Chemotherapy fails because some cancer cells behave like stem cells 
Inflammation and Cancer
Chronic inflammation is critical for cancer development
– Cytokine release from inflammatory cells
– Free radicals
– Promoting mutation
– Decreased response to DNA damage
*Inflammation generates free radicals (toxic), leads to cancer.
– The continual irritation of cells is what causes the cancer.
– Cytokines can be released, can mediate cancer.
o These cytokines can affect DNA and mutate the chromosomes, oncogenes could be expressed.
Examples:
– Smoking → Chronic bronchitis → lung cancer
– Inflammatory bowel disease (Crohn’s or Ulcerative colitis) → colorectal carcinoma
– Reflux esophagitis → irritation → esophageal carcinoma
– Skin inflammation → melanoma
Immune system and cancer
Normal immune system protects against cancer:
– NK cells mediate natural anticancer protection (immune surveillance)
– Antitumor effect of inflammatory cytokines: TNFα, IL-2,11,12
Immunosuppressive drugs can promote cancer:
– Non-Hodgkin lymphoma (10x)
Immunodeficiency diseases can promote cancer:
– Kaposi sarcoma in AIDS (1000x)
Tumors stimulate inflammatory cells to secrete cytokines that promote their survival
Tumors learn to escape adaptive immunity
– In tumor microenvironment → disable cytotoxic T cells, inhibit then from activation into Killer T (cytotoxic CD8 lymphocyte)
Infection and Cancer
Viruses:
– Hepatitis B and C viruses → Hepatocellular carcinoma
– Epstein-Barr virus (EBV) → Burkitt’s Lymphomas (t8,14)
– Kaposi sarcoma herpes virus (KSHV) → Kaposi sarcoma
– Human papillomavirus (HPV) → cervical cancer
– HTLV virus → adult T-cell leukemia/lymphoma
Bacteria
– Helicobacter pylori → stomach carcinoma, mucosa-associated lymphoid tissue (MALT) lymphoma
– Chronic bacterial cholecystitis → gall bladder cancer
Helminths
– Schistosomiasis → Bladder, liver, rectal cancer
Chemicals and Cancer
Cigarette smoke is the most common world-wide carcinogen:
– Lung (squamous cell carcinoma, adenocarcinoma, small cell carcinoma)
– Larynx /esophagus (squamous cell carcinoma)
– Pancreas (adenocarcinoma)
– Kidney (renal cell carcinoma)
– Bladder (transitional and squamous cell carcinoma)
– Cervix (cervical carcinoma)
Ethanol is associated with:
– Hepatocellular carcinoma
– Squamous cell carcinoma of the esophagus (especially in conjugation with cigarette smoke)
Arsenic; in cigarette smoke is associated with:
– Angiosarcoma of the liver
– Lung cancer
Asbestos; old buildings, is associated with
– Bronchogenic carcinoma and mesothelioma
o Asbestos used to be an insulator. Famous now for causing mesothelioma (pleural tumor).
Cancer Spread
Local spread
Spread of cancer from primary site of origin to a nearby site directly connect with it. They do not leave the organ.
Mechanisms:
– Mechanical pressure
– Release of lytic enzymes – kill tissue around them
– Decreased cell-to-cell adhesion
– Increased motility – they can push through other cells to grow
Cancer Invasion
Metastasis
Spread of cancer from primary site of origin to a distant site (not directly connected with it) 
Steps:
– Direct or continuous extension
– Penetration into lymphatics, BV or body cavities
– Travel via lymph or blood
Only few cancerous cells are required for metastasis. 
Tumor will start growing in a secondary site.
Organ tropism
– Preferential growth of cancer cells in certain organs
o Growth factors, chemokines, hormones and chemotactic factors
o E.g. Bone metastasis in prostate cancer
*Local mass though blood or lymph. No idea where it will end up. They have some preferences though: prostate likes to go to bone, liver likes to go to lung. *
Diagnosis
Tumors can be discovered on:
– Screening
– Routine investigation
– Investigation of symptoms
Diagnosis is based on
– Tumor biopsy and clinical staging
– Tumor markers
– Immunohistochemistry
– Cell phenotyping
– Genetic analysis
Tissue biopsy
Types:
Excisional/incisional biopsy:
– Removal of the entire tumor = excisional
– Removal of small part of tumor = incisional 
Needle biopsy: 
– Fine need aspiration (FNA): removal of fluid and very small pieces of tissue from the tumor
– Core needle biopsy: small cylinder of tissue
Exfoliative cytology:
– Gentle scraping or brushing some cells from the organ or tissue being tested. E.g. Pap smear
Staging
Microscopic analysis
– Stage 0: high grade dysplasia
– Stage 1: local growth (cancer only in the origin site)
– Stage 2: local invasion (cancer that is locally invasive)
– Stage 3: spread to regional structures (regional spread such as lymph nodes)
– Stage 4: distant metastasis (distant spread) 
World Health Organization’s TNM system
– T for tumor spread
– N for node involvement
– M for the presence of distant metastasis 
Clinical manifestations of Cancer
Manifestations are based on site, tumor size, effects:
– Physical pressure/obstruction
– Loss of normal function
– Distant/complex symptoms (paraneoplastic syndrome)
o Due to secretion of bioactive compounds
o Example: pancreatic tumor secreting ACTH → Cushing Syndrome
Manifestations include:
– Pain (from the pressure of the tumor, or psychological fear)
– Fatigue = most common symptom
– Symptoms of cachexia
– Symptoms of anemia, leukopenia, thrombocytopenia
– Infection
– GIT manifestations
– Hair and skin manifestations
– Mass
Pain
Little or no pain in the early stages of malignancy
Influenced by fear, anxiety, sleep loss, fatigue, and overall physical deterioration
Mechanisms
– Pressure
– Obstruction
– Invasion of sensitive structures
– Stretching of visceral surfaces
– Tissue destruction
– Inflammation
Pain leads to fatigue!
Fatigue
Most frequently reported symptom of cancer and cancer treatment
Subjective clinical manifestation
Tiredness, weakness, lack of energy, exhaustion, lethargy, inability to concentrate, depression, sleepiness, and lack of motivation
Suggested causes:
– Sleep disturbances
– Biochemical changes from circulating cytokines secondary to disease and treatment
– Psychosocial factors
– Nutritional factors
Cachexia
Syndrome of cachexia
– A syndrome of progressive weight loss, anorexia, and persistent erosion of body
cell mass in response to a malignant growth.
– Most severe form of malnutrition 
– Seen in 80% of cancer patients at death
– Includes:
o Anorexia, early satiety, weight loss
o Anemia, asthenia, taste alterations
o Altered protein, lipid and carbohydrate metabolism
o *Most of these are from the decreased amount of muscle and fat available.
Anemia
A reduction of hemoglobin/red cell mass in the blood
Mechanism:
– Chronic bleeding resulting in iron deficiency
– Severe malnutrition
– Malignancy in blood-forming organs
o E.g. Bone marrow
– Medication
Leukopenia and thrombocytopenia
Direct tumor invasion of bone marrow is a main cause
Toxic effect of chemotherapy on bone marrow is another
– Chemo affects rapid growing cells (such as bone marrow cells)
Infection
Risk increases when the absolute neutrophil and lymphocyte counts fall
Leading cause of complications in persons with malignant diseases
The advanced malignancies are immunosuppressive, and so are the radiotherapy and chemotherapy options
Gastrointestinal Symptoms
Mostly due to cancer treatment (i.e. chemotherapy and radiation)
Includes:
– Stomatitis (oral ulcers) from decreased cell turnover
– Malabsorption and diarrhea
– Nausea and vomiting
– Patient may need enteral or parenteral nutrition from malabsorption
Hair and Skin
Mostly due to cancer treatment (i.e. chemotherapy and radiation)
– Therapy injures rapid-growing cells of the body including hair and skin
– These are some of the most visible symptoms which can contribute to the psychological effects of the disease
Includes:
– Alopecia (Hair loss)
– Skin erythema, breakdown
Cancer treatment
Chemotherapy
Radiotherapy
Hormonal therapy
Surgery
Chemotherapy
Cytotoxic drugs that target vital cellular machinery or metabolic pathways critical to cell growth and replication
– They target the DNA of cancer cells.
Nonselective
Goal of therapy is to reduce cancer cells so the body’s defence can eradicate the remainder
Single or combination chemotherapy
Regimen:
– Induction: initial, for shrinkage, or disappearance of tumor
– Adjuvant: after surgical removal, to eliminate micro-metastases
– Neo-adjuvant: before surgery or radiation to reduce size. Make it easier for the surgeon
Ionizing radiation
Goals:
– Eradicate cancer without excessive toxicity
– Avoid damage to normal structure
Effect: damage of cancer cell’s DNA
Hormone therapy
Receptor activation or blockage
Interferes with cellular growth and signalling
Example:
– Androgen deprivation therapy (ADT)/castration for prostate cancer
– Anti-estrogens in breast cancer (Breast tissue growth is dependent on estrogen)
Surgery
Prevention of cancer by the removal of pre-cancerous lesions
– E.g. Colon polyps
Removal of cancer mass
Biopsy for diagnosis
Lymph node sampling for staging
Debulking surgery (in huge/invasive cancer mass)
Palliative surgery
Childhood Cancer
Incidence
– Overall, rare but leading cause of death from diseases in children
– In 2004, mortality rate was 2.4% per 100,000 cases
– Survival rates have dramatically improved over past 30 years
– 5-year survival rate is 83% → not too bad
Origin
– Most originate from the mesodermal germ layer
– Mostly sarcomas in kids
– Carcinomas in adults
– Diagnosed during peak growth periods
– Fast growing and without early signs
Childhood Cancer
Incidence
– Overall, rare but leading cause of death from diseases in children
– In 2004, mortality rate was 2.4% per 100,000 cases
– Survival rates have dramatically improved over past 30 years
– 5-year survival rate is 83% → not too bad
Origin
– Most originate from the mesodermal germ layer 
– Mostly sarcomas in kids
– Carcinomas in adults
– Diagnosed during peak growth periods
– Fast growing and without early signs
Common Types
Leukemia
Most common malignancy in children
– E.g. Acute lymphocytic leukemia (ALL)
Children with “Down Syndrome” have a 10-20 X greater risk
– Therefore, always monitor for ALL
Sarcoma
Bone tumors: E.g. Osteosarcoma and Ewing Sarcoma 
– Both bone tumors
Embryonic tumors
Originate during intrauterine life
Immature embryonic tissue unable to mature or differentiate into fully developed cells
Diagnosed early in life, E.g. Glioma (brain cancer), craniopharyngioma (pituitary gland derived tumor)
Other common cancers
Neuroblastoma (nerve tissue cancer – tends to start in adrenal glands)
Wilms tumor (nephroblastoma) = kidney cancer mass 
Rhabdomyosarcoma = muscle cancer
Retinoblastoma = cancer in the retina
Etiology of Childhood Cancers
Genetic factors
– Chromosomal abnormalities
o Aneuploidy, amplifications, deletions, translocations
o Certain congenital syndromes and cancers may occur together
• Urogenital abnormalities and Wilms tumor
• Down syndrome and leukemia
– Oncogenes and tumor-suppressor genes
o E.g. Fanconi anemia
• Autosomal recessive condition that results in impaired DNA repair and child is at risk for development of acute leukemia.
• Can cause:
o Acute myelogenous leukemia, myelodysplastic syndrome, hepatic tumors
o Child will have abnormal number of thumbs, hyperpigmentation, short stature.
Environmental factors
– Prenatal exposure
o Drugs and ionizing radiation
– Childhood exposure
o Second-hand smoke
o Ionizing radiation
o Drugs: anabolic steroids, cytotoxic agents, immunosuppressive agents
o Viral infections: Epstein-Barr virus, AIDS
Prognosis
More than 70% of children tumors can be cured
Survival rates higher in children under 15 years
Younger age more likely to. Be enrolled in clinical trials
Survivors have increased risk of cancer later in life
Residual and long-term effects of treatment
Psychologic sequelae
Cancer Epidemiology
Genetics, Epigenetics, environment in Cancer
Genetics: Heredity, DNA composition
Epigenetics: change in genetic expression (phenotype) without DNA mutation
– Involves factors that silence active genes or activate silent ones
– E.g. DNA methylation
Epigenetic processes can be influenced by environment/lifestyle including in utero
Two-thirds of cancers are caused by environmental/lifestyle factors interacting with genes