01- MCDB 135 Oncognesis
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Transcript of 01- MCDB 135 Oncognesis
3/22/14
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MCDB 135 Cell Growth and Oncogenesis
Lecture 1 (Apr 1) Introduction and Overview of Cancer
MCDB 135 Cell Growth and Oncogenesis
• Check GS regularly for updates. • Note exam schedule and review The Wise
Students’ Guide to MCDB 135. • “Required” reading is best done in advance
of lecture. • Sections are not meeting this week, but look
ahead to next week.
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LookingAhead
StartreadingHallmarksofCancer:TheNextGenera6onbyHanahanandWeinberg(2011)Thisreviewar<cleisthefounda<onofthecourse.
StartreadingTheRafInhibitorParadoxRevisitedbyCoxandDer(2013)andtheprimaryresearchar3clebyHolderfieldetal.
Thesepaperswillbecoveredindiscussionsec<onduringweek3(Exercise#2).
RobertA.Weinberg
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Thenatureofcancer….a“diseaseofchaos.”
Riskofuncontrolledcellprolifera3on:
adultshave>1013cells,manyofwhichretaintheabilitytoproliferate(cellsmustbereplenished)
~1016divisioneventsinanaveragelife3me
Cause Number % Heartdisease 597,689 24.2 Cancer 574,743 23.3Chroniclowerrespiratorydiseases 138,080 5.6Stroke(cerebrovasculardiseases) 129,476 5.2Accidents(uninten<onalinjuries) 120,859 4.9Alzheimer'sdisease 83,494 3.4Diabetes 69,071 2.8KidneyDisease 50,476 2.0InfluenzaandPneumonia 50,097 2.0Inten<onalself‐harm(suicide) 38,364 1.6
Top 10 causes of death in the US (2010; CDC Statistics)
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Percent distribution of 5 leading causes of death, by age group (US, 2010)
Historical Context of Cancer
Records from Egyptian physician dating from 3000-1500 BC describe a presumed breast cancer.
Hippocrates (460-370 BC) describes the disease– derived from Greek words for “crab,” karkinos and for “load/mass,” onkos
Galen (160 AD) – cancer caused by “black bile”
Excellentresource:Mukherjee’sTheEmperorofAllMaladies,ABiographyofCancer
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Archaeologistsdiscoverearliestcompleteexampleofahumanwithcancer,from3,000yearsago(~1200BC)
MichaelaBinder,Charlo_eRoberts,NealSpencer,DanielAntoine,CarolineCartwright.OntheAn3quityofCancer:EvidenceforMetasta3cCarcinomainaYoungManfromAncientNubia(c.1200BC).PLoSONE,2014;9(3):e90924DOI:10.1371/journal.pone.0090924
Ly<clesionin5ththoracicvertebraoftheskeleton.
A few skeletal remains have been found, revealing evidence of cancers.
Some definitions:
Neoplasia (neoplasm)
Anaplasia
Metastasis (metastic)
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The Hallmarks of Cancer
Douglas Hanahan , Robert A. Weinberg. Hallmarks of Cancer: The Next Generation. Cell, Volume 144, Issue 5, 2011, 646 - 674
Emerging Hallmarks and Enabling Characteristics
Douglas Hanahan , Robert A. Weinberg. Hallmarks of Cancer: The Next Generation. Cell, Volume 144, Issue 5, 2011, 646 - 674
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Intracellular Signaling Networks Regulate the Operations of the Cancer Cell
Douglas Hanahan , Robert A. Weinberg. Hallmarks of Cancer: The Next Generation. Cell, Volume 144, Issue 5, 2011, 646 - 674
Some basic concepts:
1. Tumors derive from normal cells, but have aberrant behaviors.
2. They can arise from different cell types.
3. Tumors can be classified (based on origin and behavior).
4. Tumors develop progressively (they evolve).
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Normal cells and cancer cells look and behave differently
Growth rate and control
Interactions with each other, neighboring cells, and the extracellular matrix (ECM)
Energy metabolism
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Clinical behavior of a tumor revealed by histopathology
BENIGN MALIGNANT
grows slowly grows rapidly
low mitotic index high mitotic index
well-defined border not defined/encapsulated
not invasive invasive
does not metastasize can spread distantly (metastasis)
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Normal cells and cancer cells look and behave differently
Growth rate and control
Interactions with each other, neighboring cells, and the extracellular matrix (ECM)
Energy metabolism
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Epithelia
Sheets of cells that normally are connected and coordinated in terms of function
~80% of all cancer deaths are derived from epithelia (carcinomas)
gastrointestinal tract, skin, mammary gland, pancreas, liver, lung, ovary, uterus, prostate, gall bladder, urinary bladder
Normally have a very well organized architecture
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Examples of epithelial tissues
collecting tubule of kidney lung bronchiole
gall bladder endometrium of uterus
Basementmembranes(basallaminas)separatecelltypeswithin<ssues
Notatruemembrane,butaspecializedECM–separatesepithelialcellsfromunderlyingsupportcellscalledthestroma
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Malignant carcinomas acquire the ability to break through the basement membrane
“epithelial to mesenchymal transition” (EMT)
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Abreastductalcarcinomainsitu(DCIS)thathasacquiredinvasiveness
The cells of the Tumor Microenvironment contribute to tumorigenesis
Douglas Hanahan , Robert A. Weinberg. Hallmarks of Cancer: The Next Generation. Cell, Volume 144, Issue 5, 2011, 646 - 674
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Classifying tumors is based on:
Differentiation state (epithelial, non-epithelial, mixed)
Biological Behavior (benign, malignant)
Embryonic origin (ectoderm, mesoderm, endoderm)
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The three “germ layers” somatic cells/tissues/organs The “germline” ( gametes)
Teratoma–tumorderivedfromgermcellthatmislocatedduringdevelopment;givesrisetobenigngrowththathasproper<esofmanycelltypes(thisonehashairandteeth).
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Normal cells and cancer cells look and behave differently
Growth rate and control
Interactions with each other, neighboring cells, and the extracellular matrix (ECM)
Energy metabolism
Normal Cells
Aerobic conditions: glucose is broken down into pyruvate in cytosol (via glycolysis) then transported to mitochondria, oxidized to form acetyl CoA, and broken down into CO2 via citric acid/Krebs cycle (36 ATP)
Hypoxic (low oxygen) conditions: glycolysis only – pyruvate reduced to lactate, which is then secreted (yields 2 ATP)
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Cancer Cells
Many types of cancer cells rely on glycolysis only, even when exposed to ample oxygen
Aerobic Glycolysis
WARBURG EFFECT (described by Otto Warburg in 1924)
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GLUcoseTransporter
GLUT1upregula<onresultsinconcentra<onofglucoseincancercells
Usethispropertytovisualizecancercells(FGD‐PETMethod)
provide2‐Deoxy‐2‐(18F)‐fluoro‐D‐glucose
ImageusingPositron‐EmissionTomography(PET)
X‐raycomputedtomography(CT)wasusedatsame<metoimageoutlineof<ssueinpa<ent
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Whatcausescancer?
Heredity(gene3cs)
Environment(physicalandlifestyle)
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Carcinogen–anagentthatcausescancer
Physical(e.g.X‐rays)
Chemical(e.g.alkyla<ngagents)
Pu\ngtogetherthepuzzle:
Early1900s–Boverinotesthatcancercellshaveaberrantchromosomes
1927–MullerdescribesX‐raysasmutagenic(DNAdamaging);suggeststhatsinceirradia<onalsocausedcancer,perhapsmuta<onswerecausingcancer
1940s–chemicalsthatcausedcancerwerealsofoundtobemutagenic(DNAdamaging)
1960s–chromosomalmuta<onlinkedtocancer(CML)
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AmesTestforgaugingmutagenicity
“Itisatruismofmodernbiomedicalsciencethatthedevelopmentoftherapiesexpectedtosloworarresttheprogressionofadiseaserequiresasdetailedanunderstandingofitsmolecularandcellularpathogenesisaspossible.”
DennisSelkoe HarvardUniversity
“Wecon<nuetoforeseecancerresearchasanincreasinglylogicalscience,inwhichmyriadphenotypiccomplexi<esaremanifesta<onsofasmallsetofunderlyingorganizingprinciples.”
DouglasHanahanandRobertWeinberg HallmarksofCancer:TheNextGeneraKon
“Cancerbeginsandendswithpeople.Inthemidstofscien<ficabstrac<on,itissome<mespossibletoforgetthisonebasicfact…”
JuneGoodfield TheSiegeofCancer