Three basic needs of dividing cell

• rapid ATP generation to maintain energy status
• increased biosynthesis of macromolecules
• maintenance of appropriate cellular redox status

Warburg Effect

• aerobic glycolysis in tumor cells
• normally in presence of O2, most glucose is converted to pyruvate and this is then oxidized by OX-PHOS
• glucose mainly converted to lactate in tumor cells
• this feature is shared with high proliferative tissue in body
• TCA still functioning (some citrate funneled out to make FA)

Why do cancer and proliferating cells

use less efficient energy metabolsm

• proliferating cells are within tissues that have abundant sugar resources
• proliferating cells have metabolic requirements that extend beyond the accumulation of ATPs

Pyruvate Kinase isoforms

• L gene(1st or 2nd exon): L isozyme in liver and allows allosteric regulation by FBP and hormonal control; R in red blood cell only allows allosteric reg by FBP
• M gene(9 or 10 exon): M1 in mutliple tissues(muscle and brian) and unregulated; M2 in fetal tissue/undifferentiated cells and allows allosteric activation by FBP and reexpressed in tumors
• PKM2 isozymes found in tumors 

PKM2

• converts PEP to pyruvate (prolif and tumor cells)
• slower then other pyruvate kinase isozymes
• it being slower allows for buildup of intermediates to go off into pentose phosphate shunt 
• tyrosine kinase can inhibt, slow it down even more (activated by growth factor)
• TCA cycle replenished with glutamine not pyruvate in these cases 
• HK activated and pyruvate dhase inhibited in these cells too

Acquired Capabilities of a cancer cell

• limitless replication potential
• self-sufficiency in growth signals
• insensitivity to anti-growth signals
• evading apoptosis
• sustained angiogenesis
• tissue invasion and metastasis
• emerging hallmarks: avoiding immune destruction, deregulation of cellular metabolism and energetics

Cancer wheel

• sustaining proliferative signaling
• evading growth suppressors
• activating invasion and metastasis
• enabling replicative immortality(telomerase)
• inducing angiogenesis
• resisting cell death

Tissue invasion and metastasis

• probably least understood of the tumor cell capacities but the most deadly
• involves proteins that thether cells to their surroundings in a tissue(in activation of integrins and cadherins)
• involves extracellular proteases

Oncogenes

• any gene that encodes a protein able to transform a cell from normal to one that is considered pre-cancerous or cancerous
• oncogenes are derived either by mutatino or over-expression from normal genes referred to as proto-oncogenes
• more than 100 oncogenes have been characterized with many more on the way for study in the future
• growth factors, growth factor receptors, signal transducers, transcription factors, programmed cell death regulators

Tumor Suppressor Genes

• Normally these genes code for proteins that control cell division, repair DNA damage, or conrol apoptosis
• tumor suppressor genes need to be tunred off for the cancer phenotype to develop
• Genes that control cell division(Rb protein and retinoblastoma), genes that repair DNA mistakes or damage(hereditary nonpolyposis colon cancer), genes involved in growth arrest and apoptosis

Lynch Syndrome

• familial nonpolyposis coli
• four genes involved in identification excision and repair of nucletotide mismatches-MLH1, MSH2, PMS2 and MSH6 (MLH1 and MSH2 90% of cases)
• 80% chance of colon carcinoma over lifetime
• As with many familial cancer syndromes, whereas the phenotype is autosomal dominant, the molecular mechanism involves an inherited mutation of one allele plus an acquired mutation of the second allele(accounts for the delay in onset and the presence of multiple tumors)
• first defined by looking at micro satalites, rep sequence of nucleotides which are particualry prone to accumulate nucleotide mismatch alterations-variation in length
• genes code for nuclear proteins-screen for a mutation by looking for the loss of expression in the nucleus of a particular protein

Breast Cancer

• Li-fraumeni: germline p53; sarcoma, breast, leukemia, melanoma and brain tumors-60% risk of breast
• cowden sydnrom(PTEN)-multiple hamartoma w/ high risk of thyroid, breast and endometrial cancers-25-50% risk of brest cancer avg age diagn 40 yrs
• Hereditary diffuse gastric cancer syndrome (aut dom CDH1 mutation) 39% risk of breast
• BRAC-1 and BRAC2-most common syndrome- breast and ovarian tumors-major caoncer in this cace. BRCA mut are seen in 1 in 500 in population

Mechanism of BRCA

associated disease

• appears to code for nuclear phosphoproteins that suppress proliferation and uspport differentiation
• may also play some role in DNA repair
• must be a two hit mechanism for tumor 
• women with BRCA1 mutation have 50-85% risk of developing breast cancer and 20-40% risk of ovarian

Li-Fraumeni Syndrome

• hereditary cancer syndrome associated with familial mutation mainly in TP53, CHEK2 mutation seen in a small number-50% cancer by 30, 90% by 60
• osteosarcoma, soft tissue, leukemia, breast, brain, adrenal cortical tumor
• classic LFS is defined as individual diagnosed w/ sarcoma at less then 45 years an 1st degree w/ any cancer then 
• p53 player in cell cycle shut down
• at risk patients should avoid radiation therapy and frequent screening
• can also cause mutation in MDM2 gene

Micro RNA and Cancer

• micro RNA can act as oncogene or tumor suppressor
• mir17-92 cluster amplification drives c-myc in lymphoma cell lines
• Let-7 family regulate RAS express, deletion of locus seen in lung cancer
• miRNA profiling shows specific expression in dif tumors
• microRNA as a therapeutic target or vehicle

X-linked dystrophinopathies

• involves protein dystrophin
• duchenne-no dystrophin (stop codon or something)
• becker-decreased or abnormal dystrophin

Autosomal limb-girdle dystrophies

• involves other proteins in the linkage between contractile elements (not dystrophin)
• sarcoglycanopathies-up to 70% of chilldhood onset and 10% of adult onset
• calpainopathies-up to 80% of later onset

Facioscapulohumeral dystrophy

• unique mechanism-deletion of tandem repeats in subtelomeric region of 4q(DZD4)
• repeats contain transcript called DUX4
• if reduction of repeats results in an arragement that can be transcribed and have a polyA tail added makes a peptide that is actually toxic to muscle-"reanimation of junk DNA"

Muscular dystrophy biopsy findings

• scattered muscle fibers have broken down are packeged with histocytes
• large hypercontracted eosinophilic fibers are also present
• in immunochemistry normal looks real crisp and solid and DMD patients look transparent

Considering Prenatal Diagnosis

(DMD)

• if the DMD mutation is known, chorionic villus sampling or amniocentesis is obtained and the sex of the fetus determined(FISH)
• argument of if only male fetuses should be tested or not
• carriers: 76% no symptoms, 19% will have mild weakness or some left ventric dilation, 8% develop some dilated cardiomyopathy and 5% will have myalgias
• if the DMD mutation is not known,  some would seggest only female pregnancies be allowed to continue

Duchenne Muscular dystrophy

• progressive disease
• affected children are usually wheelchair bound by age 12 years
• cardiac muscle is also affected and approx one third show sings of heart disease by 14 years, one half by 18 and nearly all by early 20s
• few survive beyond the third decade, with respiratory and cardiac complications responsible for death
• management: weight control, physical therapy, intervention for orthopedic complications, monit and management of cardiac disease, corticosteriods and anabolic ones might help, and myoblast transfer has been inefficient

Advanced DMD

• more advanced stage of DMD has loss of fibers with extensive replacement by fibrosis