HD Exam3 Cancer.txt

• Tissue
• of origin + suffix

Benign => -oma

Malignant => -sarcoma, -carcinoma, -blastoma

Initiation -> promotion -> progression

• (CURRV = curve)
• Chemical carcinogens
• Unknown factors
• Radiation (UV Light)
• Replication errors
• Viruses

• (Shin)
• Specific promotors
• Hormones
• Inflammation
• Normal growth promoters, etc.

• Hormones - therapeutic or physiological
• Age, surgery, radiation, etc
• Normal growth inhibitors

• –Initial permanent change, usually
• in DNA
• –Initiated cells are latent
• -not yet a tumor

• –Preferential growth stimulation
• of initiated cell into clone of cells (clonal expansion)
• –Can be reversed (i.e. loss of growth factors, stimulating agents, etc)

• –Tumors are heterogeneous
• –Selection pressure generates
• cells with increased malignant potential

Abnormal tissue mass whose growth exceeds and is uncoordinated with that of normal adjacent tissue (i.e. malignant tumors)

• •Cancer is a group of diseases
• characterized by
• –disordered growth control
• –acquisition of invasion and metastatic potential

• •Absent or minimal regulation of cell growth
• –distinguishes cancer from other modulations of growth (i.e. may have high proliferation but regulated)
• –difficult to establish cause and effect in carcinogenesis
• –treatment cannot target the instigating agent but instead must target the mass of cells

Cancer arises from the accumulation of genetic changes, not just a singular mutation

• loss of differentiated features
• Higher degree of anaplasia = Worse prognosis

• (dig 'm)
• Differentiation state
• local Invasion
• rate of Growth
• Metastasis

• •Slow growing
• •Well differentiated (looks more like parenchymal cells)
• •Localized
• •Innocuous
• •Capsulated (surrounded by fibrous membrane)

• •Rapid growth (increased metabolic activity)
• •Wide range of differentiation
• •Invades and metastasizes
• •Distinct cellular phenotype

• (SIT, LSE i.e. sit, Elsie)
• •Self sufficiency in growth
• signals

• •Insensitivity to growth
• inhibitory signals
• •Tissue invasion and metastasis
• •Limitless replicative potential
• -Sustained angiogenesis

•Evasion of apoptosis

• •Organ Failure
• –Tremendous reserve capacity
• –Occurs only once tumor is far advanced
• •Obstruction
• –GI tract, hollow organs
• •Others like cachexia and
• infection
• –Wasting syndrome
• –Impair immune defenses leading to pneumonia, septicemia, etc
• -main cause of death

• –Identification of risk factors
• –Development of prevention strategies
• –Assessment of public health policies
• (i.e. asbestos, sg warning of cigarettes)

• Number of cases:
• Men: Prostate, Lung
• Women: Breast, Lung

• Deaths:
• Men: Lung, Prostate
• Women: Lung, Breast

Differs with cancers, but 65% from environmental factors (tobacco, diet), 35% from genetic factors

• •Descriptive studies:
• –data on incidence, mortality, risk
• •Correlation studies:
• –comparisons of populations with different exposures
• •Special exposure groups:
• –study of groups with unique exposures
• •Migrant studies:
• –cancer incidence in populations migrating between areas with different cancer rates

• DNA damage
• Acquired environmental factors = chemicals, radiation, viruses
• 

•any substance or agent which enhances tumor incidence

• –Chemical
• –Radiation
• –Endogenous
• –Viral

• Procarcinogens in environment, become electrophiles, bind to DNA covalently
• 

• Metabolism can activate or detoxify carcinogens. Electrophile can react w/ hydroxyl group or nigrogen group of DNA and form adducts
• 

• •Most chemical carcinogens induce DNA damage
• •Chemical carcinogens usually require metabolism to be active (b/c reactive species. if they react w/ things in environment, no longer a carcinogen)
• •Adduct formation requires electrophilic groups on the carcinogen and nucleophilic groups on the DNA
• •Human exposure to carcinogens is ubiquitous (Can minimize but not totally get rid of)

• Know direct and indirect effects lead to DNA damage.
• Outcomes are: DNA repair, cell death, carcinogenesis
• 

• •Cellular generation of reactive oxygen species (ROS) - highly reactive, induce DNA
• damage
• •Contribute to natural (baseline) mutation rate
• •Major source: by products of oxidative metabolism (electron transport)
• 

• •Repair and return to normality
• •Extensive damage leading to cell death
• •Misreading of modified bases at next round of proliferation

Altered DNA sequence must be inherited by somatic daughter cells to be of functional significance

• •Single base changes, insertions, deletions
• •Can either have no effect, or
• –Change the KIND of protein produced (i.e.) gain/loss of function
• –Change the AMOUNT of protein produced
• •Targets are oncogenes and tumor suppressor genes

• •Altered form of normal cellular gene
• •Cellular gene is the proto-oncogene (normal gene)
• •Oncogenes encode regulatory proteins with dominant transforming properties - gain of function! (e.x. constitutively active kinases)
• --single copy is sufficient for transformation
• --presence of normal counterpart cannot block action of oncogene

• code for:
• •similar or identical mutated proteins
• •function in growth regulatory pathways
• •mutated forms generally hyperfunctional
• •drive growth factor independent proliferation; suppress apoptosis; induce invasive /metastatic potential

• •Growth factors and their receptors
• --ex: EGF receptor mutions in squamous cells -> become ligand independent
• •Non receptor tyrosine kinases
• --c-ABL, v-Ras
• •GTP binding proteins
• --c-Ras (GDP -> GTP (active))
• •Cytoplasmic serine/threonine kinases
• --MAP Kinases
• •Nuclear signaling
• --estrogen receptors
• •Transcription factors
• --c-Myc, c-fos

• •Code for proteins that inhibit trans-formation by variety of mechanisms
• •Transformation involves loss of function of tumor suppressor genes (TSGs)
• •Both alleles must be inactivated for an impact on cancer development
• •Some DNA tumor viruses code for proteins that inactivate TSGs

Tumor suppresor genes inhibit proliferation, promote apoptosis. Both copies of tumor suppressor gene have to be lost, vs. oncogenes.

Oncogenes = specific mutation to make it active

tumor suppressor = any mutation that makes it not functional

• p53 is a transcription factor, promotes apoptosis and inhibit cell proliferation, genes turned on during DNA damage, leading to apoptosis

• homozygous loss of APC [tumor suppresor gene, binds to beta catenin, prevents transcription, 50% of colon cancers have this mutation] -> mutation of Ras -> formation of adenoma -> Homozygous loss of DCC [70% of colon cancers]-> Homozygous loss of p53
• 

• Angiogenesis = sprouting of new vessels from
• existing vessels
• •Growth of blood vessels into tumor (neovascularization)
• •Essential for tumor growth > 2mm
• •Supply of oxygen, nutrients, growth factors
• •Initiated by proliferative signals
• -Vascular endothelial growth factor (VEGF)
• -Angiopoeitins
• -Basic fibroblast growth factor (bFGF)

• •Angiostatin
• –Most potent anti-angiogenic factor known
• –Specific inhibitor of endothelial cell proliferation
• –Cleavage fragment of plasminogen
• •Endostatin
• -Cleavage fragment of collagen XIII
• •Thrombospondin-1

• •Block angiogenic factors
• -VEGF antibodies
• -inhibitors of receptor kinases

• •Induce or apply anti-angiogenic factors
• -Endostatin

• •Interfere with matrix proteases
• -MMP9

• •Tumors are dormant without angiogenesis
• •Tumor progression requires switching on angiogenesis
• –Imbalance between inhibitors and activators
• –Oncogenes, TSGs contribute to angiogenic switch
• •Control of angiogenesis = control of cancer?

• • allows for tumor growth
• • provides an exit portal for metastatic tumor cell

• Metastasis = Escape of cancer cells from a
• primary tumor and re-establishment of growth at distant, secondary sites
• •Late event in cancer process, but underlying genetic changes required for metastasis may occur early
• •50% of patients present with metastases
• •Size of primary? -Often but not always predictive
• •Efficiency of metastasis? - Not very - 1/10,000 cells. However, most human cancers successfully metastasize

• •Shedding into body cavities
• –Peritoneum
• –Pleural cavity
• •Blood vessels

• –Capillaries
• –Hepatic portal vein
• •Lymphatics
• –Drain into lymph nodes
• –Empty into venous system

• •Homing mechanisms attract cancer
• cells to specific sites
• •Successful metastasis requires
• –viable seed (cancer cells)
• –appropriate soil (host organ)
• •growth factors, ECM, etc.
• Cells need to be able to proliferate at the new site

• •Series of sequential, interrelated steps
• •Failure in any one step prevents metastasis
• •Outcome depends on interactions between tumor cell and host factors

• •Motility
• •Reduced cohesiveness
• •Proteolytic activity
• •Suppression of apoptosis

Cancer cells in circulation:

• •Single cells or emboli - clusters with platelets, lymphocytes
• •Hostile environment - blood pressure, turbulence, immune attack
• •99% cell death rate

• –E-Cadherin downregulated
• •Ca++ dependent cell adhesion molecule
• •frequently lost in metastatic cells

• –Collagenase
• •Degrades ECM

• Extravasation = Exit of tumor cells at secondary site
• 

• •Cells may remain dormant
• •Specific growth factors, ECM required for proliferation
• •Cells with low growth factor requirements generally more metastatic
• •Metastases can also metastasize