CHAPTER 10: BIOLOGY OF CANCER

Cancer
- Diseases in which abdominal cells divide without control and are able to invade other tissues.
- Karkinoma – crab, where the name derived from
- Tumor: Neoplasm – new growth
o Neoplasia – proliferation and differentiation of new abnormal cells
o Anaplasia – lack of cell differentiation

Benign vs. Malignant

- Benign:
o Slow growing
o Well defined capsule
o Not invasive
o Well differentiated
o Low mitotic index (measure of how fast it grows)
o Do not metastasize
- Malignant:
o Rapidly growing
o Not encapsulated
o Invasive
o Poorly differentiated
o High mitotic index
o Can spread distantly (metastasis)

Classification and Nomenclature

- Benign tumors
o Suffix “-oma”, named according to the tissue where they arise
 Examples: lipoma, leiomyoma, meningioma
o May progress to cancer
- Malignant tumors
o Named for the tissue where they arise
 Carcinoma – epithelial tissue (light complexion, light eyes, and fair hair)
 Adenocarcinoma – from ductal or glandular tissue (breast cancer)
 Sarcoma – mesenchymal tissue
 Lymphoma – lymphatic tissue
 Leukemia – blood
- Carcinoma in situ (CIS)
o Cancer that has stayed in place and has not spread to neighboring tissues.

Biology of Cancer
- Disease of aging
- Before cancer develops, multiple mutations must happen
- Clonal expansion or proliferation – result of mutation a cell has characteristics that allow it to
have selective advantage over neighboring tissues. (increase growth/decreased apoptosis)

Mutations
- Genetic mutations may cause cancer
 - BRCA1 and BRCA2 linked to increased risk of breast cancer and ovarian cancer.

Transformation of Normal Cells

- Decreased need for growth factors to multiply
- Lack of contact inhibition – invade surrounding tissue or bulk up
- Anchorage independence – get into ducts and spread to other areas
- Immortality
- Normal cells quit growing with they “run into other things/tissues”, Cancer cells do not

8 Hallmarks of Cancer
- Sustaining proliferative signaling
- Evading growth suppressors
- Resisting cell death
- Enabling replicative immortality
- Inducing angiogenesis
- Activating invasion and metastasis
- Reprogramming of energy metabolism
- Evading immune destruction

Sustained Proliferative Signaling

- Proto-oncogenes = normal genes that direct protein synthesis and cellular growth
- Oncogenes = mutant genes
- Tumor-suppressor genes – encode proteins that negatively regulate proliferation. AKA = anti-
oncogenes (do not allow mutations of normal cells)
- Oncogene activation: regulated gene to unregulated.
o Most common genetic cause of cancer
o Point mutations occur due to changes in nucleotide base-pairs
- Translocations: Burkitt Lymphoma, Chronic myeloid leukemia, gene amplification

Genomic Instability
- Increased tendency for genomic mutations during life cycle of the cell = increase rick of cancer
- Caretaker genes – encodes for proteins that are involved in repairing damaged DNA – wont
replicate
- May result from increase silencing or modulation of gene functioning
o Promotor regions of genes altered, leading to their silencing or altered gene expression
- Chromosome instability – increase in malignant cells
o Results in chromosome loss, loss of heterozygosity, and chromosome amplification

Telomeres and Immortality

- Body cells can only divide a limited number of times – not immortal
- Telomeres – protective caps on each chromosome and are held in place by telomerase (enzyme
that blocks cell division and prevents immortality)
o Become smaller and smaller with age and each cell division
o Cancer cells can activate telomerase -> unlimited division and proliferation

Angiogenesis
- Growth of new vessels (arterial and venous)
- Advanced cancers can secrete angiogenic factors (VEGF) (stimulate blood vessel growth)
 o Vascular endothelial GF
o Platelet – derived GF
o Basic fibroblast GF
o Brain tumor is malignant by proxy – it may not be malignant but the position makes it
unable to be removed.

Reprogramming Energy Metabolism

- Warburg Effect – use of glycolysis under normal oxygen conditions (aerobic glycolysis)
o Allows products of glycolysis to be used for rapid cell growth in cancer cells
o Activated by oncogenes and mutant tumor suppressors
o There can be a reverse Warburg effect

Resisting Apoptotic Cell Death

- Apoptosis is programmed cell death – self destruction
- Defects in intrinsic or extrinsic pathways provides resistance to apoptotic cell death

Inflammation and Cancer

- Chronic inflammation: important in development of cancer
o Cytokine release from inflammatory cells
o Patients with chronic inflammation associated with ulcerative colitis have increased risk
of colon cancer
- Helicobacter pylori (80% of people worldwide infected)
o Chronic inflammation associated with: peptic ulcer disease, stomach carcinoma, and
mucosa-associated lymphoid tissue lymphomas
 Ulcerated area can develop cancer cells without going to doctor and just
treating with antacids.
- Tumor-associated macrophage (TAM)
o Key cells that promote tumor survival
o Presence frequently correlates with a worse prognosis
o Mimic m2 phenotype
o Have diminished cytotoxic response
o Develop the capacity to block t-cytotoxic cell and NK cell functions and produce
cytokines that are advantageous for tumor growth and spread

Immune System and Cancer

- Normal immune system protects against cancer
- Immunosuppression fosters cancer
o Non-hogkin lymphoma (10X more likely to develop)
o Kaposi Sarcoma (1000x) – HIV population most likely affected
 Starts with smooth dark area that looks like a birth mark that wasn’t there
before.
o Release of immunosuppressive factors into the tumor microenvironment increases
resistance of the tumor to chemotherapy and radiotherapy (radiation).

Viruses and Cancer

- Implicated
o Hepatitis B and C viruses
o Epstein-Barr virus (EBV)
 o Kaposi sarcoma herpesvirus (KSHV)
o Human papillomavirus (HPV) – spread through sexual conduct; develops into cervical
cancer and cancers in men
o Human T-cell-leukemia-lymphoma virus (HTLV)

Cancer Metastasis
- A process where cancer cells break free from the malignant tumor and travel and invade other
tissues in the body
- Metastasis via lymphatic system and the bloodstream
- Can travel to lungs, bones, liver, brain, and other areas – these are called “secondary cancers” –
arising from the primary tumor
- Direct invasion of contiguous organs (local spread)
o Cellular multiplication (mitotic rate vs cellular death rate)
o Release of lytic enzymes
o Decreased cell to cell adhesion
o Increased motility
- Distant metastases to organs through lymphatic or blood
o Selectivity of different cancers at different sites (breast cancer -> bones; lymphomas ->
spleen)
o The cancers can lie dormant
- Requires great efficiency
- Usually occurs late

Epithelial Mesenchymal Transition (EMT)

- Model for transition to metastatic cancer cells
- Epithelial characteristics lost
o Increase migratory capacity
o Increased resistance to apoptosis
o Dedifferentiated stem cell-like state
 Growth favored in foreign microenvironments

Clinical Manifestations
- Pain
o Early stages – little or no pain
o Influenced by fear, anxiety, sleep loss, fatigue and overall physical deterioration
o Mechanisms:
 Pressure
 Obstruction
 Invasion of sensitive structures
 Stretching of visceral surfaces
 Tissue destruction
 Inflammation/Infection
- Fatigue
o Most frequently reported
o Subjective
o Tiredness, weakness, lack of energy, exhaustion, lethargy, inability to concentrate,
depression, sleepiness, boredom and lack of motivation
 o Causes:
 Sleep disturbance
 Biochemical changes secondary to disease and treatment
 Psychosocial factors
 Decreased level of activity
 Nutritional status
 Environmental factors
- Syndrome of Cachexia
o Most severe form of malnutrition
o Includes anorexia, early satiety, weight loss, anemia, asthenia (weakness), taste
alterations, and altered protein, lipid and carb metabolism
 Increased mortality
 Sarcopenia – the degenerative loss of skeletal muscle mass quality and strength
associated with aging and prolonged illness. Component of frailty syndrome
(keep losing weight, very skinny)
 Major cause appears to be cytokine excess
 May also be testosterone and insulin-like growth factor I deficiency, excess
myostatin and excess glucocorticoids
 Not just a result of cancer but can be a result of numerous other diseases
 Nutritional support and orexigenic (cause to not vomit) factor play a role in the
management of cachexia
- Anemia
o Decrease of hemoglobin
o Mechanisms:
 Chronic bleeding resulting in iron deficiency
 Severe malnutrition
 Medical therapies
 Malignancy in blood-forming organs
- Leukopenia and Thrombocytopenia
o Caused by direct tumor invasion to the bone marrow
o Chemotherapy is also toxic to the bone marrow
- Infection
o Risk increases when the absolute neutrophil and lymphocyte counts fall
- Gastrointestinal
o Oral ulcers caused by decreased cell turnover from chemotherapy and radiation
o Malabsorption
o Diarrhea
o Therapy-induces nausea
- Hair and Skin
o Alopecia from chemotherapy – usually temporary
o Skin breakdown and dryness, also in mouth and eyes

Diagnosis
- Manifestations based on site and tumor size
- Diagnostic testing

Staging
- Microscopic analysis for staging – based on presence of metastasis
 o Stage I – No metastasis
o Stage II – Local invasion
o Stage III – Spread to regional structures and local lymph nodes – will metastasize
o Stage V – Distant metastasis
- World Health Organization’s TNM system
o T for tumor spread
 T – primary tumor
 T0 – breast free of tumor
 T1 – Lesion <2 cm in size
 T2 – Lesion 2-5 cm in size
 T3 – Skin and/or chest well involved by invasion
o N for node involvement
 N – Lymph node involvement
 N0 – No axillary nodes involved
 N1 – Mobile nodes involved
 N2 – Fixed nodes involved
o M for presence of distant metastasis
 M – Extent of distant metastasis
 M0 – No metastasis
 M1 – Demonstrates metastasis
 M2 – Suspected metastasis

Tumor Markers
- Tumor cell markers (biological) are substances produced by cancer cells that are found on or in
tumor cells, in the blood, CSF, or urine
o Hormones
o Enzymes
o Genes
o Antigens
o Antibodies
- Tumor markers are used to:
o Screen and identify individuals at high risk for cancer
o Diagnose specific types of tumors
o Observe clinical course of cancer (no marker -> no cancer/remission; can have false
negative and positives)

Histology
- Tumors are classified based on immunohistochemical analysis of protein expression for
improved treatment
o Supplemented by more extensive genetic analysis of tumors
o Enhanced molecular characterization subdivides cancers into therapeutically and
prognostically relevant smaller groups (breast cancer)

Cancer Treatment
- Surgery
o To prevent cancer (colon polyps)
o Biopsy for diagnosis and staging
o Lymph node sampling
 o Palliative Surgery (to provide comfort)
- Radiation
o Goal: Eradicate cancer without excessive toxicity and to avoid damage to normal
structures
o Ionizing radiation damages the cancer cell’s DNA
o Also may cause problems in surrounding tissues
- Chemotherapy
o Takes advantage of specific vulnerabilities in target cancer cells
o Usually given in combinations designed to attack a cancer from many different
weaknesses at the same time
o Types of Chemotherapy:
 Induction – for shrinkage or disappearance of tumors
 Adjuvant – Eliminate micrometastasis after surgery
 Neoadjuvant – given before localized treatment (surgery) to shrink tumor
- Immunotherapy
o Vaccines against oncogenic viruses provide protection and prevent the onset of viral-
induced tumors
o Numerous potential therapeutic vaccines have been tested with little success
o Allogeneic cancer cell vaccines continue to be tested
- Targeted disruption
o Used in combination with chemotherapy
o Highly specific
 Inactivate oncogenes
 Block angiogenesis
 Affect cell metabolism
 Induce apoptosis
 Neutralize cytokines/chemokines

CHAPTER 11: CANCER EPIDEMIOLOGY

Genetics, Epigenetics and Tissue

- Environmental-lifestyle factors and genetic factors cause cancer
- Patterns of cancer are environmental, not genetic
o Genetic alterations and abnormalities drive cancer at the cell level
o Factors influenced by the greater external environment

Incidence Trends
- Major cause of morbidity and mortality worldwide
- In the US, incidence is decreasing
- Prostate cancer and breast cancer are the most frequently diagnosed

Mortality Trends
- Death rates are decreasing for children
- Death rates for adults are decreasing in 7 of the top 15 cancer types
o Most common cancers in US
 Breast, prostate, lung, colon, bladder, melanoma, non-hogdkins, lymphoma,
thyroid, kidney, leukemia, pancreatic, and endometrial
 - Death rates increasing for cancers of pancreas, liver and uterus and for melanoma of the skin in
men.

In Utero and Early Life Conditions

- Development plasticity – degree to which an organism’s development is contingent on its
environment
o Histone modification and micro-RNAs
- Studies
o Dutch Famine Birth Cohort
o Diethylstilbestrol (DES)
- Evidence for DNA methylation marks, in utero environments, and future phenotypes is growing

Environmental-Lifestyle Factors
- Tobacco – the most important environmental risk factor for cancer
o Causes squamous and small cell adenocarcinomas
o Leading cause of preventable death in the US
o Multipotent carcinogenic mixture
o Linked to cancers of the lung, lower respiratory tract and upper aerodigestive tract,
liver, kidney, pancreas, cervix, uterus
o Linked to myeloid leukemia
o Secondhand smoke (ETS) contains many toxic chemicals
o Cigars and pipe smoking are equally harmful
- Diet
o Cooking of fat, meat or protein produces carcinogenic substances
o Meat cooked rare offers less carcinogenic substances but may lead to other issues
o Naturally occurring carcinogens associated with alkaloids or mold byproducts (like blue
cheese)
- Nutrigenomics
o Study of nutrition on the phenotypic variability of individuals based on genomic
differences

Nutrition and Cancer

- Many cellular processes affected by nutrition
- May directly influence silencing of genes that should be active or activating genes that should be
silent
- May alter hormonal axes, influence cellular proliferation, and affect phenotypes or expression of
key genes
- Xenobiotics
o Toxic, mutagenic, and carcinogenic chemicals in food
o Two defense system for countering effects:
 Phase I activation
 Phase II detoxification enzymes
o US works to keep this out of our food
- Dietary components can be activated into carcinogens or can prevent cancer
- Pathways to cancer affected by diet include:
o Cell cycle control
o Differentiation
o DNA repair
 o Gene silencing
o Inflammation
o Apoptosis
o Carcinogen metabolism

Obesity
- Correlates with body mass index (BMI)
- Three factors related to obesity and cancer:
o Insulin-IGF-1 axis
o Sex hormones
o Adipokines or adipocyte-derived cytokines
o Mechanism or obesity-associated cancer risks unclear

Alcohol Consumption
- Risk factor for oral cavity, pharynx, larynx, esophagus, liver, colorectum, and breast cancers
- Genetic factors involved
- No “safe limit” of intake
- Combination of alcohol and smoking greatly increased the risk of various cancers

Physical Activity
- Reduces cancer risk (breast and colon)
o Decreases insulin and insulin-like growth factors
o Decreases obesity
o Decreases inflammatory mediators and free radicals
o Increased gut motility

Ionizing Radiation
- Emission from x-rays, radioisotopes, radon, and other radioactive sources
- Exposure causes cell death, gene mutations and chromosome aberrations
- Mutations in germ cells are heritable
- Increased use of diagnostic testing of concern

Radiation-Induced Cancer
- Targeted effects:
o Chromosome aberrations, cell transformation, gene expression, alternative targets,
mutagenesis, in somatic cells, the biologic effects that occur in nonirradiated cells and
the effects on the microenvironment
- Nontargeted effects:
o Bystander effects
o Genomic instability
- Acute, latent and microenvironmental effects
o Organs with highly proliferative cells, especially affected by acute radiation exposure
 Nontargeted radiation effects alter cell and tissue signaling
 Microenvironment changes
o Radiation-induced cancer has latent periods
 Usually 5-10 years
Ultraviolet Radiation
- Causes basal cell carcinoma, squamous cell carcinoma and melanoma (increased incidence)
- Principal source is sunlight
- Ultraviolet A (UVA) and ultraviolet B (UVB)
- Released TNF-alpha in epidermis
- Produces ROS
- Promotes skin inflammation and release of free radicals

Electromagnetic Radiation (EMR)

- Non-ionizing, low frequency radiation
- Microwaves, radar, cell phones and power frequency radiation, associated with electricity and
radio waves, fluorescent lights, computers, and other electronic equipment
- May or may not be carcinogenic

Infection, Sexual and Reproductive Behavior

- Top cancer-causing infections
o Human Pallipomavirus (HPV)
 Most common STD in US
 50% of sexually active population
 Spread through skin contact, oral, vaginal or rectal sex
 150 related viruses
o Low risk – doesn’t cause cancer
o High risk – can cause cancer
 Causes SIX types of cancer
o Cervix
o Penis
o Vulva
o Anus
o Oropharynx (tongue and tonsils)
o Heliobacter pylori (75-89% of all stomach cancers)
o Hepatitis B (HBV)
o Hepatitis C (HCV)
o HBV and HCV account for a large majority of liver cancers

Air Pollution
- Particulate Matter – particles and liquid droplets made up of acids, organic chemicals, metal and
dust particles
o Carcinogenic and causes lung cancer
o High proportion of mutagenic factors
o Primary particles – emitted directly from source (construction sites, smoke, stacks)
o Secondary particles – emitted from power plants, industries and automobiles
- Indoor Pollution
o Generally worse than outdoor pollution
o Tobacco smoke (passive) causes formation of reactive oxygen free radicals and thus
DNA damage
o Radon gas trapped in houses forms decay products that are carcinogenic.
 Radon gas combined with cigarette smoke creates indoor pollution that is
considered worse than outdoor pollution
 o Exposures from heating and cooking sources and asbestos
o Inorganic arsenic

Chemical and Occupational Hazards

- Present in air, soil, water, household products, toys, workplaces, and homes
- Upper respiratory passages, lung, bladder, peritoneum
- Substantial number of occupational hazards consist of carcinogenic agents
o Asbestos (mesothelioma and lung cancer)
o Dyes, rubber, paint, explosives, rubber cement, heavy metals, air pollution, etc.