01- MCDB 135 Oncognesis

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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