Cancer

by

Dr. Roland Lamarine

Vera PavlovaIf there is something to desire

If there is something to desire, there will be something to regret.

If there is something to regret, there will be something to recall.

If there is something to recall, there will be nothing to regret.

If there is nothing to regret, there will be nothing to desire.

Kareem Abdul Jabbar, 2008chronic myelogenous leukemia (CML)

WBCs gone wild

1998 survival time @ 2-10 years

Today, a normal life span

“Targeted therapy”: find out what’s wrong inside the cell & cure it

CML makes a new fusion protein; Gleevic (molecular medicine)inhibits this protein

Kaplan-Meier Survival Graph:

Survival % x time

Cancer Rates 2014 Incidence rates

1. Breast 235,0002. Prostate 233,0003. Lung 224,0004. Colorectal 143,0005. Urinary system 141,000

TOTAL 1.7 million Mortality rates

1. Lung 159,0002. Colorectal 50,0003. Pancreas 46,0004. Breast 40,0005. Prostate 29,000

TOTAL 586,000 (ACS: Cancer Facts & Figures 2014)

MOST COMMON CANCERS

MALES

prostate, lung, colorectal

FEMALES

breast, lung, colorectal

13.5 million Americans have malignant cancer

CHANGES IN LIFE EXPECTANCY

Child born in 1960 life expectancy 70 years

2000 77 years

4.9 years from advances in heart disease

0.2 years cancer

A colony of cells which (1) grows in a disordered manner, (2) is invasive, and (3) can metastasize

Before 1900, cancer a rare diseaseCancer a disease of older people23 December 1971, President Nixon, National

Cancer Control Act: the “war on cancer” 1:3 Americans will get cancer

1:4 will die of cancer

CANCER

Cancer Cell Properties

1. Lose all growth constraints-no contact

inhibition; abnormal organization

2. Altered cytoskeletons, so can move

3. Altered cell communication: holes in cell

membranes for rapid communication

4. Ability to spread to distant parts of the

body via blood & lymph (metastasis)

More Cancer Properties

5. Angiogenesis: recruit blood supply (Dr. Judah Folkman, anti-angiogenesis drugs)

6. Undifferentiated cells

7. Clonal: tumors identical cells, but evolve differently over time (mutate)

8. Divide without normal constraints

9. Cancer cells immortal: telomeres do

not shorten, no apoptosis

DNA: deoxyribonucleic acid: genetic material ; a sequence of

nucleotides: adenine, thymine, cytosine, guanine (A-T, C-G)

GENE: unit of hereditary information encoded in DNA

GENOME: complete sequence of DNA (all humans share 99% of genome; 1%

difference are mutations

CHROMOSOMES: sets of genes in 23 volumes, one from each parent

MUTATION: alteration (permanent) in DNA sequence; a single mutation does not

cause cancer; most spontaneous mutations are repaired; 3 billion bases, every

day 16,000 mutated

CARCINOGEN: substance that causes cancer, a specific type of mutagen

TUMOR SUPPRESSOR GENES: slow down cancer (P53) {brakes}

ONCOGENE: gene that can cause/accelerate cancer, found in viruses e.g. MYC &

RAS; 50% of cancers have an activated RAS

PROTO-ONCOGENE: gene that can cause cancer if initiated; found in the

normal human genome

ONCOGENE FUNCTIONS

1. Control gene expression (accelerators)

2. Control cell signaling

3. Control cell death (apoptosis); e.g. by blocking programmed WBC death, mutations run wild and leukemias form

NORMAL CELL

1. cells store information in genes

2. every cell in your body has the same information

3. the use of this information is strictly regulated both by cell type and by interaction with the environment (epigenetics)

Epigenetics: change expression of DNA. In cancer DNA methylation (CH3) can turn genes off e.g. tumor suppressor genes leading to cancer

CANCER IS A MULTI-STEP DISEASE

1. Inactivation of tumor suppresors

2. Activation of oncogenes

3. Metastasis

4. Angiogenesis

Promoters are regions on DNA where copying to RNA occurs; can make things faster or slower, a switch; each gene has its own promoter; a protein called a repressor can bind to it & turn off transcription OR an activator can turn on transcription of RNA

DNA RNA proteins (amino acids)

transcription translation

HEREDITY

@ 10% of cancers are hereditary/familial(90% are sporadic)

Retinoblastoma: 40% inherited

Inherit 2 alleles for tumor suppressor genes

Dr. Knudson’s “2 Hit Hypothesis” for cancer

In familial retinoblastoma, child born with one mutant allele & then other mutates

In sporadic retinoblastoma, 2 mutations needed to get cancer

Criteria for Heredity

1. More than two first degree relatives with same rare cancer

2. Multiple tumors in one organ

3. Young age at diagnosis

Most cancers caused by multiple genes

Colon: 98% from polyps, 5% hereditary, 95% sporadic; stomach: 10% hereditary e.g. Napoleon: father, 3 sisters, brother, grandmother all had it

Hereditary Breast Cancers

Multiple tumors, both breasts, early onset, relatives with it

1st degree relatives RR

0 1.0

1 1.8

2 2.9

3+ 3.9

Breast Cancer

Age no mutant allele 1 mutant allele

40 .005 0.16

50 .02 0.59

60 .04 0.77

70 .08 (1 in 12) 0.84 (5 in 6)

(1.0 means 100% have it; .02 = 2%)

VIRUSES

@ 10% of cancers are viral in origin

viruses: DNA+ RNA, Peyton Rous, sarcoma in chickens, 1910,

Nobel prize in 1966

EBV (Epstein-Barr) mononucleosis, nasopharyngeal cancer, Burkitt’s lymphoma if malaria and chromosomal translocation also present (Dennis Burkitt & Hugh Trowell-Bantus, Uganda)

HBV (hepatitis B virus) & aflatoxin in Africa & Asia RR 250 for hepatocarcinoma (liver cancer )

HPV (human papilloma virus) venereal warts and cervical cancer when HPV DNA spliced into host cell; 40% university students carry HPV but few get cancer; vaccines available

(Monkey kidney cells used for Salk (1955) polio vaccine had SV40; many of us have antibodies for it!)

Poverty & Cancer

Poor countries consume moist grains aflatoxin G to T mutations + then HBV

infection stimulates cell division

liver cancer

China, one million new cases of liver cancer each year

ENVIRONMENTAL CAUSES

Percival Potts, 1775, chimney sweeps & scrotal cancer

Major causes of cancer: tobacco & diet

Twenty year lag time to lung cancer/RR15+

RR for passive smokers: 1.3-1.4

Obesity & cancer: BMI >35 RR 2.1 for breast, 1.6 colorectal, 1.3 prostateFruit & veggies, no effect on cancer (Epic Study)

Diet & CancerDietary fat may not cause breast but probably contributes to colorectal cancers

Aflatoxins, from fungal infections of peanuts etc. Binds to DNA during replication and changes guanine to adenine (a mutation).

Nitrous acid from salted fish, adenine binds to cytosine (normally A-T & C-G)

Tobacco Smoke

Ernst Wynder & Gerd Pfeifer: 3500 chemicals, 60 carcinogens, benzpyrene, like aflatoxin, it binds to guanine in DNA, interfering with P53. This discovery broke the back of tobacco company claims that tobacco was not carcinogenic. Then Big Tobacco made huge settlement with State Attorneys General for billions $

CAUSES OF CANCER DEATHSEnvironmental (80%)

SmokingNutritionInactivityObesity

Viruses (10%)(HBV, HPV, HIV, H. pylori: RR 2-8 for stomach cancer)

Heredity (10%)

78% diagnosed with cancer are 55 or older

Males 1:2 lifetime riskFemales 1:3 lifetime risk

<10 % cancers strongly hereditary (faulty genes)rest due to damage to genes acquired during lifetime

1.7 million new cancers/year

Cancer Causes & Types

Coal tar scrotal cancer Aflatoxin liver cancer Vinyl chloride liver Industrial dyes bladder Cigarettes lung, bladder, kidney Hormones uterine Ultraviolet skin X-radiation thyroid, skin, leukemia

SYNERGISTIC EFFECTS

CONDITION LUNG CANCER MORTALITY

No asbestosNon-smoker 1.0

AsbestosNon-smoker 5.0

No asbestosSmoker 12.0

AsbestosSmoker 53.0(1 pack/day)

2+ packs) 90.0

SKIN CANCER

2 kinds: lethal + disfiguring

Disfiguring = basal-cell carcinoma + squamous-cell carcinoma

Lethal = malignant melanoma (8800 deaths, 2011)

Over one million cases of non-melanoma skin cancer/year

Skin cancer incidence increasing due to:

1 popularity of sun tans over last 50 years

2 ozone depletion + stronger UV exposure

3 tanning booths & type A UV light

(type B causes burns but A penetrates deeper causing more long-term damage)

SKIN TUMORS

Basal cell carcinoma: deepest layer of the epidermis; accounts for 80% of all skin cancers (@800,000/yr)

Squamous cell carcinoma: upper layer of cells; more aggressive, 16% (200,000) {sometimes preceded by actinic keratinosis}

Malignant melanoma: malignant pigmented skin tumor (>60,000/yr)

Early Warning Signs: Malignant Melanoma

A. Asymmetry

B. Borders irregular

C. Colors varied

D. Diameter larger (>6 mm @1/4 inch)

SKIN CANCER RISK FACTORS1. Are you male? (no breast, so more sun)

2. Are you white? (10X higher than blacks)

3. Do you have red hair?

4. Do you have a family history of skin cancer?

5. Did you ever have a bad sunburn as a child?

6. Have you ever used a tanning bed? (only one time is enough)

7. Are you a current or former smoker? (one pack/day triples your risk)

8. Do you live at a high altitude? (thinner air = more UV)

9. Do you have freckles or a lot of moles?* (>50)

10. Does your job require you to work outside?*more than 50 moles = “a lot”

Two Requirements for Screening

1. Is there a recognized premalignant stage?

2. Does early detection improve the outcome?

Best cancers for screening:

--have a high incidence

--a long preclinical phase

--test easily done & modest cost

Reliability & Validity of Screening Tests

Reliability: is the test consistent?

Validity: is the test accurate? includes:

Sensitivity: proportion of people with the disease who test positive (rest are false - worst case scenario)

Specificity: proportion of people without the disease who test negative (rest are false + added expense, risk, worry)

Screening Tests

sensitivity specificity

Pap 95% (5% false-) 95% (5% false +)

Mamgram 80-90% >95%

Medical exam 60% 95%

BSE* 21% (79% F-) 30%(70% F+)

Colon >95% 100%

PSA* 80%(20%F-) 33% (67% F+)

Fecal 60% 80%* Not recommended

CANCER SCREENING

Colonoscopy (age 50-75) ++ Fecal occult blood (50) + Digital rectal exam (50) ++ (55%/80%) Prostate specific antigen - (50) Breast self-exam (20) -- Mammography (40? 50?) ++

(ACS vs. U.S. Preventive Services Task

Force [USPSTF])

Cancer screening caveats

U.S. Prevention Task Force recs:no BSEmammograms every 2 years, 50-74

“lead time bias”“IF you have a positive mammogram, how likely is it that you have cancer?”

“10%” have cancer

More screening caveats

Mammography 90% accurate in spotting those who have cancer (test sensitivity)

93% accurate for those who don’t have cancer (specificity)

Prevalence of breast cancer among women getting mammography = 0.8%

Out of every 1000 women screened:8 have cancer7/8 are true positives1/8 false negative992 don’t have but 922 true negatives70 false positives

After 3 mammograms: 18% women have one false positive After 10 mammograms: 49% of women have one false positive If 1000 women screened for 10 years starting at age 50: 1 life saved (other true positives over-diagnosed & treated needlessly Better to screen high risk women

TNM STAGING METHOD

T: extent of primary tumor N: regional lymph nodes M: metastases

Stage I: early; no spread Stage IV: advanced; widely spread

CANCER TREATMENT

Surgery: Wm Halstead, a legend; in1983 90% of breast surgeries were radical mastectomies, by 2000, 70%lumpectomies

Chemotherapy: first one was mustard gas to reduce WBCs; Barre, Italy 1943

Radiotherapy: cancer cells divide faster, so more damage; pancreas & brain highly susceptible to damage, breast (BRCA1) & kidney much less susceptible

SURGERY

Pros:

--no tumor resistance

--doesn’t cause cancers

--treats heterogeneous cancers

--curative if localized

Cons:

--damages normal tissue (e.g. brain)

--does not treat metastases

RADIOTHERAPY

100 rads = 1 gray; lifetime exposure .16 gy

Radiation Rx = @ 60 grays

Therapeutic Index: ratio of damage to normal cells vs. damage to tumor cells

At 21Gy 99.9% tumor cells killed but 93% normal cells killed

Dose fractionation: smaller doses of radiation over longer time periods (@5 wks).

Normal cells recover, cancer cells die

Chemotherapy Effectiveness

1. Tumor sensitivity to chemo, tumor already mutated so easier to induce apoptosis, new proteins can be targeted, high rate of cell division, poor DNA repair

2. Pharmacology of the agent

3. Clinical condition of patient & tolerance for side effects

Cancer Drugs & Therapies

Stop cells from dividing (cytostatic) Make cells go into apoptosis (cytotoxic) Also, self-vaccination vs. cancer: e.g. WBCs

stocked with special protein-immune stimulant & organ specific protein causing immune system to attack, say, prostate cells in metastasis

Treatment Outcomes

Remission: no tumor cells after 5 years

Cure: no tumor cells after 10 years

Control: tumor still there but no longer growing

(Chemotherapy usually drug combos due to tumor heterogeneity)

PREVENTIONWhat we know so far

fruit, veggies, phytoestrogens—no effect

Vit. A/beta carotene & obesity cause cancer

SPF 16+ prevents 95% UV & skin cancer

Vaccines—HBV, HPV prevent cancer

Anti-inflammatory drugs: aspirin may block

cell division

Curcumin (tumeric), silibinin (milk thistle), catechins (green tea), lycopenes (tomato), theophyline may be chemopreventive

THE FUTURE IN CANCER

Gene therapy:

1. mutation compensation: add good P53 gene using virus vector

2. RNA interference: small RNAs to block RNA expression in mice

3. Tumor-specific viruses: man-made viruses that work only in tumor cells

References

What Science Knows About Cancer

by David Sadava

The Dread Disease

by James T. Patterson

Disease: The extraordinary stories behind…

by Mary Dobson