Dental Bio: Cancer Biology

cancer

• uncontrolled growth of cells due to damage to DNA (mutations)

• mutlistep disease- the emergence of a tumor requires the accumulation of many (4-8) genetic changes over the course of years

Cell division

normally homeostasis, the balance between proliferation and programmed cell death is maintained by tightly regulatign both processes to ensure the integrity of organs and tissues

gene mutations

• increase risk for developing cancer can be inherited or acquired

• acquired genetic changes result from spontaneous or environmentally inflicted errors during DNA replication

normal cell

• DNA is replicated properly

• Chemical signals start and stop the cell cycle

• cells communicate with each other so they don’t become overcrowded

cancer cells

• mutations occur in the DNA when it is replicated

• chemical signals that start and stop the cell cycle are ignored

• cells do not communicate with each other and tumors form

characteristics of cancer cells

• resistant to apoptosis

• uncontrolled ability to divide (or immortal)

• self-sufficient with respect to growth factors

• insensitive to antigrowth factors

• have the ability to invade neighboring tissues, usually through secretion of metalloproteins that can digest extracellular matrix. they can from new tumors at distant sites (metastases)

• they secrete chemical signals that stimulate the growth of new blood vessels (angiogenesis)

benign tumor

• grow slowly

• not invase

• well-defined capsule

• well differentiated

• low mitotic index (rate of growth)

• do not metastasize

• **** names hace -oma after them

malignant tumors

• grow rapidly

• not encapsulated

• invasive

• poorly differentiated

• high mitotic index

• can spread distantly (metastasize)

• **** named with -omas after them

lymphomas

lymphatic tissue cancer

leukemia

blood-forming cell cancer

carcinoma in situ

epithelial malignant tumors that have not broken through BM or invaded the surrounding stroma

environmental risk factors

• tobacco

• radiation

• alcohol

• sexual behavior

• diet

• obesity

• occupational hazards

• electromagnetic fields

xenobiotics

• toxic, mutagenic, and carcinogenic chemicals in food

• activated by phase 1 activation enzymes

• defended by phase 2 detoxification enzymes

mutations that lead to cancer

• Virus: HPV → cervical cancer, insertional mutagenesis

• Bacteria: H. pylori -→ gastric cancer (stomach)

• Chemicals: B[a]P → lung cancer, DNA adducts

• UV and ionizing radiation: skin cancer, single and double-strand DNA breaks

inflammation

• important factor in the development of cancer

• Cytokine release from inflammatory cells

• free radicals

• mutation promotion

• decreased response to DNA damage

principles of carcinogenesis

• neoplastic transformation is a progressive process involving multiple hits or genetic changes

• alterations in DNA cause changes in one or more of the following types of genes

  • proto-oncogenes

  • tumor supressor genes

  • genes regulate apoptosis

  • DNA repair genes

normal cell growth

1. any external stimuli leads to stimulation of growth by growth stimulating gene called proto-oncogene

2. this should be stopped by gene which will control the growth called tumor supressor gene

3. any mutated gene will be either repaired by DNA repair gene or killed by gene called apoptosis gene

non-lethal genetic damage that leads to cancer

• loss/damage to supressor genes

• overexpression of promoter genes

• loss/damage to apoptosis genes

• loss/damage of DNA repair genes

oncogene

dominant-acting stimulatory genes that cause cancer

proto-oncogenes

responsible for basic cellular functions in normal cells; when mutated, they become oncogenes

tumor suppressors

• guardian of the genome

• often involved in maintaining genomic integrity

• mutations in tumor suppressor genes lead to the mutator phenotype (mutation rates increase)

• often the 1st mutation in a developing cancer

• either have a damaging or repressive effect on the regulation of the cell cycle or promote apoptosis

• p53, Rb, BRCA-1, BRCA-2

role of p53

1. senses DNA damage

2. induces G1 arrest

3. induces DNA repair process

4. induces apoptosis in cells with unrepairable DNA

5. guardian of the genome

homozygous loss leads to accumulation of damaged DNA may result in malignancy

Rb

1. binds to a protein called E2F1

2. E2F1 initiates the G1/S cell cycle transition

3. When bound, E2F1 cannot function

4. thus it is a crucial cell cycle checkpoint

C-MYC

a major transcription factor that encodes nuclear DNA binding proteins that regulate cell growth, transformation, angiogenesis, cell-cycle control and apoptosis. This could explain the aggressiveness and poor prognosis associates with tumors over expressing these proteins

HER-1

• codes for epidermal growth factor receptor (EGFR), which has extracellular ligand binding domain and cytoplasmic domain with high tyrosine kinase activity

• plays an important role in cell proliferation, migration, and protection against apoptosis

• poor prognosis of breast tumor

• targeted by inhibiting its extracellular ligand binding domain using monoclonal antibodies and/or its tyrosine kinase activity in cytoplasmic domain by tyrosine kinase inhibitors

6 hallmarks of cancer

• self sufficient growth signals: constitutively activated growth factor signaling

• resistance to anti-growth signals: inactivated cell cycle checkpoint

• immortality: inactivated cell death pathway

• resistance to cell death: activated anti-cell death signaling

• sustained angiogenesis: activated VEGF signaling

• invasion and metastasis: loss of cell-to-cell interactions

genomic instability and inflammation of cancer

cancer cells reprogram cellular metabolism and capability to evade immunological destruction (in particular T and B lymphocytes, macrophages, and NK cells)

stages of cancer spread

stage 1: transformation, confined to the organ of origin

stage 2: growth, locally invasive

stage 3: invasion, spread to lymph nodes

stage 4: metastasis, spread to distant sites

signal transduction

how the normal cell cycle is controlled

• growth factors bind to surface receptors on the cell (ex: tyrosine kinase receptors; G protein receptors)

growth factors

1. growth factors stimulate cell division

2. growth inhibiting factors inhibit cell division

healthy cells divide only when growth factor and growth inhibiting factor balance favors cell division; but cancer cells divide without constraint