Cancer

• Endocrine (distant)
• Paracrine (near)
• Juxtacrine (touching)
• Autocrine (self)

• 2nd messenger (between proteins)
• Phosphorylatin (kinase or auto)
• Direct contact (association)

Phosphorylation is most common example

GTP binding and hydrolysis of G proteins is common example

Ligand has an intracellular carrier molecule or is small and hydrophilic and can enter nucleus

• Dimer receptor comes together when ligand binds (cytokine)
• JAK recruited phosphorylates intracellular region of receptor which binds STAT gene regulatory protein
• STAT enters nucleus and binds other gene regulatory proteins and they activate transcription of growth factors

Multimeric (many receptors interact)

• Juxtacrine between delta jagged and notch
• Errors in this receptor cause T cell acute lymphoid luekemia

Conformational change to expose hydrophib region acts as signal

• Secondary messenger multiple cleavage sites
• phospholipase A2 results in arachidonic acid (AA)
• phospholipase C results in diacyl glycerol (DAG/DG) and inositol 1,4,5 triphosphate (IP3)
• phospholipase D results in phosphatidic acid (PA)

• Receptor can be endocytosed and recylced to membrane or degraded
• Receptor desensitization
• Begins with aggonist binding to receptor. G protein receptor kinase (GRK) phosphorylates 7Tm so that beta arrestin (betaArr) can bind, inhibiting G protein binding and promoting endocytosis (degrade or recylce)

• Fight or flight
• Sight, smell, taste

• Three subunit alpha(membrane bound), beta(covalent)gamma(membrane bound)
• Signal molecule to receptor recruits G protein
• GDP to GTP releases beta and gamma until it hydrolyzes
• Specific to certain pathway (many types!)

• alpha subunit of activated G protein activates phospholipase C to cleave PIP2
• diacyl glycerol in membrane goes to activate protein kinase C (PKC)
• inostol 1,4,5 triphosphate (IP3) in cytosol opens ER Ca channel
• Ca also activates protein kinase C (PKC)

• alpha subunit of activated G protein activates adenylyl cyclase to make ATP to cAMP
• cAMP activate protein kinase A (PKA)
• Protein kinase A phosphorylates a gene regulatory protein in the nucleus to activate target genes

• GTP hydrolysis inhibition causing over production of cAMP
• Decreases Na absorption and increases Cl secretion
• Dehydration through rice water stool

• Gi (inhibitory G protein) is deactivated so that it cannot inhibit adenylyl cyclase
• cAMP depresses immune system leukocytes

• Localized to membrane via acylation by farnesyl transferase (remember FTI from metabolism?) or via geranylgeranyl transferase depending on tissue
• mSOS (activated by Grb2 associated with receptor tyrosine kinase) changes GDP to GTP in Ras
• Ras activates Raf, which activates Mek (kinase) actiavtes Erk (Map kinases)
• GTPase (hydrolysis) in Ras is performed by Gap upon receiving a signal
• Gef does nucleotide exchange to activate Ras
• Loss of Gap leaves Ras always on and leads to neurofibromatosis

• Bind ligand
• Receptor and non-receptor (JAK)
• Commonly involved in cancer

• Phosphorylate SH2
• Opens up proline rich domain when activated, which autophosphorylates
• Then does kinase activity
• Dephosphorylate SH2 to inactivate
• Related to 1st tumor virus, 1st oncogene, 1st tyrosine kinase, 1st to have signaling motifs for protein-protein complexes

• Adaptors and scaffolds
• Often related to tyrosine kinase
• The target of specific signal transduction therapies (imatinib)

Docking protein scaffold that is phosphorylated by receptor tyrosine kinase when insulin binds

• Chronic myeloid leukemia
• Translocation of 9;22 at breakpoint (Bcr) of 22 adds Abl gene of 9 to make bcr/abl
• Bcr/Abl has tyrosine kinase activity and acts as a signal transduction scaffold molecule
• Activates Ras pathway (MAPK pathway), JAK/STAT

• Self sufficiency in growth signals
• Insensitivity to growth inhibitory signals
• Apoptosis evasion
• DNA repair defects
• Telomerase activity
• Sustained angiogenesis
• Metastatic capability

• Promote cell growth in tumors
• Can be inserted by virus insertional mutagenesis near protooncogene
• Dominant
• EGFR overexpression in lung tumors, gliblastomas and head and neck
• ERB-B2 (HER2/neu) in breast cancer
• Ras (carcinoma kras, bladder hras, hematopoietic nras)
• Myc (Burkitt lymphoma by ebstein barr virus, amplification in breast, colon, lung, N-Myc amplification in neuroblastoma)

• Imatinib targets Bcr/Abl in chronic myeloid leukemia
• Herceptin targets HER-2/neu in breast cancer
• c-kit targeted in GI stromal tumors

• Recessive
• WT-1 in Wilms tumor
• vonHippel Lindau (VHL) gene in clear cell renal carcinoma
• Regulators of the cell cycle (cyclin D, CDK4, Rb, p16INK4a)

• Can predict chemo responsiveness of tumor
• >50% of tumors
• Cell cycle arrest and apoptosis

• Mutated APC allele causes thousand of colon polyps that can become malignant
• Beta Catenin also causes colon tumors

• Prototypic anti-apoptotic gene
• B-cell follicular lymphomas

• Essential to supply nutrients and growth factors like PDGF
• Tortuous and leaky
• Endostatin inhibits angiogenesis

• Invasion of extracellular matrix by
• detachment of self, attachment of matrix, proteases, tumor platelet aggregates
• Homing of tumor cells by
• readherance to endothelium, protease through basement membrane, favorable soil and classic locations, uses many cytokines and chemokines

• Defects in repair genes leads to genomic instability syndromes with mutator phenotypes
• BRCA1/2 homologous recombination

First hit, 2nd hit, non aggresive, further mutation makes it carcinoma

• Oncogenes and tumor suppressor
• High risk for malignancy development

• Affect genomic stability
• DNA repair genes
• Lower risk for malignancy development

• Initiation and promotion then progression (accumulation of genetic mutations causes invasive and metastatic tumor)
• Adenoma-carcinoma sequence of colorectal
• Requires initiator
• Requires high promoter frequency (not spread out over time)

• Electrophilic to bind nucleophilic DNA and create adducts
• Indirect (metabolism required)
• Direct are electrophilic
• Initators must be strong electrophiles
• Use Ames test (direct and indirect) sensitivity of 50-70%

• Direct chemical carcinogen
• Chlorambucil, melphalan, cyclophosphamide
• Secondary cancers (leukemias) post treatment
• Can attack crosslinked gene to fix...or cause cancer

• Smoking (90%)
• Squamous cell carcinoma in the dysplastic epithelium of bronchial lining
• DNA adduct formed by benzo[a]pyrene metabolized by cyt p450

• Grains and yellow mold of peanuts
• Common in asia and africa where it synergizes with hepatitis A B C
• Aflatoxin B1 forms DNA adducts, mutating p53 at codon 249 in high aflatoxin regions

Thymine dimers fixed by nucleotide excision repair

• Basal and squamous are associated with total sun exposure
• Melanoma is with heavy sun exposure like tanning

• Inorganic scatters (zinc oxide)
• Organic absorbs and disperses as IR heat
• Need UVA/B (broadspectrum), SPF30 and water resistant
• Especially during childhood!

Atomic blast, x rays for techs and patients, radium dial painters

Thyroid cancer in children increased from 1989 to 2000s

• Chrysolite (serpintine flexible) more common
• Crocidolite (amphibole rigid rod) travels deeper
• Intersitial fibrosis, carcinoma, mesothelioma
• Macrophages digest and cause chronic inflammation
• 20 year latency

• Creates E6 and E7 (usually repressed by E1 and E2
• Both inhibit p53
• E7 inhibits p21 and Rb-E2F

• Makes proteins that interfere with signaling pathways to increase cytokines/chemokines
• Inflammatory modulators and growth factors
• All that causes inflamation

• Hemochromatosis (hepatic cancer), acid reflux (esophageal), viral hepatitis B and C(hepatic), asbestos (mesothelioma), heliobacter pylori (gastric), inflammatory bowel disease (colon)
• Affects epithelium to lead to cancer
• Affects stroma to lead to metastasis by landscape effects

There are many different types

• oma-benign
• sarcoma-malignant mesenchymal
• carcinoma-malignant epithelial
• lymphoma-malignant lympocytic
• melanoma-malignant melanocytic

• Benign
• Well differentiated, slow growth rate, non invasive, circumscribed (fibrous capsule/expansile nodule)
• Malignant, anaplasitc (poorly differentiated), pleomorphic, fast rate of growth, invasive, metastatic capability

• What proportion divide
• How frequently they divide
• Ratio of division to death

• Lymphatic (goes to lymph nodes)
• Hematogenous through small veins to other organs
• Seeding of body cavities (like peritoneum)

• T (tissues) size and adjacent tissues involved
• N (nodes) how many, how far, what kind
• M (metastatic spread) distant metasteses
• Overall staging based off of certain TNM score, cancer specific

Destruction or invasion of adjacent tissues (bowel obstruction or seizure etc)

• Linked to cytokines and host response
• Wasting, loss of appetite, lethargy
• Also due to chemo

• Remote effects due to local primary tumor effects
• Ectopic hormone production (can cause hypercalcemia for example)
• Autoimmune antibodies against host

• High cytokine levels can lead to immunosupression leading to infection (also chemo)
• Inflammatory reponse activates platelets
• Decreased platelets due to chemo and cancer
• Anemia from inflammation and cancer

• In US over time are driven by society, screening and nonmedical technology
• Most geographical risks are environmental, not racial like HBV and diet