

institutions are beginning to investigate and make use of alternative therapies.

Homeopathy.Biofeedback.Acupuncture.Exotic foods.Nutrition (foods, vitamins A, C).

58

59

Historical FocusThe Immortal Henrietta

Lacks(See book entitled The Immortal Life of

Henrietta Lacks by Rebecca Skloot)

60