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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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!""#$%& ()*+,
SLarL readlng !"##$"%&' )* +",-.%/ 01. 2.34
5.,.%"6), by Panahan and Welnberg (2011)
1hls revlew arucle ls Lhe foundauon of Lhe course.
SLarL readlng 01. 7"* 8,19:94)% ;"%"<)3
7.=9'94.< by Cox and uer (2013) and Lhe
-.$/+.0 .*1*+.2) +.324* 50 6"4,*.7*4, *8 +4.
1hese papers wlll be covered ln dlscusslon secuon durlng week 3 (Lxerclse #2).
9"5*.8 (: ;*$%5*.&
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<)* %+8=.* "> 2+%2*.?: + @,$1*+1* "> 2)+"1:A
9$1# "> =%2"%8."44*, 2*44 -."4$>*.+3"%B
adulLs have >10
13
cells, many of whlch reLaln
Lhe ablllLy Lo prollferaLe (cells musL be
replenlshed)
CDE
DF
,$G$1$"% *G*%81 $% +% +G*.+&* 4$>*3/*
H+=1* I=/5*. J
PearL dlsease 397,689 24.2
Cancer 374,743 23.3
Chronlc lower resplraLory dlseases 138,080 3.6
SLroke (cerebrovascular dlseases) 129,476 3.2
AccldenLs (unlnLenuonal ln[urles) 120,839 4.9
Alzhelmer's dlsease 83,494 3.4
ulabeLes 69,071 2.8
kldney ulsease 30,476 2.0
lnßuenza and Þneumonla 30,097 2.0
lnLenuonal self-harm (sulclde) 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”
LxcellenL resource: Mukher[ee's !"# %&'#()( )* +,, -.,./0#12 + 30)4(.'"5 )* 6.78#(
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(.2)+*"4"&$181 ,$12"G*. *+.4$*18 2"/-4*8* *K+/-4* "> + )=/+% L$8) 2+%2*.M
>."/ NMEEE 0*+.1 +&" OCDPEEQHR
Mlchaela 8lnder, Charloue 8oberLs, neal Spencer, uanlel AnLolne, Carollne
CarLwrlghL. S% 8)* (%3T=$80 "> H+%2*.B UG$,*%2* >". V*8+18+32 H+.2$%"/+ $%
+ W"=%& V+% >."/ (%2$*%8 I=5$+ O2: DPEEQHR. 9:); <=%, 2014, 9 (3): e90924
uCl: 10.1371/[ournal.pone.0090924
Lyuc leslon ln 3
Lh
Lhoraclc verLebra of Lhe skeleLon.
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
8asemenL membranes (basal lamlnas) separaLe cell Lypes wlLhln ussues
noL a Lrue &#&>(.7#, buL a speclallzed LCM - separaLes eplLhellal cells from
underlylng supporL cells called Lhe sLroma
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Malignant carcinomas acquire the ability to break
through the basement membrane
“epithelial to mesenchymal transition” (EMT)
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A breasL ducLal carclnoma ln slLu (uClS) LhaL has acqulred lnvaslveness
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)
<*.+8"/+ - Lumor derlved from germ cell LhaL
mlslocaLed durlng developmenL, glves rlse Lo
benlgn growLh LhaL has properues of many cell
Lypes (Lhls one has halr and LeeLh).
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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 CO
2
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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X!Ycose
<ransporLer
CLu11 up regulauon resulLs ln concenLrauon of glucose ln cancer cells
use Lhls properLy Lo vlsuallze cancer cells (lCu-ÞL1 MeLhod)
provlde 2-ueoxy-2-(
18
l)-ßuoro-
u-glucose
lmage uslng ÞoslLron-Lmlsslon
1omography (ÞL1)
x-ray compuLed Lomography (C1)
was used aL same ume Lo lmage
ouLllne of ussue ln pauenL
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;)+8 2+=1*1 2+%2*.Z
6*.*,$80 O&*%*321R
U%G$."%/*%8 O-)01$2+4 +%, 4$>*1804*R
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H+.2$%"&*% - an agenL LhaL causes cancer
Þhyslcal (e.g. x-rays)
Chemlcal (e.g. alkylaung agenLs)
[=\%& 8"&*8)*. 8)* -=]]4*B
Larly 1900s - 8overl noLes LhaL cancer cells have
aberranL chromosomes
1927 - Muller descrlbes x-rays as muLagenlc (unA
damaglng), suggesLs LhaL slnce lrradlauon also caused
cancer, perhaps muLauons were causlng cancer
1940s - chemlcals LhaL caused cancer were also found
Lo be muLagenlc (unA damaglng)
1960s - chromosomal muLauon llnked Lo cancer (CML)
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Ames 1esL for gauglng muLagenlclLy
ºlL ls a Lrulsm of modern blomedlcal sclence LhaL Lhe developmenL
of Lheraples expecLed Lo slow or arresL Lhe progresslon of a dlsease
requlres as deLalled an undersLandlng of lLs molecular and cellular
paLhogenesls as posslble."
?#7701 ;#,@)#
A.(B.(/ C70B#(10D5
ºWe conunue Lo foresee cancer research as an lncreaslngly loglcal
sclence, ln whlch myrlad phenoLyplc complexlues are
manlfesLauons of a small seL of underlylng organlzlng prlnclples."
?)E4,.1 A.7.".7 .7/ F)>#(D G#07>#(4
A.,,&.(@1 )* 6.78#(H !"# =#ID J#7#(.K)7
ºCancer beglns and ends wlLh people. ln Lhe mldsL of sclenuñc
absLracuon, lL ls someumes posslble Lo forgeL Lhls one baslc facL."
LE7# J))/M#,/
!"# ;0#4# )* 6.78#(