Basic Concepts of Cancer. Neoplasia b b Disease of cell growth, division, and differentiation b b...

Basic Concepts of CancerBasic Concepts of Cancer

Neoplasia

Disease of cell growth, division, and differentiation

Benign tumors• Localized, clear margins (encapsulated), non-

invasive, slow growing, well differentiated• Functional adenomas if glandular tissue

Malignant neoplasms

Rapid growth, no clear margins (invasive) Aneuploidy, uncontrolled cellular

multiplication, lytic enzymes Decreased cell adhesion, increased motility

(metastatic) Angiogenesis---abnormal vessels

Classifications of malignancies

Carcinoma--epithelial Sarcoma—CT or muscle Glioma--glial cells Neuroblastoma--neurons Lymphoma Leukemia

Cancer is a genetic disorder, but it is rarely inherited

Epigenetic modifications p53 protein—guardian of the genome

– Errors in p53 show up in ~50% of all cancers– Different mutations seem to prevail in different

cancers Telomerase—prevents normal shortening of

telomeres at end of chromosomes– Absent in most somatic cells, present in 85% of

cancers– Allows for infinite number of divisions

Multi-step Model for Cause of Cancer

One cell suffers multiple genetic mutations, One cell suffers multiple genetic mutations, • Proto-oncogenes induce cell proliferation and Proto-oncogenes induce cell proliferation and

growth (normal function)growth (normal function)– Defined by what happens when turned onDefined by what happens when turned on

• Tumor suppressor genes suppress cell growthTumor suppressor genes suppress cell growth– Defined by what happens when turned offDefined by what happens when turned off

– P53--guardian of genome, halts faulty cycleP53--guardian of genome, halts faulty cycle

Initiation--promotion--progression theory

Initiation is first insult or series of insults to genome

Types of Initiation StepsTypes of Initiation Steps

Changes in proto-oncogenes oncogenes

Point mutations—always dominant (ras gene, telomerase gene)

Gene amplification Chromosomal rearrangement Viral insertion and activation

• human papillomavirus, hepatitis B and C, Epstein Barr (?)

Changes in tumor suppressor genes (p53 is #1 example)

Removes controls on cell cycleRemoves controls on cell cycle Removes review/editing of DNA copying Removes review/editing of DNA copying

mistakesmistakes Typically recessive mutations, so need 2 Typically recessive mutations, so need 2

hitshits

Chemical damage to DNA

Epigenetic modifications, base substitutions Aromatic hydrocarbons, aromatic amines Insecticides, asbestos Anti-neoplastic drugs Aflatoxins Nitrosamines and nitrosamides in food,

water

Physical damage to DNA

Breaks, deletions, translocations Sunlight (ultraviolet) Radiation--therapy or diagnostic use

Predisposing factors

Age, sex, heredity 15-20% of all cancers are caused by

infection(usually viruses) Exposure to DNA damaging compounds Precancerous lesions

• Colon polyps• Metaplastic cells

Promotion = Proliferation

Intracellular antioxidant enzymes should repair damaged DNA

Apoptosis should remove damaged cells Cancers become more malignant with each

generation of transformed cells

Immune surveillance by cytotoxic T cells should remove transformed cells• Tumor associated antigens presented by MHC 1

molecules• Decrease in thymus activity with age means

more cancers in older individuals

Progression--becoming malignant

Rate of growth depends on cell cycle time and rate of angiogenesis

• Epithelial cancers usually grow faster

To metastasize, must separate from original cluster of cells and invade blood or lymph vessel

• Must penetrate basement membrane

• Metastasis is NOT inevitable once penetrate vessels

• First downstream capillary bed and lymph node are most vulnerable

Clinical Manifestations of Cancer

Fatigue is the #1 complaint• Starts early, for unknown reasons• May last months after tumor is gone• Causes most severe decrease in quality of life

Pain—may not arise until late stages• caused by compression local tissue,

inflammation, or nerve injury (therapy)

Cachexia

Malnutrition from metabolic demands of tumor, release of cachectin (TNF)• anorexia, weight loss• weakness, anemia

Additional problemsAdditional problems

60-80% of late stage cancer patients will 60-80% of late stage cancer patients will experience clinical depressionexperience clinical depression

Lack of sleepLack of sleep FearFear

Alterations in carbohydrate metabolism

Tumors metabolize glucose anaerobically• Patient must convert lactate back to pyruvate

for use• Higher than normal insulin suggests post

receptor abnormalities• Metabolic changes persist after tumor removal

TNF will increase insulin resistance in body

Alterations in protein metabolism

Patient loses muscle mass• Resembles situation in burn/sepsis/hyperthyroid

patients• Protein metabolism shifts to support tumor• Acute phase protein response--liver makes proteins for

tumor, not the body– Associated with poor prognosis

Alterations in amino acid levels that persist after tumor removal

Alterations in fat metabolism

Decrease in fat synthesis, increase in lipolysis• Lipid mobilizing factor found in urine• Increases cAMP levels, acts like lipolytic

enzymes• TNF-alpha stimulates lipolysis• High levels of Ω-3 fatty acids may have benefit

Other complications

Increased risk of infection due to leukopenia, therapy

Anemia Bleeding disorders—thrombocytopenia,

vascular invasion, therapy Malnutrition from GI dysfunction

Prognosis

Tumor Grading System—based on microscopic exam of cells by pathologist

• I Well differentiated• II Moderately well differentiated• III Poorly differentiated• IV Undifferentiated

PrognosisPrognosis

Staging the tumorStaging the tumor Stages 1-4Stages 1-4

• Depends on number of sites, involvement of Depends on number of sites, involvement of lymph nodeslymph nodes

• Automatically get Stage 3 if tumor and/or mets Automatically get Stage 3 if tumor and/or mets cross the midline or the diaphragmcross the midline or the diaphragm

Prognosis

TNM Classification System• Tumor 1-4 (based on size)

– Tx—cannot be assessed

– Tis—carcinoma in situ

• Nodes 0-3 • Metastasis 0-1

Etiology of cancer—various cancers have specific progressions